Next Article in Journal
Relationship of Early Anemia with Neurodevelopment and Brain Injury in Very Low Birth Weight Preterm Infants—A Prospective Cohort Study
Next Article in Special Issue
Nongenomic Activities of Vitamin D
Previous Article in Journal
Association of α-Dicarbonyls and Advanced Glycation End Products with Insulin Resistance in Non-Diabetic Young Subjects: A Case-Control Study
Previous Article in Special Issue
Month-of-Birth Effect on Muscle Mass and Strength in Community-Dwelling Older Women: The French EPIDOS Cohort
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Nutrients
Volume 14
Issue 22
10.3390/nu14224927
nutrients-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands

by
Miguel A. Maestro
1,* and
Samuel Seoane
2
1
Department of Chemistry-CICA, University of A Coruña, Campus da Zapateira, s/n, 15008 A Coruña, Spain
2
Department of Physiology-CIMUS, University of Santiago, Campus Vida, 15005 Santiago, Spain
*
Author to whom correspondence should be addressed.
Nutrients 2022, 14(22), 4927; https://doi.org/10.3390/nu14224927
Submission received: 3 October 2022 / Revised: 14 November 2022 / Accepted: 16 November 2022 / Published: 21 November 2022
(This article belongs to the Special Issue A Commemorative Issue in Honor of Centennial of the Discovery of Vitamin D-The Central Role of Vitamin D in Physiology)
Browse Figures
Review Reports Versions Notes

Abstract

:
Since the discovery of vitamin D a century ago, a great number of metabolites, analogs, hybrids and nonsteroidal VDR ligands have been developed. An enormous effort has been made to synthesize compounds which present beneficial properties while attaining lower calcium serum levels than calcitriol. This structural review covers VDR ligands published to date.

1. Introduction

Since the chemical structure of vitamin D3 (1, Figure 1 [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36], cholecalciferol) was established in 1932, successive studies have shown it to be essential in physiological processes. Two hydroxylations of 1 are necessary before attaining its most biologically active form. The first is a 25-hydroxylation, which occurs mainly in the liver and produces the most abundant circulating metabolite, 25-hydroxyvitamin D3 (11, Figure 1, 25-hydroxycholecalciferol, calcidiol, 25OHD3) [12]. Subsequently, a second hydroxylation at the 1α position generates the vitamin D hormone, 1α,25-dihydroxyvitamin D3 (13, Figure 1, 1α,25-dihydroxycholecalciferol, calcitriol, 1,25(OH)2D3) [14]. This is a pleiotropic hormone that exerts genomic actions by binding to its specific receptor (the vitamin D receptor, VDR), which is present on target cells and found in more than 200 different tissues.
The biological role of 1,25(OH)2D3 has been related to calcium and phosphorus homeostasis. However, the effects of vitamin D are not limited to mineral homeostasis, skeletal health maintenance, or immune modulation. In addition, this hormone also has fundamental effects on cellular proliferation and differentiation, regulating genes involved in the cell cycle and apoptosis both in normal and tumor cells. These properties and its wide distribution have led to the study of its effects on various pathologies, such as osteoporosis and cancer, thus arousing interest in the field of health and the pharmaceutical industry. Unfortunately, the therapeutic use of 1,25(OH)2D3 also leads to an increase in the concentration of calcium in blood (hypercalcemia), which can cause significant side effects. Therefore, numerous attempts have been made to synthesize noncalcemic analogs of 1,25(OH)2D3 for use in health treatment.
In recent decades, structure–function relationships (SARs) have been determined to support the chemical modifications of the secosteroid structure of 1,25(OH)2D3. The novel structures’ goal is to reduce their calcemic activity in comparison with calcitriol while exerting their interesting biological properties. A huge synthesis effort has been carried out, yielding interesting chemical reviews in this regard [2]. The current review updates the scientific information on the structural library of VDR ligands and incorporates nonsteroidal VDR ligands.

2. Materials and Methods

All compounds contained in this review were collected from published papers and patents. Most of the materials were freely accessible via the Internet, and paper copies were available in other cases. After careful reading, relevant structures were drawn using CHEMDRAW software [3]. No database was generated. A structural analysis of this collection may require future elaboration of a database.

3. Results

We found 1778 VDR compounds, which are displayed chronologically in 31 figures. All of these compounds are ligands that specifically bind to their VDR receptor. This binding allows the interaction of the 1,25(OH)2D3-VDR complex with target genes in the cell nucleus, modulating their expression and mediating a biological response. The following color scheme was used in the figures: dark blue corresponds to marketed compounds (Figures 1, 3, 4, 8 and 9), light violet to outstanding compounds with interesting properties (Figures 2, 4–10, 12–15, 17–21 and 23–31), and dark green to non-secosteroidal VDR ligands (Figures 9, 11, 12, 15 and 20–27).
Vitamin D is closely associated with calcium and phosphorus homeostasis. No scientific rational has yet been found for the calcemic properties of a compound in comparison with calcitriol. Therefore, structure–function relationships (SARs) were carried out in order to validate the key modifications in the structure of 1,25(OH)2D3 that may alter biological and calcemic properties. After more than 50 years of study, some hints have been obtained. For example, it is known that C-19 methylene deletion yields low calcemic analogs; it is also known that deletion/substitution of the steroidal cycles de-A ring, de-C ring, and/or de-D ring may yield low calcemic analogs. Lowering the calcemic side effects of the vitamin D analogs is important; however, we must not lose sight of other modifications that may increase the antiproliferative and prodifferentiation activity (side-chain modification with extra double and or triple bonds) as well as increase the metabolic stability (fluorine atom incorporation). In summary, the following main structural topics are covered in the current review:
  • C-21 Methyl epimerization;
  • C-19 Methylene deletion;
  • Incorporation of fluorine atoms;
  • Deletion/substitution of steroidal cycles: de-A ring, de-C ring, and/or de-D ring;
  • C-2 Functionalization;
  • C-3 Epimerization;
  • Side-chain modification with extra double and/or triple bonds, heteroatoms, and/or branched hydrocarbons.
What is novel in this collection is the incorporation of non-secosteroidal VDR ligands (dark green). In 1999, Boehm [4] hypothesized that “non-secosteroidal VDR ligands might display different profiles of activity and metabolism than do secosteroidal l,25(OH)2D3, analogs, including less calcemic properties, which might render them attractive as both topical and oral pharmaceuticals for treating a variety of diseases. This hypothesis was based in part on the success that nonsteroidal androgen receptor (AR) and estrogen receptor (ER) modulators have had as drugs. Nonsteroidal compounds have been synthesized that modulate the activity of these receptors and show enhanced tissue selectivity in comparison to the steroids”.
Figure 1 (1931–1978) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Vitamin D3 (1, cholecalciferol) [1] was discovered in 1922, but it was not chemically characterized until 1931. Dihydrotachysterol2 (5) [10] was introduced in 1934, and it is still on the market as an antitetanic agent AT-10. In 1968, the most abundant metabolite of vitamin D3 was discovered as 25-hydroxyvitamin D3 (11, 25-hydroxycholecalciferol) [18], and in 1971, 1α,25-dihydroxyvitamin D3 13, 1α,25-dihydroxycholecalciferol, calcitriol, 1α,25(OH)2D3 [21], the vitamin D3 hormone, was identified. Later, 1α-hydroxyvitamin D3 (21, Alfacalcidiol) [25], a synthetic analog, was marketed for the treatment of secondary hyperparathyroidism (2HPT), renal failure, and osteoporosis.
Figure 2 (1978–1982) [37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52]. 25-Hydroxyvitamin D3 26(23)-lactones (58–61) were discovered in 1980 [50,51,52], and they behave as antagonists of gene transcription induced by VDR. They were the first compounds discovered to have antagonist properties.
Figure 3 (1982–1987) [53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78]. 26,26,26,27,27,27-Hexafluoro-1α,25-dihydroxyvitamin D3 (70, Falecalcitriol) [60] is used in the treatment of 2HPT and osteoporosis. 1α,25-Dihydroxy-22-oxavitamin D3 (100, Maxacalcitol) [76] is used in 2HPT and psoriasis.
Figure 4 (1987–1991) [78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94]. 111 (Calcipotriol, MC903) [79] is marketed as a treatment with exceptional clinical response in psoriasis. 1α,25-Dihydroxy-22(23)-didehydrovitamin D3 (116) [83] has shown potent antiproliferative activity. 2β-(Hydroxypropoxy)-1α,25-dihydroxyvitamin D3 (131, ED-71) [85] is used in osteoporosis treatment.
Figure 5 (1991–1992) [95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117]. Compound 186 [107] is an important analog functionalized at C-11 that may allow the synthesis of haptens, without disturbing the VDR ligand anchoring groups (1α-OH, 3β-OH and 25-OH).
Figure 6 (1993–1994) [118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136]. Compounds 225 [93] and 208 [108] were independently developed by different research groups and are important analogs functionalized at C-18 and C-11, respectively. They may allow the synthesis of haptens without disturbing the VDR ligand anchoring groups.
Figure 7 (1994–1997) [136,137,138,139,140,141,142,143,144,145,146,147,148]. Compounds 308 and 309 [147] present an interesting property by exhibiting only nongenomic rapid effects at physiological concentrations. Moreover, 1α-hydroxyl group addition (309) does not alter the sensitivity of nongenomic effects of 308.
Figure 8 (1997–1999) [149,150,151,152,153,154,155,156,157,158]. 1α-Hydroxyvitamin D2 (325, Doxercalciferol) [151] is marketed as a 2HPT treatment. (22E,24E)-Diene-24,26,27-trishomo-19-nor-1α,25-dihydroxyvitamin D3 (348, Ro 25-8584) [152] represents an outstanding compound inhibiting the proliferation in myeloid leukemia cell lines. When 2-methylene-19-nor-1α,25-dihydroxyvitamin D3 (349, 2MD) [156] is given as oral therapy, it is at least 100 times more potent than 1α,25(OH)2D3 in stimulating bone mass increase. A randomized clinical trial showed that 349 increased bone turnover but not BMD (bone mass density) in postmenopausal woman with osteopenia.
Figure 9 (1999) [158,159,160,161,162,163,164,165,166,167,168]. 24R,25-Dihydroxyvitamin D3 (388, Tacalcitol) [160] is prescribed for psoriasis. 24,26,27-Trishomo-1α,25-dihydroxyvitamin D3 (406, Seocalcitol, EB 1089) [163] acts as a powerful antiproliferative used in breast, colon, or pancreas tumor models.
Figure 10 (2000–2001) [169,170,171,172,173,174,175,176,177,178,179,180,181,182]. 1α-Hydroxy-26(27)-dehydro-25-(butylcarboxylate)-vitamin D3 (433, ZK159222) and 1α-hydroxy-26(27)-dehydro-25-(ethylpropenoate)-vitamin D3 (434, ZK168281) [170] have been identified as VDR antagonists, though 434 is more potent than 433. Both compounds selectively stabilize an antagonist conformation of the VDR-LBD (ligand-binding domain). 1α,25-Dihydroxy-21-(3-hydroxy-3-methylbutyl)-vitamin D3 (435, Gemini) [171] has emerged as the lead compound with superior gene transcription activity and tumor-cell-line inhibition.
Figure 11 (2001–2002) [183,184,185,186,187,188,189,190,191,192,193,194,195,196]. 1α,25-(OH)2-16-ene-20-epi-23-yne-3-epi-D3 (493), 1α,25(OH)2-16-ene-23-yne-hexafluoro-3-epi-D3 (494), and 1α,25(OH)2-16-ene-3-epi-D3 (495) are potent inducers of apoptosis of HL-60 cells. Their 3-natural (3β-OH) analogs have been shown to be potent modulators of HL-60 cell growth and differentiation [184]. This is the first report to demonstrate that the epimerization of the hydroxyl group at C-3 of the A-ring of 1α,25(OH)2D3 plays an important modulation role for HL-60 cell differentiation and apoptosis. 2,2-Difluoro-1α,25-dihydroxyvitamin D3 (507) [185] is similar to 1,25(OH)2D3 in terms of in vitro antiproliferative activity, but it is different in terms of transcriptional activity. In addition, 507 is 2–3 times more transcriptionally active than calcitriol, with similar in vivo calcemic activity. 2,2-Dimethyl-1α,25-dihydroxy-19-norvitamin D3 (509) [186] is 7.5 times less transcriptionally active than calcitriol and considerably less calcemic. Moreover, 509 strongly suppresses parathyroid hormone (PTH) secretion.
Figure 12 (2002) [197,198,199,200,201,202,203,204]. Seco-C-9,11-bisnor-17-methyl-26,26,26,27,27,27-hexafluoro-20-epi-1α,25-dihydroxyvitamin D3 (533, WY1112) [197] and seco-C-9,11,21-trisnor-17-methyl-23(24)-didehydro-26,26,26,27,27,27-hexafluoro-1α,25-dihydroxyvitamin D3 (559, CD578) [198] display high differentiation ratios between antiproliferative and calcemic affects. 26,27-Bishomo-1α-fluoro,25-hydroxy-23-en-vitamin D3 (582, Ro-26-9228) [203] is used for treatment of osteoporosis.
Figure 13 (2003–2004) [205,206,207,208,209,210,211,212,213,214,215,216,217,218]. Dienyne 646 [215] represents the first locked side-chain analog of calcitriol with remarkable VDR transcriptional activity. Lactone 657 [217] showed one order of magnitude higher antagonist activity than lactone 66 (Figure 2).
Figure 14 (2004–2006) [218,219,220,221,222,223]. Further development in double side-chain vitamin D analogs, the Gemini series, made it possible to assess the steric VDR requirements of drug candidates. Compounds 684–695 [220] present two different side chains at C-20 that improve their toxicity profiles and pharmacokinetic drug performance.
Figure 15 (2006–2007) [224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240]. C-20 cyclopropyl vitamin D3 analog 755 [233] showed high MLR (mixed lymphocyte reaction) activity for the suppression of interferon-γ release with no calcemic activity. Immunomodulatory activity was measured by suppression of interferon-γ release in mixed lymphocyte reaction cells. The inhibition of clonal proliferation was evaluated in the leukemia HL-60, breast cancer MCF-7, prostate PC-3, and LNCaP cell lines. Significant separation of the immunomodulatory activity from hypercalcemic effects (MTD, maximum tolerated dose) was observed. Compound 747 was 2900 times more active and 100 times less hypercalcemic than 1α,25(OH)2D3, while 755 was 29 times more active and 100 less hypercalcemic. In the breast cancer MCF-7 cell line, compounds 753, 754, 755, and 757 were ten thousand times more active but equally or less hypercalcemic than 1α,25(OH)2D3. Metabolism of 16-ene-20-cyclopropyl compounds is arrested at the 24-keto stage, which explains the increased biological activity of the 16-ene variants.
Figure 16 (2006–2008) [241,242,243,244,245,246,247,248,249,250,251,252,253]. Intensive research activity was carried out on the leading structures with outstanding biological properties, i.e., Gemini compounds 799–803 [246,247]. These studies focused on the structural modifications of Gemini that influenced the differentiation-inducing, antiproliferative, and transcriptional activity of the compounds in human leukemia cells. The cyclopropyl modification at the pro-R side chain decreased the activity of the compound compared to 1α,25(OH)2D3, and further A-ring modifications did not restore this activity. Cyclopropyl modification at the pro-S side chain of Gemini increased the VDR-induced transcriptional activity. In addition, privileged VDR antagonists lactones 804–832 and 833–864 [243,244] were studied. The antagonistic activity was markedly affected by the structure of the lactone ring, including length of the alkyl chain and the stereochemistries on the C23 and C24 positions. The VDR binding affinity of the (23S,24S)-24-alkylated vitamin D3 lactones increased 2.3–3.7-fold as compared to the unsubstituted lactones 64–67 (Figure 2). The antagonistic activity of (23S,24S)-isomers were enhanced to be 2.2-,3.5-, 1.8-, and 1.7-fold higher compared to the unsubstituted lactones 64–67 (Figure 2).
Figure 17 (2008–2009) [254,255,256,257,258,259,260,261,262,263,264]. 2-Methylene-19-nor-(20S)-1α-hydroxy-bishomopregnacalciferol 942 [20(S)-2MbisP] [263] were able to suppress PTH at levels that did not stimulate bone resorption, intestinal calcium, or phosphate absorption and may have potential for use in the treatment of 2HPT in chronic kidney disease.
Figure 18 (2009–2010) [265,266,267,268,269,270]. Hybrid compounds 1020 (26,27-bis-nor-25-bishomo-19-nor-25’-oxo-25”-methylcarboxamide-1α-hydroxyvitamin D3) and 1022 (26,27-bis-nor-25-homo-19-nor-25’-(2aminophenyl)-carboxamide-1α-hydroxyvitamin D3) [270] showed antiproliferative activity against AT84 carcinoma cells; neither of them induced hypercalcemia even at concentrations 100-fold higher than those tolerated for 1,25D. This demonstrates that it is possible to create a wide range of bifunctional molecules that possess VDR agonism and HDACi (histone deacetylases inhibitor) activity. Structural latitude is significant with a wide variety of ZBGs (zinc-binding group) amenable to incorporation into the side chain of vitamin D-like secosteroids. Importantly, several of these molecules function as antiproliferative agents against AT84 cells in vitro, while possessing minimal hypercalcemic activity in vivo.
Figure 19 (2009–2010) [271,272,273,274,275,276,277,278,279,280,281,282,283]. Intensive research activity was carried out on Gemini compounds 1053–1069 [273]. Calcitriol was implicated in many cellular functions including cell growth and differentiation. It was shown that Gemini compounds were active in gene transcription induction with enhanced antitumor activity. Fine tuning of their structurally derived biological properties would be required for therapeutic use.
Figure 20 (2010–2012) [284,285,286,287,288,289,290,291,292,293,294,295,296,297,298]. 25-Diethylphosphite-1α-hydroxy-23(24)-didehydrovitamin D3 1131 [290] was tested for antiproliferative effects on several human and murine tumor cell lines: human squamous cell carcinoma HN12, human glioma T98G, and Kaposi sarcoma SVEC vGPCR cell lines. Furthermore, in human glioma T98G and human squamous cell carcinoma HN12 cell lines, the antiproliferative effects exerted by compound 1131 were greater than those elicited by 1α,25(OH)2D3. Visual observation of internal animal organs such as liver, duodenum, lungs, and kidneys showed no macroscopic morphological alterations after treatment with this compound. This compound appears to be well tolerated even at high doses. Altogether, these results suggest that compound 1131 exerts considerable antiproliferative activity at nonhypercalcemic dosages and may have therapeutic potential for the treatment of various hyperproliferative disorders. Non-secosteroidal VDR ligand (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-hydroxyacetamide 1173 [295] was confirmed to significantly prevent bone loss after daily treatment without inducing hypercalcemia. These types of compound are potent inhibitors of the Hh (Hedgehog) signaling pathway. Studies show that, contrary to secosteroidal hybrids, the optimal location for incorporating the highly hydrophilic hydroxamic acid corresponds to the portion of the molecules that serve as secosteroidal A-ring mimetics. The best hybrid, 1173, is a full VDR agonist, as assessed by several criteria, and an efficacious antiproliferative agent against both 1,25D-sensitive (SCC25, AT84) and 1α,25(OH)2D3-resistant (SCC4) squamous carcinoma cell lines. Importantly, the activity in 1α,25(OH)2D3-resistant SCC4 cells required both the VDR agonism and HDACi activity of 1173. This study revealed the remarkable flexibility in the conversion of calcitriol analogs into fully integrated bifunctional molecules, suggesting that it may be possible to extend fully integrated bifunctionalization to other pharmacophores.
Figure 21 (2012–2013) [298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313]. 24S-Methyl-21-epi-2-methylene-22-oxa-1α,25-dihydroxyvitamin D3 (1191, VS-105) [306] bound to VDR is highly inductive of functional responses in vitro and effectively suppresses PTH in a dose range that does not affect serum calcium in 5/6 NX uremic rats. [6-(4-{1-Ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methylphenyl]propyl}-2-methylphenyl)pyridin-3-yl]acetic acid (1218) [308] showed excellent ability to prevent BMD loss in mature rats in an osteoporosis model, without severe hypercalcemia and with good PK profiling.
Figure 22 (2013–2014) [313,314,315,316]. Compounds 1247–1301 (non-secosteroidal VDR ligands) [315] were analyzed and presented better therapeutic efficacy when compared to 1α,25(OH)2D3 in experimental models of cancer and osteoporosis with less induction of hypercalcemia, a major potential adverse effect in the clinical application of VDR ligands. Compounds 1302–1313 [316] were analyzed for their binding affinity and inhibitory activity against CYP24A1 (24-hydroxylase; this mitochondrial protein initiates the degradation of 1α,25(OH)2D3 by hydroxylation of the side chain), and the imidazole styrylbenzamides 1305–1309 were identified as potent inhibitors of CYP24A1, with similar or greater CYP27B1 (1α-hydroxylase; the protein encoded by this gene it hydroxylates 25OHD3 at the 1α-position, producing 1α,25(OH)2D3) selectivity than standard ketoconazole. Further evaluation of the 3,5-dimethoxy (1308) and 3,4,5-trimethoxy derivatives (1309) in chronic lymphocytic leukemia cells revealed that cotreatment of 1α,25-dihydroxyvitamin D3 and inhibitor upregulated GADD45α (growth arrest and DNA damage 45 gen) and CDKN1A (cyclin-dependent kinase inhibitor 1A gen).
Figure 23 (2014) [317,318,319,320,321]. Intensive research activity was carried out on Gemini compounds 1338–1364 [320].
Figure 24 (2014–2015) [322,323,324,325,326,327,328,329,330,331,332,333,334,335,336]. 1α,20S,24R-Trihydroxyvitamin D3 (1410) [332] showed a higher degree of activation, anti-inflammatory activity, and antiproliferative activity than vitamin D3 receptor.
Figure 25 (2015–2017) [337,338,339,340,341,342,343,344,345,346,347,348,349,350,351]. 1α,25-Dihydroxy-21-(3-hydroxy-3-methyl-1-methylene-butyl)vitamin D3 (1428, UV1) [337] presented potent antitumoral effects over a wide panel of tumor cell lines without inducing hypercalcemia or toxicity in vivo. The first vitamin D analog carrying an o-carborane in the side chain 1436 [340] showed that the substitution of hydroxyl group at C-25 by this apolar bulky group was possible. VDR binding was half of calcitriol’s, the transcriptional activity was similar, and the calcemic induction was significantly lower. 1436 is an outstanding B-carrier containing 10 boron atoms, which notably bind to VDR, a nuclear receptor. This suggests that 1436 may be interesting as a BNCT (boron neutron capture therapy) drug.
Figure 26 (2017–2018) [351,352,353,354,355,356,357,358]. 1,1’-([4-(3-[4-(3-Hydroxypropoxy)-3-methylphenyl]pentan-3-yl)-1,2-phenylene]bis(oxy))bis(3,3-dimethylbutan-2-ol) (1503) [358] displayed efficient inhibitory activity against collagen deposition and fibrotic gene expression in chronic pancreatitis. It also showed physicochemical and pharmacokinetic properties with antitumor activity, highlighting its potential therapeutic applications in cancer treatment.
Figure 27 (2018) [359,360,361,362,363,364]. (1R,3S,Z)-5-{(E)-3-[3-(6-Hydroxy-6-methylheptyl)phenyl]pent-2-en-1-ylidene}-4-methylenecyclohexane-1,3-diol (1573) [359] exhibited significant tumor growth inhibition and increased survival in SCID mouse models implanted with MDA-MB-231 breast tumor cells. Des-C-ring aromatic D-ring analog 1587 [363] showed remarkable lack of calcemic activity together with its significant antiproliferative and transcriptional activities in breast cancer cell lines, suggesting the therapeutical potential of 1587 for the treatment of breast tumors.
Figure 28 (2018–2019) [365,366,367,368,369,370,371,372,373,374,375,376,377,378]. 21-nor-17(S)-Methyl-20(22),23(24)-didehydro-26,26,26,27,27,27-hexafluoro-1α,25-dihydroxyvitamin D3 (1600) [368] bound strongly to VDR ligand binding domain and induced VDR transcriptional activity. Hybrid 1619 [371] was found to be a potent inhibitor of Hh (Hedgehog) signaling pathway.
Figure 29 (2019–2020) [379,380,381,382,383]. It is known that 25(OH)D3, down-regulates SREBP (sterol regulatory element-binding protein) independently of VDR. A screening of over 250 vitamin D congeners was carried out for their ability to inhibit the activity of an SREBP-responsive luciferase reporter. This is a VDR-responsive reporter assay. A comparison of the relative activity of the six compounds revealed 1639 [379] as the VDR-selective activator.
Figure 30 (2020–2022) [384,385,386,387,388,389]. Des-C-ring aromatic D-ring analogs 1712 and 1713 [373] showed a remarkable lack of calcemic activity together with significant antiproliferative and transcriptional properties in breast cancer cell lines, suggesting a therapeutical potential for 1712 and 1713 in breast tumor treatment.
Figure 31 (2021–2022) [390,391,392]. KK-052 (1746) [391], was found to be the first vitamin D-based SREBP (sterol regulatory element-binding proteins) inhibitor that mitigates hepatic lipid accumulation without calcemic action in mice. KK-052 maintained the ability of 25-hydroxyvitamin D3 to induce the degradation of SREBP but lacked VDR-mediated activity. KK-052 serves as a valuable compound for interrogating SREBP/SCAP in vivo and may represent an unprecedented translational opportunity for synthetic vitamin D analogs.
Nutrients 14 04927 g001 550
Figure 1. (1931–1978) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36].
Figure 1. (1931–1978) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36].
Nutrients 14 04927 g001
Nutrients 14 04927 g002 550
Figure 2. (1978–1982) [37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52].
Figure 2. (1978–1982) [37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52].
Nutrients 14 04927 g002
Nutrients 14 04927 g003 550
Figure 3. (1982–1987) [53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78].
Figure 3. (1982–1987) [53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78].
Nutrients 14 04927 g003
Nutrients 14 04927 g004 550
Figure 4. (1987–1991) [78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94].
Figure 4. (1987–1991) [78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94].
Nutrients 14 04927 g004
Nutrients 14 04927 g005 550
Figure 5. (1991–1992) [95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117].
Figure 5. (1991–1992) [95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117].
Nutrients 14 04927 g005
Nutrients 14 04927 g006 550
Figure 6. (1993–1994) [118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136].
Figure 6. (1993–1994) [118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136].
Nutrients 14 04927 g006
Nutrients 14 04927 g007 550
Figure 7. (1994–1997) [136,137,138,139,140,141,142,143,144,145,146,147,148].
Figure 7. (1994–1997) [136,137,138,139,140,141,142,143,144,145,146,147,148].
Nutrients 14 04927 g007
Nutrients 14 04927 g008 550
Figure 8. (1997–1999) [149,150,151,152,153,154,155,156,157,158].
Figure 8. (1997–1999) [149,150,151,152,153,154,155,156,157,158].
Nutrients 14 04927 g008
Nutrients 14 04927 g009 550
Figure 9. (1999) [158,159,160,161,162,163,164,165,166,167,168].
Figure 9. (1999) [158,159,160,161,162,163,164,165,166,167,168].
Nutrients 14 04927 g009
Nutrients 14 04927 g010 550
Figure 10. (2000–2001) [169,170,171,172,173,174,175,176,177,178,179,180,181,182].
Figure 10. (2000–2001) [169,170,171,172,173,174,175,176,177,178,179,180,181,182].
Nutrients 14 04927 g010
Nutrients 14 04927 g011 550
Figure 11. (2001–2002) [183,184,185,186,187,188,189,190,191,192,193,194,195,196].
Figure 11. (2001–2002) [183,184,185,186,187,188,189,190,191,192,193,194,195,196].
Nutrients 14 04927 g011
Nutrients 14 04927 g012 550
Figure 12. (2002) [197,198,199,200,201,202,203,204].
Figure 12. (2002) [197,198,199,200,201,202,203,204].
Nutrients 14 04927 g012
Nutrients 14 04927 g013 550
Figure 13. (2003–2004) [205,206,207,208,209,210,211,212,213,214,215,216,217,218].
Figure 13. (2003–2004) [205,206,207,208,209,210,211,212,213,214,215,216,217,218].
Nutrients 14 04927 g013
Nutrients 14 04927 g014 550
Figure 14. (2004–2006) [218,219,220,221,222,223].
Figure 14. (2004–2006) [218,219,220,221,222,223].
Nutrients 14 04927 g014
Nutrients 14 04927 g015 550
Figure 15. (2006–2007) [224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240].
Figure 15. (2006–2007) [224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240].
Nutrients 14 04927 g015
Nutrients 14 04927 g016 550
Figure 16. (2006–2008) [241,242,243,244,245,246,247,248,249,250,251,252,253].
Figure 16. (2006–2008) [241,242,243,244,245,246,247,248,249,250,251,252,253].
Nutrients 14 04927 g016
Nutrients 14 04927 g017 550
Figure 17. (2008–2009) [254,255,256,257,258,259,260,261,262,263,264].
Figure 17. (2008–2009) [254,255,256,257,258,259,260,261,262,263,264].
Nutrients 14 04927 g017
Nutrients 14 04927 g018 550
Figure 18. (2009–2010) [265,266,267,268,269,270].
Figure 18. (2009–2010) [265,266,267,268,269,270].
Nutrients 14 04927 g018
Nutrients 14 04927 g019 550
Figure 19. (2009–2010) [271,272,273,274,275,276,277,278,279,280,281,282,283].
Figure 19. (2009–2010) [271,272,273,274,275,276,277,278,279,280,281,282,283].
Nutrients 14 04927 g019
Nutrients 14 04927 g020 550
Figure 20. (2010–2012) [284,285,286,287,288,289,290,291,292,293,294,295,296,297,298].
Figure 20. (2010–2012) [284,285,286,287,288,289,290,291,292,293,294,295,296,297,298].
Nutrients 14 04927 g020
Nutrients 14 04927 g021 550
Figure 21. (2012–2013) [298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313].
Figure 21. (2012–2013) [298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313].
Nutrients 14 04927 g021
Nutrients 14 04927 g022 550
Figure 22. (2013–2014) [313,314,315,316].
Figure 22. (2013–2014) [313,314,315,316].
Nutrients 14 04927 g022
Nutrients 14 04927 g023 550
Figure 23. (2014) [317,318,319,320,321].
Figure 23. (2014) [317,318,319,320,321].
Nutrients 14 04927 g023
Nutrients 14 04927 g024 550
Figure 24. (2014–2015) [322,323,324,325,326,327,328,329,330,331,332,333,334,335,336].
Figure 24. (2014–2015) [322,323,324,325,326,327,328,329,330,331,332,333,334,335,336].
Nutrients 14 04927 g024
Nutrients 14 04927 g025 550
Figure 25. (2015–2017) [337,338,339,340,341,342,343,344,345,346,347,348,349,350,351].
Figure 25. (2015–2017) [337,338,339,340,341,342,343,344,345,346,347,348,349,350,351].
Nutrients 14 04927 g025
Nutrients 14 04927 g026 550
Figure 26. (2017–2018) [351,352,353,354,355,356,357,358].
Figure 26. (2017–2018) [351,352,353,354,355,356,357,358].
Nutrients 14 04927 g026
Nutrients 14 04927 g027 550
Figure 27. (2018) [359,360,361,362,363,364].
Figure 27. (2018) [359,360,361,362,363,364].
Nutrients 14 04927 g027
Nutrients 14 04927 g028 550
Figure 28. (2018–2019) [365,366,367,368,369,370,371,372,373,374,375,376,377,378].
Figure 28. (2018–2019) [365,366,367,368,369,370,371,372,373,374,375,376,377,378].
Nutrients 14 04927 g028
Nutrients 14 04927 g029 550
Figure 29. (2019–2020) [379,380,381,382,383].
Figure 29. (2019–2020) [379,380,381,382,383].
Nutrients 14 04927 g029
Nutrients 14 04927 g030 550
Figure 30. (2020–2022) [384,385,386,387,388,389].
Figure 30. (2020–2022) [384,385,386,387,388,389].
Nutrients 14 04927 g030
Nutrients 14 04927 g031 550
Figure 31. (2021–2022) [390,391,392].
Figure 31. (2021–2022) [390,391,392].
Nutrients 14 04927 g031

4. Conclusions

A century has passed since vitamin D was discovered. The structural diversity achieved among vitamin D receptor ligands (1785 ligands involving metabolites, analogs, hybrids, and nonsteroidal ligands). Seeing as vitamin D plays a ubiquitous role in human physiology, VDR ligands have been found to cure or ameliorate the symptoms of various diseases. It is disheartening to note that for more than twenty years no drug based on a VDR ligand (i.e., analogues, hybrids, or nonsteroidal ligands) has been placed on the market because the structural diversity achieved in the VDR ligands might encode new therapies for other illness different than the calcium–phosphorous homeostasis.

Author Contributions

Conceptualization, M.A.M.; methodology, M.A.M.; investigation, M.A.M. and S.S.; writing—original draft preparation, M.A.M.; writing—review and editing, M.A.M. and S.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Askew, F.A.; Bruce, H.M.; Callow, R.K.; Philpot, L., Jr.; Webster, T.A. Crystalline vitamin D. Nature 1931, 128, 758. [Google Scholar] [CrossRef]
  2. Havinga, E.; Bots, J.P.L. Studies on vitamin D I. The synthesis of vitamin D3 3 14C. Rec. Trav. Chim. 1954, 73, 393–400. [Google Scholar] [CrossRef]
  3. Bouillon, R.; Okamura, W.H.; Norman, A.W. Structure-function relationships in vitamin D endocrine system. Endocrine Rev. 1995, 16, 200–257. [Google Scholar] [CrossRef]
  4. Zhu, G.-D.; Okamura, W.H. Synthesis of vitamin D (calciferol). Chem. Rev. 1995, 95, 1877–1952. [Google Scholar] [CrossRef]
  5. Saito, N.; Kittaka, A. Highly potent vitamin D receptor antagonists; design, synthesis and biological evaluation. ChemBioChem 2006, 7, 1478–1490. [Google Scholar] [CrossRef]
  6. Posner, G.H.; Kahraman, M. Organic chemistry on vitamin D analogues (Deltanoids). Eur. J. Org. Chem. 2003, 2003, 3889–3895. [Google Scholar] [CrossRef]
  7. PerkinElmer. CHEM DRAW v.21.0.028 Chemical Drawing Software; PerkinElmer Informatics, Inc.: Waltham, MA, USA, 2011. [Google Scholar]
  8. Boehm, M.F.; Fitzgerald, P.; Zou, A.; Elgort, M.G.; Bischoff, E.D.; Mere, L.; Mais, D.E.; Bissonnette, R.P.; Heyman, R.A.; Nadzan, A.M.; et al. Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3. Chem. Biol. 1999, 6, 265–275. [Google Scholar] [CrossRef] [Green Version]
  9. Windaus, A.; Linsert, O.; Lütringhaus, A.; Weidlich, G. Über das krystallisierte vitamin D2. Ann. Chem. 1932, 492, 226–241. [Google Scholar] [CrossRef]
  10. Jordans, G.H.W. A.T. 10, a new drug against tetany. Ned. Tijdschr. 1934, 78, 2750–2756. [Google Scholar]
  11. Albright, F.; Sulkowitch, H.W.; Bloomberg, E. A comparison of the effects of vitamin D, dihydrotachysterol (A.T. 10) and parathyroid extract on the disordered metabolism of rickets. J. Clin. Inv. 1939, 18, 165. [Google Scholar] [CrossRef] [Green Version]
  12. Verloop, A.; Koevoet, A.L.; Havinga, E. Studies on vitamin D compounds and related compounds III. Short communication on the cis-trans isomerization of calciferol and properties of “trans”-vitamin D2. Rec. Trav. Chim. 1955, 74, 1125–1130. [Google Scholar] [CrossRef]
  13. Koevoet, A.L.; Verloop, A.; Havinga, E. Studies on vitamin D compounds and related compounds II. Preliminary communication on the interconversion and the possible cis-trans isomerism of previtamin D and tachysterol. Rec. Trav. Chim. 1955, 74, 788–792. [Google Scholar] [CrossRef]
  14. Westerhof, P.; Keverling Buisman, J.A. Investigations on sterols. VI. The preparation of dihydrotachysterol2. Rec. Trav. Chim. 1956, 75, 453–462. [Google Scholar] [CrossRef]
  15. Inhoffen, H.H.; Quinkert, G.; Hess, H.-J.; Hirschfeld, H. Studien in der vitamin D-reihe, XXIV. Photo-isomerisierung der trans-vitamin D2 un D3 zu den vitaminen D2 und D3. Chem Ber. 1957, 90, 2544–2553. [Google Scholar] [CrossRef]
  16. Westerhof, P.; Keverling Buisman, J.A. Investigations on sterols. IX. Dihydroderivatives of ergocalciferol. Rec. Trav. Chim. 1957, 76, 679–688. [Google Scholar] [CrossRef]
  17. Inhoffen, H.H.; Irmscher, K.; Hirschfeld, H.; Stache, U.; Kreutzer, A. Partial synthesis of vitamin D2 and D3. J. Chem. Soc. 1959, 385–386. [Google Scholar] [CrossRef]
  18. Blunt, J.W.; DeLuca, H.F.; Schnoes, H.K. 25-Hydroxycholecalciferol. A biologically active metabolite of vitamin D3. Biochemistry 1968, 7, 3317–3322. [Google Scholar] [CrossRef]
  19. Suda, T.; DeLuca, H.F.; Schnoes, H.K.; Tanaka, Y.; Holick, M.F. 25,26-Dihydroxycholecalciferol, a metabolite of vitamin D3 with intestinal calcium transport activity. Biochemistry 1970, 9, 4776–4780. [Google Scholar] [CrossRef]
  20. Redel, J.; Bell, P.; Delbarre, F.; Kodicek, E. Synthese du dihydydroxy-25,26 cholecalciferol, metabolite de la vitamine D3. C. R. Acad. Sc. Paris Serie D 1973, 276, 2907–2909. [Google Scholar]
  21. Holick, M.F.; Schnoes, H.K.; DeLuca, H.F. Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine. Proc. Nat. Acad. Sci. USA 1971, 68, 803–804. [Google Scholar] [CrossRef] [Green Version]
  22. Norman, A.W.; Myrtle, J.F.; Midgett, R.J.; Noviki, H.G.; Williams, V.; Popják, G. 1,25-Dihydroxycholecalciferol: Identification of the proposed active form of vitamin D3 in the intestine. Science 1971, 173, 51–54. [Google Scholar] [CrossRef] [PubMed]
  23. Lawson, D.E.M.; Fraser, D.R.; Kodicek, E.; Morris, H.R.; Dudley, H.W. Calcitriol, identificaction of 1,25-dihydroxycholecalciferol, a new kidney controlling calcium metabolism. Nature 1971, 230, 228–230. [Google Scholar] [CrossRef] [PubMed]
  24. Lam, H.-Y.; Schnoes, H.K.; DeLuca, H.F.; Chen, T.C. 24,25-Dihydroxyvitamin D3. Synthesis and biological activity. Biochemistry 1973, 12, 4851–4855. [Google Scholar] [CrossRef] [PubMed]
  25. Chalmers, T.M.; Hunter, J.O.; Davie, M.W.; Szaz, K.F.; Pelc, B.; Kodicek, E. 1-α-Hydroxycholecalciferol as a substitute for the kidney hormone 1,25-dihydroxycholecalciferol in chronic renal failure. Lancet 1973, 2, 696–699. [Google Scholar] [CrossRef]
  26. Fürst, A.; Labler, L.; Meier, W.; Pfoertner, K.-H. Synthese von 1α-hydroxycholecalferol. Helv. Chim. Acta 1973, 56, 1708–1710. [Google Scholar] [CrossRef]
  27. Barton, D.H.R.; Hesse, R.H.; Pechet, M.M.; Rizzardo, E. A convenient synthesis of 1α-hydroxyvitamin D3. J. Am. Chem. Soc. 1973, 95, 2748–2749. [Google Scholar] [CrossRef]
  28. Harrison, R.G.; Lythgoe, B.; Wright, P.W. Total synthesis of 1α-hydroxyvitamin D3. Tet. Lett. 1973, 14, 3649–3652. [Google Scholar] [CrossRef]
  29. Harrison, R.G.; Lythgoe, B.; Wright, P.W. Calciferol and its relatives. Part XVIII. Total synthesis of 1α-hydroxy-vitamin D3. J. Chem. Soc. Perkin I 1974, 2654–2657. [Google Scholar] [CrossRef]
  30. Lam, H.Y.; Schnoes, H.K.; DeLuca, H.F. 1α-Hydroxyvitamin D2. Potent synthetic analog of vitamin D2. Science 1974, 186, 1038–1040. [Google Scholar]
  31. Ikekewa, N.; Morisaki, M.; Koizumi, N.; Kato, Y.; Takeshita, T. Synthesis of active forms of vitamin D. VIII. Synthesis of [24R]- and [24S]-1α,24,25-trihydroxyvitamin D3. Chem. Pharm. Bull. 1975, 23, 695–697. [Google Scholar] [CrossRef] [Green Version]
  32. Morisaki, M.; Koizumi, N.; Ikekewa, N. Synthesis of active forms of vitamin D. IX. Synthesis of 1α,24-dihydroxycholecalciferol. J. Chem. Soc. Perkin I 1975, 1421–1424. [Google Scholar] [CrossRef] [PubMed]
  33. Lythgoe, B.; Moran, T.A.; Nambudiry, M.E.N.; Ruston, S.; Tideswell, J.; Wright, P.W. Allylic phosphine oxides as precusors of dienes of defined geometry: Synthesis of 3-deoxyvitamin D2. Tet. Lett. 1975, 44, 3863–3866. [Google Scholar] [CrossRef]
  34. Okamura, W.H.; Hammond, M.L.; Rego, A.; Norman, A.W.; Wing, R.M. Studies on vitamin D (calciferol) and its analogues. 12. Structural and synthetic studies of 5,6-trans-vitamin D3 and stereoisomers of 10,19-dihydrovitamin D3 including dihydrotachysterol3. J. Org. Chem. 1977, 42, 2284–2291. [Google Scholar] [CrossRef] [PubMed]
  35. Mouriño, A.; Blair, P.; Wecksler, W.; Johnson, R.L.; Norman, A.W.; Okamura, W.H. Studies on vitamin D (calciferol) and its analogues. 15. 24-Nor-1α,25-dihydroxyvitamin D3 and 14-nor-25-hydroxy-5,6-trans-vitamin D3. J. Med. Chem. 1978, 21, 1025–1029. [Google Scholar] [CrossRef] [PubMed]
  36. Mouriño, A.; Okamura, W.H. Studies on vitamin D (calciferol) and its analogues. 14. On the 10,19-dihydrovitamins related to vitamin D2 including dihydrotachysterol2. J. Org. Chem. 1978, 43, 1653–1656. [Google Scholar] [CrossRef]
  37. Yamada, S.; Ohmori, M.; Takayama, H. Synthesis of 24,24-difluoro-1α,25-dihydroxyvitamin D3. Chem. Pharm. Bull. 1979, 27, 3196–3198. [Google Scholar] [CrossRef] [Green Version]
  38. Onisko, B.L.; Schnoes, H.K.; DeLuca, H.F. 25-Aza-vitamin D3, an inhibitor of vitamin D metabolism and action. J. Biol. Chem. 1979, 254, 3493–3496. [Google Scholar] [CrossRef]
  39. Kocienski, P.J.; Lythgoe, B.; Rutson, S. Calciferol and its relatives. Part 24. A synthesis of vitamin D4. J. Chem. Soc. Perkin I 1979, 1290–1293. [Google Scholar] [CrossRef]
  40. Kobayahi, Y.; Taguchi, T.; Terada, T. Synthesis of 24,24-difluoro- and 24-fluoro-25-hydroxyvitamin D3. Tet. Lett. 1979, 20, 2023–2026. [Google Scholar] [CrossRef]
  41. Yamada, S.; Ohmori, M.; Takayama, H. Synthesis of 24,24-difluoro-25-hydroxyvitamin D3. Tet. Lett. 1979, 20, 1859–1862. [Google Scholar] [CrossRef]
  42. Napoli, J.L.; Fivizzani, M.A.; Schnoes, H.K.; DeLuca, H.F. 1-Fluorovitamin D3, a vitamin D3 analogue more active on bone-calcium mobilization than on intestinal-calcium transport. Biochemistry 1979, 18, 1641–1646. [Google Scholar] [CrossRef] [PubMed]
  43. Ishizuka, S.; Bannai, K.; Naruchi, T.; Hashimoto, Y.; Noguchi, T.; Hosoya, N. Studies on the mechanism of action of 1α,24-dihydroxyvitamin D3. I. Synthesis of 1α,24(R)- and 1α,24(S)-dihydroxy-[24-3H]- vitamin D3 and their metabolism in the rat. J. Biochem. 1980, 88, 87–95. [Google Scholar] [PubMed]
  44. Holick, S.A.; Holick, M.F.; Frommer, J.E.; Henley, J.W.; Lenz, J.A. Synthesis of [3α-3H]-3-epivitamin D3 and its metabolism in the rat. Biochem 1980, 19, 3993–3997. [Google Scholar] [CrossRef]
  45. Onisko, B.L.; Schnoes, H.K.; DeLuca, H.F. Inhibitors of the 25-hydroxylation of vitamin D3 in the rat. Bioorg. Chem. 1980, 9, 187–198. [Google Scholar] [CrossRef]
  46. Kobayashi, Y.; Taguchi, T.; Kanuma, N. Synthesis of 26,26,26,27,27,27-hexafluoro-25-hydroxyvitamin D3. J. Chem Soc. Chem. Comm. 1980, 459–460. [Google Scholar] [CrossRef]
  47. Jacobus, D.P.; Jones, H.; Yang, S.S. Cholecalciferol and Dihydrotachysterol3 Derivatives in Metabolic Blocking Drugs. Federal Republic Germany. DE2646240 A1, 28 April 1977. [Google Scholar]
  48. Kocienski, P.J.; Lythgoe, B. Calciferol and its relatives. Part 27. A synthesis of 1α-hydroxyvitamin D3 by way of 1α-hydroxytachysterol3. J. Chem. Soc. Perkin I 1980, 1400–1404. [Google Scholar] [CrossRef]
  49. Oshida, J.-I.; Morisaki, M.; Ikekawa, N. Synthesis of 2β-fluoro-1α-hydroxyvitamin D3. Tet. Lett. 1980, 21, 1755–1756. [Google Scholar] [CrossRef]
  50. Ohmura, N.; Bannai, K.; Yamaguchi, H.; Hashimoto, Y.; Norman, A.W. Isolation of a new metabolite of vitamin D produced in vivo, 1α,25-dihydroxyvitamin D3-26,23-lactone. Arch. Biochem. Biophys. 1980, 204, 387–391. [Google Scholar] [CrossRef]
  51. Wichmann, J.K.; Paaren, H.E.; Fivizzani, M.A.; Schnoes, H.K.; DeLuca, H.F. Synthesis of 25-hydroxyvitamin D3 26,23-lactone. Tet. Lett. 1980, 21, 4667–4670. [Google Scholar] [CrossRef]
  52. Eguchi, T.; Takatsuto, S.; Hirano, Y.; Ishiguro, M.; Ikekawa, N. Synthesis of four isomers of 25-hydroxyvitamin D3 26,23-lactone. Heterocycles 1982, 17, 359–375. [Google Scholar]
  53. Paaren, H.E.; Fivizzani, M.A.; Schnoes, H.K.; DeLuca, H.F. 1α,25-Difluorovitamin D3: An inert vitamin D analog. Arch. Biochem. Biophys. 1981, 209, 579–583. [Google Scholar] [CrossRef]
  54. Wichmann, J.; Schnoes, H.K.; DeLuca, H.F. Isolation and identification of 24(R)-hydroxyvitamin D3 from chicks given large doses of vitamin D3. Biochemistry 1981, 20, 2350–2353. [Google Scholar] [CrossRef] [PubMed]
  55. Wichmann, J.; Schnoes, H.K.; DeLuca, H.F. 23,24,25-Trihydroxyvitamin D3, 24,25,26-trihydroxyvitamin D3, 24-keto-25-hydroxyvitamin D3 and 23-dehydro-25-hydroxyvitamin D3. Biochemistry 1981, 20, 7385–7391. [Google Scholar] [CrossRef] [PubMed]
  56. Esvelt, R.P.; Fivizzani, M.A.; Paaren, H.E.; Schnoes, H.K.; DeLuca, H.F. Synthesis of calcitroic acid, a metabolite of 1α,25-dihydroxycholecalciferol. J. Org. Chem. 1981, 46, 456–458. [Google Scholar] [CrossRef]
  57. Eguchi, T.; Takatsuto, S.; Ishiguro, M.; Ikekawa, N.; Tanaka, Y.; DeLuca, H.F. Synthesis and determination of configuration of natural 25-hydroxyvitamin D3 26,23-lactone. Proc. Nat. Acad. Sci. USA 1981, 78, 6579–6583. [Google Scholar] [CrossRef] [Green Version]
  58. Kobayashi, Y.; Taguchi, T.; Kanuma, N. Synthesis of 26,26,26-trifluoro-25-hydroxy and 27-nor-26,26,26-trifluoro-25-hydroxyvitamin D3. Tet. Lett. 1981, 22, 4309–4312. [Google Scholar] [CrossRef]
  59. Matoba, K.; Kondo, K.; Yamazaki, T. Syntheses of vitamin D analogs I. Chem. Pharm. Bull. 1982, 30, 4593–4596. [Google Scholar] [CrossRef] [Green Version]
  60. Kobayashi, Y.; Taguchi, T.; Mitsihashi, S.; Eguchi, T.; Ohshima, E.; Ikekawa, N. Studies on organic fluorine compounds. XXXIX. Studies on steroids. LXXXIX. Synthesis of 1α,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D3. Chem. Pharm. Bull. 1982, 30, 4297–4303. [Google Scholar] [CrossRef] [Green Version]
  61. Haces, A.; Okamura, W.H. Heterocalciferols: Novel 3-thia and 3-sulfinyl analogues of 1α-hydroxyvitamin D3. J. Am. Chem. Soc. 1982, 104, 6105–6109. [Google Scholar] [CrossRef]
  62. Yamada, S.; Ohmori, M.; Takayama, H.; Takasaki, Y.; Suda, T. Isolation and identification of 1α- and 23-hydroxylated metabolites of 25-hydroxy-24-oxo-vitamin D3 from in vitro incubates of chick kidney homogenates. J. Biol. Chem. 1983, 258, 457–463. [Google Scholar] [CrossRef]
  63. Wovkulich, P.M.; Barcelos, F.; Batcho, A.D.; Sereno, J.F.; Baggiolini, E.G.; Hennessy, B.M.; Uskokovic, M.R. Stereoselective total synthesis of 1α,25S,26-trihydroxycholecalciferol. Tetrahedron 1984, 40, 2283–2296. [Google Scholar] [CrossRef]
  64. Barner, R.; Hübscher, J.; Daly, J.J.; Schönholzer, P. Zur Konfiguration des Vitamin D3-Metaboliten 25,26-Dihydroxycholecalciferol: Synthese von (25S,26)- und (25R,26)-Dihydroxy-cholecalciferol. Helv. Chim. Acta 1981, 64, 915–938. [Google Scholar] [CrossRef]
  65. Toh, H.T.; Okamura, W.H. Studies on a convergent route to side-chain analogues of vitamin D: 25-hydroxy-23-oxavitamin D3. J. Org. Chem. 1983, 48, 1414–1417. [Google Scholar] [CrossRef]
  66. Midgley, J.M.; Upton, R.M.; Watt, R.A.; Whalley, W.B.; Zhang, X.M. Unsaturated steroids. Part 11. Synthesis of 1α-hydroxy-25-methyl vitamin D3. J. Chem. Res., Synopses 1983, 11, 273. [Google Scholar]
  67. Taguchi, T.; Mitsuhashi, S.; Yamanouchi, A.; Kabayashi, Y. Synthesis of 23,23-difluoro-25-hydroxyvitamin D3. Tet. Lett. 1984, 25, 4933–4936. [Google Scholar] [CrossRef]
  68. Yamada, S.; Yamamoto, K.; Naito, H.; Suzuki, T.; Ohmori, M.; Takayama, H.; Shiina, Y.; Miyaura, C.; Tanaka, H.; Abe, E.; et al. Synthesis and differentiating action of vitamin D endoperoxides. Singlet oxygen adducts of vitamin D derivatives in human myeloid leukemia cells (HL-60). J. Med. Chem. 1985, 28, 1148–1153. [Google Scholar] [CrossRef]
  69. Dauben, W.G.; Kohler, B.; Roesle, A. Synthesis of 6-fluorovitamina D3. J. Org. Chem. 1985, 50, 2007–2010. [Google Scholar] [CrossRef]
  70. Tanaka, Y.; Sicinski, R.R.; DeLuca, H.F.; Sai, H.; Ikekawa, N. Unique rearrangement of ergosterol side chain in vivo; production of a biologically highly active homologue of 1α,25-dihydroxyvitamin D3. Biochemistry 1986, 25, 5512–5518. [Google Scholar] [CrossRef]
  71. Reddy, G.S.; Tserng, K.-Y. Isolation and identification of 1,24,25-trihydroxyvitamin D2, 1,24,25,28-tetrahydroxyvitamin D2 and 1,24,25,26-tetrahydroxyvitamin D2: New metabolites of 1,25-dihydroxyvitamin D2 produced in rat kidney. Biochemistry 1986, 25, 5328–5336. [Google Scholar] [CrossRef]
  72. Kubodera, N.; Miyamoto, K.; Ochi, K.; Matsunaga, M. Synthetic studies of vitamin D analogues. VII. Synthesis of 20-oxa-21-norvitamin D3 analogues. Chem. Pharm. Bull. 1986, 34, 2286–2289. [Google Scholar] [CrossRef] [Green Version]
  73. Sai, H.; Takatsuto, S.; Ikekawa, N.; Tanaka, I.; DeLuca, H.F. Synthesis of side-chain homologues of 1,25-dihydroxyvitamin D3 and investigation of their biological activities. Chem. Pharm. Bull. 1986, 34, 4508–4515. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Sardina, F.J.; Mouriño, A.; Castedo, L. Studies on the synthesis of side-chain hydroxylated metabolites of vitamin D. 2. Stereocontrolled synthesis of 25-hydroxyvitamin D2. J. Org. Chem. 1986, 51, 1264–1269. [Google Scholar] [CrossRef]
  75. Mascareñas, J.L.; Mouriño, A.; Castedo, L. Studies on the synthesis of side-chain hydroxylated metabolites of vitamin D. 3. Synthesis of 25-ketovitamin D3 and 25-hydroxyvitamin D3. J. Org. Chem. 1986, 51, 1269–1272. [Google Scholar] [CrossRef]
  76. Murayama, E.; Miyamoto, K.; Kubodera, N.; Mori, T.; Matsunaga, M. Synthetic studies of vitamin D analogues. VIII. Synthesis of 22-oxavitamin D3 analogues. Chem. Pharm. Bull. 1986, 34, 4410–4413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Sicinski, R.R.; DeLuca, H.F.; Schnoes, H.K.; Tanaka, Y.; Smith, C.M. Δ22-Unsaturated analogs of vitamin D3 and their C(1)-hydroxylated derivatives. Bioorg. Chem. 1987, 15, 152–166. [Google Scholar] [CrossRef]
  78. Ikekawa, N.; Eguchi, T.; Hara, N.; Takatsuto, S.; Honda, A.; Mori, Y.; Otomo, S. 26,27-Diethyl-1α,25-dihydroxyvitamin D3 and 24,24-difluoro-24-homo-1α,25-dihydroxyvitamin D3: Highly potent inducer for differentiation of human leukemia cells HL-60. Chem. Pharm. Bull. 1987, 35, 4362–4365. [Google Scholar] [CrossRef] [Green Version]
  79. Calverley, M.J. Synthesis of MC 903, a biologically active vitamin D metabolite analogue. Tetrahedron 1987, 43, 4609–4619. [Google Scholar] [CrossRef]
  80. Eguchi, T.; Sai, H.; Takatsuto, S.; Hara, N.; Ikekawa, N. Synthesis of 26,27-dialkyl analogues of 1α,25-dihydroxyvitamin D3. Chem. Pharm. Bull. 1988, 36, 2303–2311. [Google Scholar] [CrossRef] [Green Version]
  81. Shiuey, S.-J.; Partridge, J.J.; Uskokovic, M.R. Triply convergent synthesis of 1α,25-dihydroxy-24(R)-fluorocholecalciferol. J. Org. Chem. 1988, 53, 1040–1046. [Google Scholar] [CrossRef]
  82. Barrack, S.A.; Gibbs, R.A.; Okamura, W.H. Potential inhibitors of vitamin D metabolism: An oxa analogue of vitamin D. J. Org. Chem. 1988, 53, 1790–1796. [Google Scholar] [CrossRef]
  83. Baggiolini, E.G.; Hennessy, B.M.; Truitt, G.A.; Uskokovic, M.R. Dehydrocholecalciferol Derivatives. U.S. US14532882A, 20 January 1988. [Google Scholar]
  84. Kutner, A.; Perlman, K.L.; Lago, A.; Sicinski, R.R.; Schnoes, H.K.; DeLuca, H.F. Novel convergent synthesis of side-chain modified analogues of 1α,25-dihydroxycholecalciferol and 1α,25-dihydroxyergocalciferol. J. Org. Chem. 1988, 53, 3450–3457. [Google Scholar] [CrossRef]
  85. Okano, T.; Tsugawa, N.; Masuda, S.; Takeuchi, A.; Kobayashi, T.; Takita, Y.; Nishii, Y. Regulatory activities of 2β-(3-hydroxypropoxy)-1α,25-dihydroxy-vitamin D3, a novel synthetic vitamin D3 derivative, on calcium metabolism. Biochem. Biophys. Res. Commm. 1989, 163, 1444–1449. [Google Scholar] [CrossRef]
  86. Eguchi, T.; Yoshida, M.; Ikekawa, N. Synthesis and biological activities of 22-hydroxy and 22-methoxy derivatives of 1α,25-dihydroxyvitamin D3: Importance of side chain conformation for biological activities. Bioorg. Chem. 1989, 17, 294–307. [Google Scholar] [CrossRef]
  87. Dauben, W.G.; Ollmann, R.R., Jr.; Funhoff, A.S.; Neidlein, R. The synthesis of 25-oxo-25-phosphavitamin D3. Tett. Lett. 1989, 30, 677–680. [Google Scholar] [CrossRef]
  88. Perlman, K.; Kutner, A.; Prahl, J.; Smith, C.; Inaba, M.; Schnoes, H.K.; DeLuca, H.F. 24-Homologated 1,25-dihydroxyvitamin D3 compounds: Separation of calcium and cell differentiation activities. Biochemistry 1990, 29, 190–196. [Google Scholar] [CrossRef] [PubMed]
  89. Gill, H.S.; Londonwski, J.M.; Corradino, R.A.; Zinsmeister, A.R.; Kumar, R. Synthesis and biological activity of novel vitamin D analogues: 24,24-difluoro-25-hydroxy-26,27-dimethylvitamin D3 and 24,24-difluoro-1α,25-dihydroxy-26,27-dimethyl vitamin D3. J. Med. Chem. 1990, 33, 480–490. [Google Scholar] [CrossRef]
  90. Hara, N.; Eguchi, T.; Ikekawa, N.; Ishizuka, S.; Sato, J.-i. Synthesis and biological activity of (22E,25R)- and (22E,25S)-22-dehydro-1α,25-dihydroxy-26-methylvitamin D3. J. St. Biochem. 1990, 35, 655–664. [Google Scholar] [CrossRef]
  91. Binderup, L.; Latini, S.; Binderup, E.; Bretting, C.; Calverley, M.; Hansen, K. 20-epi-vitamin D3 analogues: A novel class of potent regulators of cell growth and immune responses. Biochem. Pharm. 1991, 42, 1569–1575. [Google Scholar] [CrossRef]
  92. Kubodera, N.; Miyamoto, K.; Akiyama, M.; Matsumoto, M.; Mori, T. Synthetic studies of vitamin D analogues. IX. Synthesis and diffrentiation-inducing activity of 1α,25-dihydroxy-23-oxa-, thia-, and azavitamin D3. Chem. Pharm. Bull. 1991, 39, 3221–3224. [Google Scholar] [CrossRef] [Green Version]
  93. Figadere, B.; Norman, A.W.; Henry, H.L.; Koeffler, H.P.; Zhou, J.Y.; Okamura, W.H. Arocalciferols: Synthesis and biological evaluation of aromatic side-chain analogues of 1α,25-dihydroxyvitamin D3. J. Med. Chem. 1991, 34, 2452–2463. [Google Scholar] [CrossRef]
  94. Okamura, W.H.; Aurrecoechea, J.M.; Gibbs, R.A.; Norman, A.W. Synthesis and biological activity of 9,11-dehydrovitamin D3 analogues: Stereoselective preparation of 6β-vitamin D vinylallenes and concise enynol synthesis for preparing the A-ring. J. Org. Chem. 1989, 54, 4072–4083. [Google Scholar] [CrossRef]
  95. Eguchi, T.; Kakinuma, K.; Ikekawa, N. Synthesis of 1α-[19-13C]hydroxyvitamin D3 and 13C NMR analysis of the conformational equilibrium of the A-ring. Bioorg. Chem. 1991, 19, 327–332. [Google Scholar] [CrossRef]
  96. Chodynski, M.; Kutner, A. Synthesis of side-chain homologated analogs of 1,25-dihydroxycholecalciferol and 1,25-dihydroxyergocalciferol. Steroids 1991, 56, 311–315. [Google Scholar] [CrossRef]
  97. Baggiolini, E.G.; Hennessy, B.M.; Shiuey, S.J.; Truitt, G.A.; Uskokovic, M.R. Preparation of Dehydrocholecalciferol Derivatives for Treatment of Hyperproliferative Skin Diseases and Neoplasms and Pharmaceutical Compositions Containing Them. European Patent Organization. EP325279A1, 26 July 1989. [Google Scholar]
  98. Maestro, M.A.; Sardina, F.J.; Castedo, L.; Mouriño, A. Stereoselective synthesis and thermal rearrangement of the first analogue of (7Z)-vitamin D. J. Org. Chem. 1991, 56, 3582–3587. [Google Scholar] [CrossRef]
  99. Ray, R.; Bouillon, R.; Van Baelen, H.; Holick, M.F. Synthesis of 25-hydroxyvitamin D3 3β-3’-[N-(4-azido-2-nitrophenyl)amino]propyl ether, a second-generation photoaffinity analogue of 25-hydroxyvitamin D3. Photoaffinity labeling of rat serum vitamin D binding protein. Biochemistry 1991, 30, 4809–4813. [Google Scholar] [CrossRef] [PubMed]
  100. Perlman, K.L.; Swenson, R.E.; Paaren, H.E.; Schnoes, H.K.; DeLuca, H.F. Novel synthesis of 19-nor-vitamin compounds. Tet. Lett. 1991, 32, 7663–7666. [Google Scholar] [CrossRef]
  101. Perlman, K.L.; DeLuca, H.F. 1α-Hydroxy-19-nor-vitamina D C-22 aldehyde. A versatile intermediate in the synthesis of side chain modified 1α,25-dihydroxy-19-nor-vitamina D3. Tet. Lett. 1992, 33, 2937–2940. [Google Scholar] [CrossRef]
  102. Mascareñas, J.L.; Sarandeses, L.A.; Castedo, L.; Mouriño, A. Palladium-catalysed coupling of vinyl triflates with enynes and its application to the synthesis of 1α,25-dihydroxyvitamin D3. Tetrahedron 1991, 47, 3485–3498. [Google Scholar] [CrossRef]
  103. Kubodera, N.; Miyamoto, K.; Matsumoto, M.; Kawanishi, T.; Ohkawa, H.; Mori, T. Synthetic studies of vitamin D analogues. X. Synthesis and biological activity of 1α,25-dihydroxy-21-norvitamin D3. Chem. Pharm. Bull. 1992, 40, 648–651. [Google Scholar] [CrossRef] [Green Version]
  104. Iseki, K.; Nagal, T.; Kobayashi, Y. Synthesis of 24-homo-26,26,26,27,27,27-hexafluoro-1α,22.25-trihydroxyvitamin D3. Chem. Pharm. Bull. 1992, 40, 1346–1348. [Google Scholar] [CrossRef] [Green Version]
  105. Kubodera, N.; Watanabe, H.; Kawanishi, T.; Matsumoto, M. Synthetic studies of vitamin D analogues. XI. Synthesis and differentiation-inducing activity of 1α,25-dihydroxy-22-oxavitamin D3 analogues. Chem. Pharm. Bull. 1992, 40, 1494–1499. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Ohira, Y.; Taguchi, T.; Iseki, K.; Kobayashi, Y. Preparation of (22S)- and (22R)-24-homo-26,26,26,27,27,27-hexafluoro-1,22,25-trihydroxy-24-yne-vitamin D3. Chem. Pharm. Bull. 1992, 40, 1647–1649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Bouillon, R.; Allewaert, K.; van Leeuwen, P.T.M.; Tan, B.-K.; Xiang, D.Z.; De Clercq, P.; Vandewalle, M.; Pols, H.A.P.; Bos, M.P.; Van Baelen, H.; et al. Structure function analysis of vitamin D analogs with C-ring modifications. J. Biol. Chem. 1992, 267, 3044–3051. [Google Scholar] [CrossRef]
  108. Okamura, W.H.; Palenzuela, J.A.; Plumet, J.; Midland, M.M. Vitamin D: Structure-function analyses and the design of analogs. J. Cell Biochem. 1992, 49, 10–18. [Google Scholar] [CrossRef] [PubMed]
  109. Maynard, D.F.; Norman, A.W.; Okamura, W.H. 18-Substituted derivatives of vitamin D: 18-acetoxy-1α,25-dihydroxyvitamin D3 and related analogues. J. Org. Chem. 1992, 57, 3214–3217. [Google Scholar] [CrossRef]
  110. Lee, A.S.; Norman, A.W.; Okamura, W.H. 3-Deoxy-3-thia-1α,25-dihydroxyvitamin D3 and its 1β-epimer: Synthesis and biological evaluation. J. Org. Chem. 1992, 57, 3846–3854. [Google Scholar] [CrossRef]
  111. Craig, A.S.; Norman, A.W.; Okamura, W.H. Two novel allenic side chain analogues of 1α,25-dihydroxyvitamin D3. J. Org. Chem. 1992, 57, 4374–4380. [Google Scholar] [CrossRef]
  112. Maestro, M.A.; Castedo, L.; Mouriño, A. A convergent appoach to the dihydrotachysterol diene system. Application to the synthesis of dihydrotachysterol2 (DHT2), 25-hydroxydihydrotachysterol2 (25-OH-DHT2), 10(R),19-dihydro-(5E)-epivitamina D2 and 25-hydroxy-10(R),19-dihydro-(5E)-epivitamina D2. J. Org. Chem. 1992, 57, 528–5213. [Google Scholar] [CrossRef]
  113. Torneiro, M.; Fall, Y.; Castedo, L.; Mouriño, A. An efficient route to 1α,25-dihydroxyvitamin D3 functionalized at C-11. Tet. Lett. 1992, 33, 105–108. [Google Scholar] [CrossRef]
  114. Vallés, M.J.; Castedo, L.; Mouriño, A. Functionalization of vitamin D metabolites at C-18 and application to the synthesis of 1α,18,25-trihydroxyvitamin D3 and 18,25-dihydroxyvitamin D3. Tet. Lett. 1992, 33, 1503–1506. [Google Scholar] [CrossRef]
  115. Sarandeses, L.A.; Mascareñas, J.L.; Castedo, L.; Mouriño, A. Synthesis of 1α,25-dihydroxy-19-norprevitamin D3. Tet. Lett. 1992, 33, 5445–5448. [Google Scholar] [CrossRef]
  116. Posner, G.H.; Nelson, T.D.; Guyton, K.Z.; Kensler, T.W. New vitamin D3 derivatives with unexpected antiproliferative activity: 1-(hydroxymethyl)-25-hydroxyvitamin D3 homologs. J. Med. Chem. 1992, 35, 3280–3287. [Google Scholar] [CrossRef] [PubMed]
  117. Steinmeyer, A.; Neef, G.; Kirsch, G.; Schwarz, K.; Rach, P.; Habery, M.; Thieroff-Ekerdt, R. Synthesis and biological activities of 8(14)a-homocalcitriol. Steroids 1992, 57, 447–452. [Google Scholar] [CrossRef]
  118. Kutner, A.; Chodynski, M.; Halkes, S.J.; Brugman, J. Novel concurrent synthesis of side-chain analogues of vitamina D2 and D3: 24,24-dihomo-25-hydroxycholecalciferol and (22E)-22-dehydro-24,24-dihomo-25-hydroxycholecalciferol. Bioorg. Chem. 1993, 21, 13–23. [Google Scholar] [CrossRef]
  119. Calverley, M.J.; Bretting, C.A.S. 1α,24S-Dihydroxy-26,27-cyclo-22-yne-vitamin D3: Tha side chain triple bond analogue of MC 903 (calcipotriol). Bioorg. Med. Chem. Lett. 1993, 3, 1841–1844. [Google Scholar] [CrossRef]
  120. Calverley, M.J.; Binderup, L. Synthesis and biological evaluation of MC 1357, a new 20-epi-23-oxa-1α,25-dihydroxy-vitamin D3 analogue with potent non-classical effects. Bioorg. Med. Chem. Lett. 1993, 3, 1845–1848. [Google Scholar] [CrossRef]
  121. Batcho, A.D.; Sereno, J.F.; Hennessy, B.M.; Baggiolini, E.G.; Uskokovic, M.R.; Horst, R.L. Total synthesis of 1α,25,28-trihydroxyergocalciferol. Bioorg. Med. Chem. Lett. 1993, 3, 1821–1824. [Google Scholar] [CrossRef]
  122. Nilsson, K.; Vallés, M.J.; Castedo, L.; Mouriño, A.; Halkes, S.J.; van de Velde, J.P. Synthesis and biological evaluation of 18-substituted analogs of 1α,25-dihydroxyvitamin D3. Bioorg. Med. Chem. Lett. 1993, 3, 1855–1858. [Google Scholar] [CrossRef]
  123. Posner, G.H.; Dai, H. 1-(Hydroxyalkyl)-25-hydroxyvitamin D3 analogs of calcitriol. 1. Synthesis. Bioorg. Med. Chem. Lett. 1993, 3, 1829–1834. [Google Scholar] [CrossRef]
  124. Allewaert, K.; Van Baelen, H.; Bouillon, R.; Zhao, X.-y.; De Clercq, P.; Vandewalle, M. Synthesis and biological evaluation of 23-oxa-, 23-thia- and 24-oxa-24-oxo-1α,25-dihydroxyvitamin D3. Bioorg. Med. Chem. Lett. 1993, 3, 1859–1862. [Google Scholar] [CrossRef]
  125. Sarandeses, L.A.; Vallés, M.J.; Castedo, L.; Mouriño, A. Synthesis of 24-oxavitamin D3 and 1α-hydroxy-24-oxavitamin D3. Tetrahedron 1993, 49, 731–738. [Google Scholar] [CrossRef]
  126. Okabe, M.; Sun, R.-C. An efficient synthesis of (22E,25R)-1α,25,26-trihydroxy-Δ22-vitamin D3. Tet. Lett. 1993, 34, 6533–6536. [Google Scholar] [CrossRef]
  127. Curtin, M.L.; Okamura, W.H. 1α,25-Dihydroxyprevitamin D3: Synthesis of the 9,14,19,19,19-pentadeuterio derivative and a kinetic study of its [1,7]-sigmatropic shift to 1α,25-dihydroxyvitamin D3. J. Am. Chem. Soc. 1991, 113, 6958–6966. [Google Scholar] [CrossRef]
  128. Zhao, X.-y.; De Clercq, P.; Vandewalle, M.; Alkwaert, K.; Van Baelen, I.; Bouillon, R. Synthesis and biological evaluation of some 25,26-epoxy-1α,24-dihydroxyvitamin D3. Bioorg. Med. Chem. Lett. 1993, 3, 1863–1867. [Google Scholar] [CrossRef]
  129. Allewaert, K.; Zhao, X.-Y.; Zhao, J.; Glibert, F.; Branisteanu, D.; De Clercq, P.; Vandewalle, M.; Bouillon, R. Biological evaluation of epoxy analogs of lα,25-dihydroxyvitamin D3. Steroids 1995, 60, 324–336. [Google Scholar] [CrossRef]
  130. Choudhry, S.C.; Belica, P.S.; Coffen, D.L.; Focella, A.; Maehr, H.; Manchand, P.S.; Serico, L.; Yang, R.T. Synthesis of a biologically active vitamin D2 metabolite. J. Org. Chem. 1993, 58, 1496–1500. [Google Scholar] [CrossRef]
  131. Muralidharan, K.R.; de Lera, A.R.; Isaeff, S.D.; Norman, A.; Okamura, W.H. Studies on the A-ring diastereomers of 1α,25-dihydroxyvitamin D3. J. Org. Chem. 1993, 58, 1895–1899. [Google Scholar] [CrossRef]
  132. Sicinski, R.R.; Perlman, K.L.; DeLuca, H.F. Synthesis and biological activity of 2-hydroxy and 2-alkoxy analogs of 1α,25-dihydroxy-19-norvitamin D3. J. Med. Chem. 1994, 37, 3730–3738. [Google Scholar] [CrossRef]
  133. Schoerder, N.J.; Trafford, D.J.H.; Cunningham, J.; Jones, G.; Makin, H.L.J. In vivo dihydrotachysterol2 metabolism in normal man: 1α- and 1β-hydroxylation of 25-hydroxytachysterol2 and effects on plasma parathyroid hormone and 1α,25-dihydroxyvitamin D3 concentrations. J. Clin. Endocr. Met. 1994, 78, 1841–1847. [Google Scholar] [CrossRef]
  134. Perlman, K.L.; Prahl, J.M.; Smith, C.; Sicinski, R.R.; DeLuca, H.F. 26,27-Dihomo-1α-hydroxy- and 26,27-dihomo-1α,25-hydroxyvitamina D2 analogs that differ markedly in biological activity in vivo. J. Biol. Chem. 1994, 269, 24014–24019. [Google Scholar] [CrossRef]
  135. Ishida, H.; Shimizu, M.; Yamamoto, K.; Iwasaki, Y.; Yamada, S. Syntheses of 1-alkyl-1,25-dihydroxyvitamin D3. J. Org. Chem. 1995, 60, 1828–1833. [Google Scholar] [CrossRef]
  136. VanAlstyne, E.M.; Norman, A.W.; Okamura, W.H. 7,8-Cis Geometric isomers of the steroid hormone 1α,25-dihydroxyvitamin D3. J. Am. Chem. Soc. 1994, 116, 6207–6216. [Google Scholar] [CrossRef]
  137. Okamoto, M.; Fujii, T.; Tanaka, T. The first convergent synthesis of 1α,24(R)-dihydroxyvitamin D3 via diastereoselective isopropylation and alkylative enyne cyclization. Tetrahedron 1995, 51, 5543–5556. [Google Scholar] [CrossRef]
  138. Schwarz, K.; Neef, G.; Kirsh, G.; Müller-Fahrnow, A.; Steinmeyer, A. Synthesis of 20-fluorovitamin D analogues. Tetrahedron 1995, 51, 9543–9550. [Google Scholar] [CrossRef]
  139. Iseki, K.; Oishi, S.; Namba, H.; Taguchi, T.; Kobayashi, Y. Preparation and biological activity of 24-epi-26,26,26,27,27,27-hexafluoro-1α,25-dihydroxyvitamin D2. Chem. Pharm. Bull. 1995, 43, 1897–1901. [Google Scholar] [CrossRef]
  140. Sabbe, K.; D’Hallewyn, C.; De Clercq, P.; Vandewalle, M.; Bouillon, R.; Verstuyf, A. Synthesis of CD-ring modified 1α,25-dihydroxyvitamin D analogues: E-ring analogues. Bioorg. Med. Chem. Lett. 1996, 6, 1697–1702. [Google Scholar] [CrossRef]
  141. Zhu, G.-D.; Chen, Y.; Zhou, X.; De Clercq, P.; Vandewalle, M.; Bouillon, R.; Verstuyf, A. Synthesis of CD-ring modified 1α,25-dihydroxyvitamin D analogues: C-ring analogues. Bioorg. Med. Chem. Lett. 1996, 6, 1703–1708. [Google Scholar] [CrossRef]
  142. Yamamoto, K.; Sun, W.Y.; Ohta, M.; Hamada, K.; DeLuca, H.F.; Yamada, S. Conformationally restricted analogs of 1α,25-dihydroxyvitamin D3 and its 20-epimer: Compounds for study of the three-dimension structure of vitamin D responsible for binding to the receptor. J. Med. Chem. 1996, 39, 2727–2737. [Google Scholar] [CrossRef]
  143. Yong, W.; Ling, S.; D’Hallewyn, C.; Van Haver, D.; De Clercq, P.; Vandewalle, M.; Bouillon, R.; Verstuyf, A. Synthesis of CD-ring modified 1α,25-dihydroxyvitamin D analogues: Five membered D-ring analogues. Bioorg. Med. Chem. Lett. 1997, 7, 923–928. [Google Scholar] [CrossRef]
  144. Linclau, B.; De Clercq, P.; Vandewalle, M.; Bouillon, R.; Verstuyf, A. The synthesis of CD-ring modified 1α,25-dihydroxyvitamin D: Six-membered D-ring analogues I. Bioorg. Med. Chem. Lett. 1997, 7, 1461–1464. [Google Scholar] [CrossRef]
  145. Linclau, B.; De Clercq, P.; Vandewalle, M.; Bouillon, R.; Verstuyf, A. The synthesis of CD-ring modified 1α,25-dihydroxyvitamin D: Six-membered D-ring analogues II. Bioorg. Med. Chem. Lett. 1997, 7, 1465–1468. [Google Scholar] [CrossRef]
  146. Scheddin, D.; Mayer, H.; Wittmann, S.; Schönecker, B.; Gliesing, S.; Reichenbächer, M. Synthesis and biological activities of 26-hydroxy-27-nor-derivatives of 1α,25-dihydroxyvitamin D3. Steroids 1996, 61, 598–608. [Google Scholar] [CrossRef]
  147. Hedlund, T.E.; Moffatt, K.A.; Uskokovic, M.R.; Miller, G.J. Three synthetic vitamin D analogues induce protate-specific acid phosphate and protate-specific antigen while inhibiting the growth of human prostate cancer cells in a vitamin D receptor-depenent fashion. Clin. Cancer Res. 1997, 3, 1331–1338. [Google Scholar] [PubMed]
  148. Kabat, M.M.; Burger, W.; Guggino, S.; Hennessy, B.; Iacobelli, J.A.; Takeuchi, K.; Uskokovic, M.R. Total synthesis of 25-hydroxy-16,23E-diene vitamin D3 and 1α,25-dihydroxy-16,23E-diene vitamin D3: Separation of genomic and non-genomic vitamin D activities. Bioorg. Med. Chem. 1998, 6, 2051–2059. [Google Scholar] [CrossRef]
  149. Asou, H.; Koike, M.; Elstner, E.; Cambel, M.; Le, J.; Uskokovic, M.R.; Kamada, N.; Koeffler, H.P. 19-nor Vitamin D analogs: A new class of potent inhibitors of proliferation and differentiation of human myeloid leukemia cell lines. Blood 1998, 92, 2441–2449. [Google Scholar] [CrossRef]
  150. Torneiro, M.; Fall, Y.; Castedo, L.; Mouriño, A. A short, efficient copper-mediated synthesis of 1α,25-dihydroxyvitamin D2 (1α,25-dihydroxyergocalciferol) and C-24 analogs. J. Org. Chem. 1997, 62, 6344–6352. [Google Scholar] [CrossRef]
  151. Andrews, D.R.; Barton, D.H.R.; Cheng, K.P.; Finet, J.P.; Hesse, R.H.; Johnson, G.; Pechet, M.M. A direct, regio- and stereoselective 1α-hydroxylation of (5E)-calciferol derivative. J. Org. Chem. 1986, 51, 1635–1637. [Google Scholar] [CrossRef]
  152. Konno, K.; Maki, S.; Fujishima, T.; Liu, Z.; Miura, D.; Chokki, M.; Takayama, H. A novel and practical route to A-ring enyne synthon for 1α,25-dihydroxyvitamin D3 analogues: Synthesis of A-ring diastereomers of 1α,25-dihydroxyvitamin D3 and 2-methyl-1α,25-dihydroxyvitamin D3. Bioorg. Med. Chem. Lett. 1998, 8, 151–156. [Google Scholar] [CrossRef]
  153. Fujishima, T.; Liu, Z.; Miura, D.; Chokki, M.; Ishizuka, S.; Konno, K.; Takayama, H. Synthesis and biological activity of 2-methyl-20-epi-1α,25-dihydroxyvitamin D3. Bioorg. Med. Chem. Lett. 1998, 8, 2145–2148. [Google Scholar] [CrossRef]
  154. Grue-Sørensen, G.; Hansen, C.M. New 1α,25-dihydroxyvitamin D3 analogues with side chains attached to C-18: Synthesis and biological activity. Bioorg. Med. Chem. 1998, 6, 2029–2039. [Google Scholar] [CrossRef]
  155. Posner, G.H.; Lee, J.K.; White, M.C.; Hutchings, R.H.; Dai, H.; Kachinski, J.L.; Dolan, P.; Kensler, T.W. Antiproliferative hibrid analogs of the hormone 1α,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation. J. Org. Chem. 1997, 62, 3299–3314. [Google Scholar] [CrossRef]
  156. Sicinski, R.R.; Prahl, J.M.; Smith, C.M.; DeLuca, H.F. New 1α,25-dihydroxy-19-norvitamin D3 compounds of high biological activity: Synthesis and biological evaluation of 2-hydroxymethyl, 2-methyl, and 2-methylene analogues. J. Med. Chem. 1998, 41, 4662–4674. [Google Scholar] [CrossRef] [PubMed]
  157. Posner, G.H.; Lee, J.K.; Wang, Q.; Peleg, S.; Burke, M.; Brem, H.; Dolan, P.; Kensler, T.W. Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1α,25-dihydroxyvitamin D3. Synthesis and preliminary biological evaluation. J. Med. Chem. 1998, 41, 3008–3014. [Google Scholar] [CrossRef] [PubMed]
  158. Posner, G.H.; Wang, Q.; Han, G.; Lee, J.K.; Crawford, K.; Zand, S.; Brem, H.; Peleg, S.; Dolan, P.; Kensler, T.W. Conceptually new sulfone analogues of the hormone 1α,25-dihydroxyvitamin D3: Synthesis and preliminary biological evaluation. J. Med. Chem. 1999, 42, 3425–3435. [Google Scholar] [CrossRef] [PubMed]
  159. Odrzywolska, M.; Chodynski, M.; Zorgdrager, J.; Van de Velde, J.-P.; Kutner, A. Diasteroselective synthesis, binding affinity for vitamin D receptor, and chiral stationary phase chromatography of hydroxy analogs of 1α,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol. Chirality 1999, 11, 701–706. [Google Scholar] [CrossRef]
  160. Kawashima, H.; Hoshina, K.; Hashimoto, Y.; Takeshita, T.; Ishimoto, S.; Noguchi, T.; Ikekawa, N.; Morisaki, M.; Orimo, H. Biological activity of 1α,24-dihydroxycholecalciferol: A new synthetic analog of the hormonal form of vitamin D. FEBS Lett. 1977, 76, 177–181. [Google Scholar] [CrossRef] [Green Version]
  161. Miura, D.; Manabe, K.; Gao, Q.; Norman, A.W.; Ishizuka, S. 1α,25-Dihydroxyvitamin D3-26,23-lactone analogs antagonize differentiation of human leukemia cells (HL-60 cells) but not of human acute promyelocytic leukemia cells (NB4 cells). FEBS Lett. 1999, 460, 297–302. [Google Scholar] [CrossRef] [Green Version]
  162. Fujishima, T.; Konno, K.; Nakagawa, K.; Kurobe, M.; Okano, T.; Takayama, H. Efficient synthesis and biological evaluation of all A-ring diastereomers of 1α,25-dihydroxyvitamin D3 and its 20-epimer. Bioorg. Med. Chem. 2000, 8, 123–134. [Google Scholar] [CrossRef]
  163. El Abdaimi, K.; Dion, N.; Papavasiliou, V.; Cardinal, P.-E.; Binderup, L.; Goltzman, D.; Ste-Marie, L.-G.; Kremer, R. The vitamin D analogue EB1039 prevents skeletal metastasis and prolongs survival time in nude mice transplanted with human breastcancer cells. Cancer Res. 2000, 60, 4412–4418. [Google Scholar]
  164. Colston, K.W.; Mackay, A.G.; James, S.Y.; Binderup, L.; Chander, S.; Coombes, R.C. EB1089: A new vitamin D analog that inhibits the growth of breast cancer cells in vivo and in vitro. Biochem. Pharmacol. 1992, 44, 2273–2280. [Google Scholar] [CrossRef]
  165. Zhou, X.; Zhu, G.-D.; Van Haver, D.; Vandewalle, M.; De Clercq, P.; Verstuyf, A.; Bouillon, R. Synthesis, biological activity, and conformational analysis of four seco-D-15,19-bisnor-1α,25-dihydroxyvitamin D3 analogues, diastereomeric at C17 and C20. J. Med. Chem. 1999, 42, 3439–3456. [Google Scholar] [CrossRef] [PubMed]
  166. Rey, M.A.; Martínez-Pérez, J.A.; Fernández-Gacio, A.; Halkes, K.; Fall, Y.; Mouriño, A. New synthetic strategies to vitamin D analogues modified at the side chain and D ring. Synthesis of 1α,25-dihydroxy-16-ene-vitamin D3 and C-20 analogues. J. Org. Chem. 1999, 64, 3196–3206. [Google Scholar] [CrossRef]
  167. Pérez Sestelo, J.; Mouriño, A.; Sarandeses, L.A. Design and synthesis of a 1α,25-dihydroxyvitamin D3 dimer as a potential chemical inducer of vitamin D receptor dimerization. Org. Lett. 1999, 1, 1005–1007. [Google Scholar] [CrossRef] [PubMed]
  168. Hisatake, J.-I.; Kubota, T.; Hisatake, Y.; Uskokovic, M.; Tomoyasu, S.; Koeffler, H.P. 5,6-trans-16-ene-Vitamin D3: A New Class of Potent Inhibitors of Proliferation of Prostate, Breast, and Myeloid Leukemic Cells. Cancer Res. 1999, 59, 4023–4029. [Google Scholar] [PubMed]
  169. Ikeda, M.; Takahashi, K.; Dan, A.; Koyama, K.; Kubota, K.; Tanaka, T.; Hayashi, M. Synthesis and biological evaluations of A-ring isomers of 26,26,26,27,27,27-hexafluoro-1α,25-dihydroxyvitamin D3. Bioorg. Med. Chem. 2000, 8, 2157–2166. [Google Scholar] [CrossRef]
  170. Herdick, M.; Steinmeyer, A.; Calberg, C. Carboxylic ester antagonist of 1α,25-dihydroxyvitamin D3 show cell-specific actions. Chem. Biol. 2000, 7, 885–894. [Google Scholar] [CrossRef]
  171. Norman, A.W.; Manchand, P.S.; Uskokovic, M.R.; Okamura, W.H.; Takeuchi, J.A.; Bishop, J.E.; Hisatake, J.-i.; Koeffler, H.P.; Peleg, S. Characterization of a novel analogue of 1α,25(OH)2-vitamin D3 with two side chains: Interaction with its nuclear receptor and cellular actions. J. Med. Chem. 2000, 43, 2719–2730. [Google Scholar] [CrossRef]
  172. Verlinden, L.; Verstuyf, A.; Van Camp, M.; Marcelis, S.; Sabbe, K.; Zhao, X.-Y.; De Clercq, P.; Vandewalle, M.; Bouillon, R. Two novel 14-epi-analogs of 1α,25-dihydroxyvitamin D3 inhibitthe growth of human breast cancer cells in vitro and in vivo. Cancer Res. 2000, 60, 2673–2679. [Google Scholar]
  173. Fernández-Gacio, A.; Vitale, C.; Mouriño, A. Synthesis of new aromatic (C17-C20)-locked side-chain analogues of calcitriol (1α,25-dihydroxyvitamin D3). J. Org. Chem. 2000, 65, 6978–6983. [Google Scholar] [CrossRef]
  174. Fall, Y.; Fernández, C.; Vitale, C.; Mouriño, A. Stereoselective synthesis of vitamin D analogues with cyclic side chains. Tet. Lett. 2000, 41, 7323–7326. [Google Scholar] [CrossRef]
  175. Codesido, E.M.; Cid, M.M.; Castedo, L.; Mouriño, A.; Granja, J.R. Synthesis of vitamin D analogues with a 2-hydroxy-3-deoxy ring A. Tet. Lett. 2000, 41, 5861–5864. [Google Scholar] [CrossRef]
  176. Bonasera, T.A.; Grue-Sørensen, G.; Ortu, G.; Binderup, E.; Bergström, M.; Björkling, F.; Långström, B. The synthesis of [26,26-11C]dihydroxyvitamin D3, a tracer for positron emission tomography (PET). Bioorg. Med. Chem. 2001, 9, 3123–3128. [Google Scholar] [CrossRef]
  177. Gabriëls, S.; Van Haver, D.; Vandewalle, M.; De Clercq, P.; Verstuyf, A.; Bouillon, R. Development of analogues of 1α,25-dihydroxyvitamin D3 with biased side chain orientation: Methylated des-CD-homo analogues. Chem. Eur. J. 2001, 7, 520–532. [Google Scholar] [CrossRef]
  178. Calverley, M. Novel side chain analogs of 1α,25-dihydroxyvitamin D3: Design and synthesis of the 21,24-methano derivatives. Steroids 2001, 66, 249–255. [Google Scholar] [CrossRef]
  179. Fujishima, T.; Zhaopeng, L.; Konno, K.; Nakagawa, K.; Okano, T.; Yamaguchi, K.; Takayama, H. Highly potent cell diffrentiation-inducing analogues of 1α,25-dihydroxyvitamin D3: Synthesis and biological activity of 2-methyl-1α,25-dihydroxyvitamin D3 with side-chain modifications. Bioorg. Med. Chem. 2001, 9, 525–535. [Google Scholar] [CrossRef]
  180. Kamao, M.; Tatematsu, S.; Reddy, G.S.; Hatakeyama, S.; Sugiura, M.; Ohashi, N.; Kubodera, N.; Okano, T. Isolation, identification and biological activity of 24R,25-dihydroxy-3-epi-vitamin D3; a novel metabolite of 24R,25-dihydroxyvitamin D3 produced in rat osteosarcoma (UMR 106). J. Nutr. Sci. Vitaminol. 2001, 47, 108–115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  181. Ishizuka, I.; Miura, D.; Ozono, K.; Saito, M.; Eguchi, H.; Chokki, M.; Norman, A.W. (23S)- and (23R)-25-Dehydro-1α-hydroxyvitamin D3-26,23-lactone function as antagonist of vitamin D receptor-mediated genomic actions of 1α,25-dihydroxyvitamin D3. Steroids 2001, 66, 227–237. [Google Scholar] [CrossRef]
  182. Steinmeyer, A.; Schwarz, K.; Haberey, M.; Langer, G.; Wiesinger, H. Synthesis and biological activities of a new series of secosteroids: Vitamin D phosphonate hybrids. Steroids 2001, 66, 257–266. [Google Scholar] [CrossRef]
  183. White, M.C.; Burke, M.D.; Peleg, S.; Brem, H.; Posner, G.H. Conformationally restricted hybrid analogues of the hormone of 1α,25-dihydroxyvitamin D3: Design, synthesis and biological evaluation. Bioorg. Med. Chem. 2001, 9, 1691–1699. [Google Scholar] [CrossRef]
  184. Mäenpää, P.H.; Väisänen, S.; Jääskeläinen, T.; Ryhänen, S.; Rouvinen, J.; Duchier, C.; Mahonen, A. Vitamin D3 analogs (MD 1288, KH 1060, EB 1089, GS 1558, and CD 1093): Studies on their mechanism of action. Steroids 2001, 66, 223–225. [Google Scholar] [CrossRef]
  185. Hatakeyama, S.; Kawase, A.; Uchiyama, Y.; Maeyama, J.; Iwabuchi, Y.; Kubodera, N. Synthesis and biological characterization of 1α,24,25-trihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (24-hydroxylated ED-71). Steroids 2001, 66, 267–276. [Google Scholar] [CrossRef]
  186. Takayama, H.; Konno, K.; Fujishima, T.; Maki, S.; Liu, Z.; Miura, D.; Chokki, M.; Ishizuka, S.; Smith, C.; DeLuca, H.F.; et al. Systematic studies on synthesis, structural elucidation and biological evaluation of A-ring diastereomers of 2-methyl-1α,25-dihydroxyvitamin D3 and 20-epi-2-methyl-1α,25-dihydroxyvitamin D3. Steroids 2001, 66, 277–285. [Google Scholar] [CrossRef]
  187. Schuster, I.; Egger, H.; Astecker, N.; Herzig, G.; Schüssler, M.; Vorisek, G. Selective inhibitors of CYP24: Mechanistic tools to explore vitamin D metabolism in human keratinocytes. Steroids 2001, 66, 451–462. [Google Scholar] [CrossRef]
  188. Bury, Y.; Herdick, M.; Uskokovic, M.R.; Calberg, C. Gene regulatory potential of 1α,25-dihydroxyvitamin D3 analogues with two side chains. J. Cell Biochem. 2001, Supp. 36, 179–190. [Google Scholar] [CrossRef]
  189. Nakagawa, K.; Sowa, Y.; Kurobe, M.; Ozono, K.; Siu-Caldera, M.-L.; Reddy, G.S.; Uskokovic, M.R.; Okano, T. Differential activities of 1α,25-dihydroxy-16-ene-vitamin D3 analogs and their 3-epimers on human promyelocytic leukemia (HL-60) cell differentaition and apoptosis. Steroids 2001, 66, 327–337. [Google Scholar] [CrossRef]
  190. Fall, Y.; Fernández, C.; González, V.; Mouriño, A. Stereoselective synthesis of (22R)- and (22S)-22-methyl-1α,25-dihydroxyvitamin D3. Synlett 2001, 1567–1568. [Google Scholar] [CrossRef]
  191. Hilpert, H.; Wirz, B. Novel versatile approach to an enantiopure 19-nor,des-CD vitamin D3 derivative. Tetrahedron 2001, 57, 681–694. [Google Scholar] [CrossRef]
  192. Posner, G.H.; Woodard, B.T.; Crawford, K.R.; Peleg, S.; Brown, A.J.; Dolan, P.; Kensler, T.W. 2,2-Disubstituted analogues of the natural hormone 1α,25-dihydroxyvitamin D3: Chemistry and biology. Bioorg. Med. Chem. 2002, 10, 2353–2365. [Google Scholar] [CrossRef]
  193. Fall, Y.; Barreiro, C.; Fernández, C.; Mouriño, A. Vitamin D heterocyclic analogues. Part 1: A stereoselective route to CD systems with pyrazole rings on their side chains. Tet. Lett. 2002, 43, 1433–1436. [Google Scholar] [CrossRef]
  194. Fernández-Gacio, A.; Mouriño, A. Studies on the introduction of a photoreactive aryldiazirine group into the vitamin D skeleton. Eur. J. Org. Chem. 2002, 2529–2534. [Google Scholar] [CrossRef]
  195. Pérez-Sestelo, J.; de Uña, O.; Mouriño, A.; Sarandeses, L.A. Synthesis of the first 24-aminovitamin D3 derivatives by diastereoselective conjugate addition to a chiral methyleneoxazolidinone in aqueous media. Synlett 2002, 719–722. [Google Scholar] [CrossRef]
  196. Suhara, Y.; Kittaka, A.; Kishimoto, S.; Calverley, M.J.; Fujishima, T.; Saito, N.; Sugiura, T.; Waku, K.; Takayama, H. Synthesis and testing of 2α-modified 1α,25-dihydroxyvitamin D3 analogues with a double side chain: Marked cell diffrentiation activity. Bioorg. Med. Chem. Lett. 2002, 12, 3255–3258. [Google Scholar] [CrossRef]
  197. Wu, Y.; Sabbe, K.; De Clercq, P.; Vandewalle, M.; Bouillon, R.; Verstuyf, A. Vitamin D3: Synthesis of seco C-9,11,21-trisnor-17-methyl-1α,25-dihydroxy vitamin D3 analogues. Bioorg. Med. Chem. Lett. 2002, 12, 1629–1632. [Google Scholar] [CrossRef]
  198. Wu, Y.; De Clercq, P.; Vandewalle, M.; Bouillon, R.; Verstuyf, A. Vitamin D3: Synthesis of seco C-9,11-bisnor-17-methyl-1α,25-dihydroxy vitamin D3 analogues. Bioorg. Med. Chem. Lett. 2002, 12, 1633–1636. [Google Scholar] [CrossRef]
  199. Chodynski, M.; Wietrzyk, J.; Marcinkowska, E.; Opolski, A.; Szelejewski, W.; Kutner, A. Synthesis and antiproliferative activity of side-chain unsaturated and homologated analogs of 1α,25-dihydroxyvitamin D2 (24E)-(1S)-24-dehydro-24a-homo-1,25-dihydroxyergalciferol and congeners. Steroids 2002, 67, 789–798. [Google Scholar] [CrossRef]
  200. Varela, C.; Nilsson, K.; Torneiro, M.; Mouriño, A. Synthesis of tetracyclic analogues of calcitriol (1α,25-dihydroxyvitamin D3) with side-chain-locked spatial orientations at C(20). Helv. Chim. Acta 2002, 85, 3251–3261. [Google Scholar] [CrossRef]
  201. Cornella, I.; Pérz-Sestelo, J.; Mouriño, A.; Sarandeses, L.A. Synthesis of 18-substituted analogues of calcitriol using photochemical remote functionalization. J. Org. Chem. 2002, 67, 4707–4714. [Google Scholar] [CrossRef]
  202. Okamura, W.H.; Zhu, G.-D.; Hill, D.K.; Thomas, R.J.; Ringe, K.; Borchardt, D.B.; Norman, A.W.; Mueller, L.J. Synthesis and NMR studies of 13C-labeled vitamin D metabolites. J. Org. Chem. 2002, 67, 1637–1650. [Google Scholar] [CrossRef]
  203. Brandl, M.; Wu, X.; Liu, Y.; Pease, J.; Holper, M.; Hooijmaaijer, E.; Lu, Y.; Wu, P. Chemical reactivity of Ro-26-9228, 1α-fluoro-25-hydroxy-10,23E-diene-26,27-bishomo-20-epi-cholecalciferol in aqueous solution. J. Pharm. Sci. 2003, 92, 1981–1989. [Google Scholar] [CrossRef]
  204. Swann, S.L.; Bergh, J.; Farach-Carson, M.C.; Ocasio, C.A.; Koh, J.T. Structure-Based design of selective agonists for a rickets-associated mutant of the vitamin D receptor. J. Am. Chem. Soc. 2002, 124, 13795–13805. [Google Scholar] [CrossRef]
  205. Fujishima, T.; Kojima, Y.; Azumaya, I.; Kittaka, A.; Takayama, H. Design and synthesis of potent vitamin D receptor antagonists with A-ring modificactions: Remarkable effects of 2α-methyl introduction an antagonist activity. Bioorg. Med. Chem. 2003, 11, 3621–3631. [Google Scholar] [CrossRef]
  206. Honzawa, S.; Suhara, Y.; Nihei, K.-I.; Saito, N.; Kishimoto, S.; Fujishima, T.; Kurihara, M.; Sugiura, T.; Waku, K.; Takayama, H.; et al. Concise synthesis and biological activities of 2α-alkyl and 2α-(ω-hydroxyalkyl)-20-epi-1α,25-dihydroxyvitamin D3. Bioorg. Med. Chem. Lett. 2003, 13, 3503–3506. [Google Scholar] [CrossRef]
  207. Verlinden, L.; Verstuyf, A.; Verboven, C.; Eelen, G.; De Ranter, C.; Gao, L.-J.; Chen, Y.-J.; Murad, I.; Choi, M.; Yamamoto, K.; et al. Previtamin D3 with a trans-fused decalin CD-ring has pronounced genomic activity. J. Biol. Chem. 2003, 278, 35476–35482. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  208. Hanazawa, T.; Koyama, A.; Nakata, K.; Okamoto, S.; Sato, F. New convergent synthesis of 1α,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling between A-ring and C,D-ring parts. J. Org. Chem. 2003, 68, 9767–9772. [Google Scholar] [CrossRef] [PubMed]
  209. Blæhr, L.K.A.; Björkling, F.; Calverley, M.J.; Binderup, E.; Begtrup, M. Synthesis of novel hapten derivatives of 1α,25-dihydroxyvitamin D3 and its 20-epi analogue. J. Org. Chem. 2003, 68, 1367–1375. [Google Scholar] [CrossRef]
  210. Ono, K.; Yoshida, A.; Saito, N.; Fujishima, T.; Honzawa, S.; Suhara, Y.; Kishimoto, S.; Sugiura, T.; Waku, K.; Takayama, H.; et al. Efficent synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D3 with Julia olefination: High potency in induction of the differentiation on HL-60 cells. J. Org. Chem. 2003, 68, 7407–7415. [Google Scholar] [CrossRef]
  211. Kato, H.; Hashimoto, Y.; Nagasawa, K. Novel heteroatom-containing vitamin D3 analogs: Efficient synthesis of 1α,25-dihydroxyvitamin D3-26,23-lactam. Molecules 2003, 8, 488–499. [Google Scholar] [CrossRef]
  212. Chen, Y.-J.; Gao, L.-J.; Murad, I.; Verstuyf, A.; Verlinden, L.; Verboven, C.; Bouillon, R.; Viterbo, D.; Van Haver, D.; Vandewalle, M.; et al. Synthesis, biological activity, and conformational analysis of CD-ring modified trans-decalin 1α,25-dihydroxyvitamin D3 analogs. Org. Biomol. Chem. 2003, 1, 257–267. [Google Scholar] [CrossRef]
  213. Fujishima, T.; Kittaka, A.; Yamaoka, K.; Takeyama, K.-i.; Kato, S.; Takayama, H. Synthesis of 2,2-dimethyl-1α,25-dihydroxyvitamin D3: A-ring structural motif that modulates interactions of vitamin D receptor with transcriptional activators. Org. Biomol. Chem. 2003, 1, 1863–1869. [Google Scholar] [CrossRef]
  214. González-Avión, X.C.; Mouriño, A. Functionalization at C-12 of 1α,25-dihydroxyvitamin D3 strongly modulates the affinity for the vitamin D receptor (VDR). Org. Lett. 2003, 5, 2291–2293. [Google Scholar] [CrossRef]
  215. Pérez-García, X.; Rumbo, A.; Larriba, M.J.; Ordóñez, P.; Muñoz, A.; Mouriño, A. The first locked side-chain analogues of calcitriol (1α,25-dihydroxyvitamin D3) induce vitamin D receptor transcriptional activity. Org. Lett. 2003, 5, 4033–4036. [Google Scholar] [CrossRef] [PubMed]
  216. Saito, N.; Matsunaga, T.; Fujishima, T.; Anzai, M.; Saito, H.; Takenouchi, K.; Miura, D.; Takayama, H.; Kittaka, A. Remarkable effect of 2α-modification on the VDR antagonistic activity of 1α-hydroxyvitamin D3-26,23-lactones. Org. Biomol. Chem. 2003, 1, 4396–4402. [Google Scholar] [CrossRef] [PubMed]
  217. Saito, N.; Saito, H.; Anzai, M.; Yoshido, A.; Fujishima, T.; Takenouchi, K.; Miura, D.; Ishizuka, I.; Takayama, H.; Kittaka, A. Dramatic enhancement of antagonistic activity on vitamin D receptor: A double functionalization of 1α-hydroxyvitamin D3- 26,23-lactones. Org. Lett. 2003, 5, 4859–4862. [Google Scholar] [CrossRef] [PubMed]
  218. Unten, S.; Ishihara, M.; Sakagami, H. Relationship between differentiation-inducing activity and hypercalcemic activity of hexafluorotrihydroxyvitamin D derivatives. Anticancer Res. 2004, 24, 683–690. [Google Scholar] [PubMed]
  219. Kato, H.; Nakano, Y.; Sano, H.; Tanatani, A.; Kobayashi, H.; Shimazawa, R.; Koshino, H.; Hashimoto, Y.; Nagasawa, K. Synthesis of 1α,25-dihydroxyvitamin D3-26,23-lactams, a novel series of 1α,25-dihydroxyvitamin D3 antagonist. Bioorg. Med. Chem. Lett. 2004, 14, 2579–2583. [Google Scholar] [CrossRef] [PubMed]
  220. Maehr, H.; Uskokovic, M.R. Formal desymmetrization of the diastereotopic chains in Gemini calcitriol derivatives with two different side chains at C-20. Eur. J. Org. Chem. 2004, 1703–1713. [Google Scholar] [CrossRef]
  221. Takenouchi, K.; Sogawa, R.; Manabe, K.; Saitoh, H.; Gao, Q.; Miura, D.; Ishizuka, S. Synthesis and structure-activity relationships of TEI-9647 derivatives as vitamin D3 antagonists. J. St. Biochem. Mol. Biol. 2004, 89–90, 31–34. [Google Scholar] [CrossRef]
  222. Schepens, W.; Van Haver, D.; Vandewalle, M.; De Clercq, P.; Bouillon, R.; Verstuyf, A. Synthesis and biological activity of 22-oxa CD-modified analogues of 1α,25-dihydroxyvitamin D3: Spiro[5,5]-undecane CF-ring analogues. Bioorg, Med. Chem. Lett. 2004, 14, 3889–3892. [Google Scholar] [CrossRef]
  223. Maehr, H.; Uskokovic, M.R.; Adorini, L.; Reddy, G.S. Calcitriol derivatives with two different side chains at C20. II. Diastereo selective synthesis of the metabolically produced 24(R)-Gemini. J. Med. Chem. 2004, 47, 6476–6484. [Google Scholar] [CrossRef]
  224. Momán, E.; Nicoletti, D.; Mouriño, A. Synthesis of novel analogues of 1α,25-dihydroxyvitamin D3 with side chains at C-18. J. Org. Chem. 2004, 69, 4615–4625. [Google Scholar] [CrossRef]
  225. Saito, N.; Suhara, Y.; Kurihara, M.; Fujishima, T.; Honzawa, S.; Takayanagi, H.; Kozono, T.; Matsumoto, M.; Ohmori, M.; Miyata, N.; et al. Design and efficient synthesis of 2α-(ω-hydroxyalkoxy)-1α,25-dihydroxyvitamin D3 analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity. J. Org. Chem. 2004, 69, 7463–7471. [Google Scholar] [CrossRef] [PubMed]
  226. Wu, S.-Y.; de Keczer, S.A.; Masjedizadeh, M.R. [3H] and [14C]-Ro0275646, a vitamin D analog. Synth. Appl Isot. Labl. Comp. 2004, 8, 203–206. [Google Scholar]
  227. Posner, G.H.; Tony Lee, S.H.; Kim, H.J.; Peleg, S.; Dolan, P.; Kensler, T.W. Novel A-ring analogs of the hormone 1α,25-dihydroxyvitamin D3: Synthesis and preliminary biological evaluation. Bioorg. Med. Chem. 2005, 13, 2959–2966. [Google Scholar] [CrossRef] [PubMed]
  228. Hatcher, M.A.; Peleg, S.; Dolan, P.; Kensler, T.W.; Sarjeant, A.; Posner, G.H. A-ring hydroxymethyl 19-nor analogs of the natural hormone 1α,25-dihydroxyvitamin D3: Synthesis and preliminary biological evaluation. Bioorg. Med. Chem. 2005, 13, 3964–3976. [Google Scholar] [CrossRef]
  229. Gómez-Reino, C.; Vitale, C.; Maestro, M.; Mouriño, A. Pd-Catalyzed carbocyclization-Negishi cross-coupling cascade: A novel approach to 1α,25-dihydroxyvitamin D3 and analogues. Org. Lett. 2005, 7, 5885–5887. [Google Scholar] [CrossRef]
  230. Shimizu, M.; Miyamoto, Y.; Kobayashi, E.; Shimazaki, M.; Yamamoto, K.; Reischl, W.; Yamada, S. Synthesis and biological activities of new 1α,25-dihydroxy-19-norvitamin D3 analogs with modifications in both A-ring and the side chain. Bioorg. Med. Chem. 2006, 14, 4277–4294. [Google Scholar] [CrossRef]
  231. Shimizu, K.; Kawase, A.; Haneishi, T.; Kato, Y.; Kinoshita, K.; Ohmori, M.; Furuta, Y.; Emura, T.; Kato, N.; Mitsui, T.; et al. Design and evaluation of new antipsoriatic antedrug candidates having 16-en-22-oxa-vitamin D3 structures. Bioorg. Med. Chem. Lett. 2006, 16, 3323–3329. [Google Scholar] [CrossRef]
  232. Hatakeyama, S.; Nahashima, S.; Imai, N.; Takahashi, K.; Ishihara, J.; Sugita, A.; Nihei, T.; Saito, H.; Takahashi, F.; Kubodera, N. Synthesis and biological evaluation of a 3-position diastereomer of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71). Bioorg. Med. Chem. 2006, 14, 8050–8056. [Google Scholar] [CrossRef]
  233. Uskokovic, M.R.; Manchand, P.; Marezak, S.; Maehr, H.; Jankowski, P.; Adorini, L.; Reddy, G.S. C-20 Cyclopropyl vitamin D analogs. Curr. Top. Med. Chem. 2006, 6, 1289–1296. [Google Scholar] [CrossRef]
  234. Oves, D.; Fernández, S.; Verlinden, L.; Bouillon, R.; Verstuyf, A.; Ferrero, M.; Gotor, V. Novel A-ring homodimeric C-3-carbamate analogues of 1α,25-dihydroxyvitamin D3: Synthesis and preliminary biological evaluation. Bioorg. Med. Chem. 2006, 14, 7512–7519. [Google Scholar] [CrossRef]
  235. Hosoda, S.; Tanatani, A.; Wakabayashi, K.-i.; Makishima, M.; Imai, K.; Miyachi, H.; Nagasawa, K.; Hashimoto, Y. Ligands with a 3,3-diphenylpentane skeleton for nuclear vitamin D and androgen receptors: Dual activities and metabolic activation. Bioorg Med. Chem. 2006, 14, 5489–5502. [Google Scholar] [CrossRef] [PubMed]
  236. Schuster, I.; Egger, H.; Nussbaumer, P.; Kroemer, T. Inhibitors of vitamin D hydroxylases: Structure-activity relationships. J. Cell. Biochem. 2003, 88, 372–380. [Google Scholar] [CrossRef] [PubMed]
  237. Peleg, S.; Petersen, K.S.; Suh, B.C.; Dolan, P.; Agoston, E.S.; Kensler, T.W.; Posner, G.H. Low-calcemic, antiproliferatives, 1-difluoromethyl hybrid analogs of the hormone 1α,25-dihydroxyvitamin D3: Design, synthesis and preliminary biological evaluation. J. Med. Chem. 2006, 49, 7513–7517. [Google Scholar] [CrossRef] [PubMed]
  238. Schepens, W.; Van Haver, D.; Vandewalle, M.; Bouillon, R.; Verstuyf, A.; De Clercq, P. Synthesis of spiro[4,5]-decane CF-ring analogues of 1α,25-dihydroxyvitamin D3. Org. Lett. 2006, 8, 4247–4250. [Google Scholar] [CrossRef]
  239. Ono, Y.; Watanabe, H.; Taira, I.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.; Kubodera, N. Synthesis of putative metabolites of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71). Steroids 2006, 71, 529–540. [Google Scholar] [CrossRef]
  240. Riveiros, R.; Rumbo, A.; Sarandeses, L.A.; Mouriño, A. Synthesis and conformational analysis of 17α,21-cyclo-22-unsaturated analogues of calcitriol. J. Org. Chem. 2007, 72, 5477–5485. [Google Scholar] [CrossRef]
  241. Yamamoto, K.; Abe, D.; Yoshimoto, N.; Choi, M.; Yamagishi, K.; Tokiwa, H.; Shimizu, M.; Makishima, M.; Yamada, S. Vitamin D receptor: Ligand recognition and allosteric network. J. Med. Chem. 2006, 49, 1313–1324. [Google Scholar] [CrossRef]
  242. Lee, H.J.; Wislocki, A.; Goodman, C.; Ji, Y.; Ge, R.; Maehr, H.; Uskokovic, M.R.; Reiss, M.; Suh, N. A vitamin D derivative activates bone morphogenetic protein signaling in MCF10 breast epithelial cells. Mol. Pharm. 2006, 69, 1840–1848. [Google Scholar] [CrossRef]
  243. Yoshimoto, N.; Inaba, Y.; Yamada, S.; Makishima, M.; Shimizu, M.; Yamamoto, K. 2-Methylene-19-nor-25-dehydro-1α-hydroxyvitamin D3-26,23-lactones; synthesis, biological activities and molecular basis of passive antagonism. Bioorg. Med. Chem. 2008, 16, 457–473. [Google Scholar] [CrossRef]
  244. Saito, N.; Matsunaga, T.; Saito, H.; Anzai, M.; Takenouchi, K.; Miura, D.; Namekawa, J.-i.; Ishizuka, S.; Kittaka, A. Further synthetic and biological studies on vitamin D hormone antagonist based on C24-alkylation and C2α-functionalization of 25-dehydro-1α-hydroxyvitamin D3-26,23-lactones. J. Med. Chem. 2006, 49, 7063–7075. [Google Scholar] [CrossRef]
  245. González-Avión, X.C.; Mouriño, A.; Rochel, N.; Moras, D. Novel 1α,25-dihydroxyvitamin D3 analogs with side chain at C12. J. Med. Chem. 2006, 49, 1509–1516. [Google Scholar] [CrossRef] [PubMed]
  246. Maehr, H.; Uskokovic, M.R.; Adorini, L.; Penna, G.; Mariani, R.; Panina, P.; Passini, N.; Bono, E.; Perego, S.; Biffi, M.; et al. Calcitriol derivatives with two different side chains at C20. III. An epimeric pair of the Gemini family with unprecedented antiproliferative effects on tumor cells and renin mRNA expression inhibition. J. St. Biochem. Mol. Biol. 2007, 103, 277–281. [Google Scholar] [CrossRef] [PubMed]
  247. Garay, E.; Jankowski, P.; Lizano, P.; Marczak, S.; Maehr, H.; Adorini, L.; Uskokovic, M.R.; Studzinski, G.P. Calcitriol derivatives with two different side chains at C20. Part 4. Further side chain modifications that alter VDR-dependent monocytic differentiation potency inhuman leukemia cells. Bioorg. Med. Chem. 2007, 15, 4444–4455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  248. Yamamoto, K.; Inaba, Y.; Yoshimoto, N.; Choi, M.; DeLuca, H.F.; Yamada, S. 22-Alkyl-20-epi-1α,25-dihydroxyvitamin D3 compounds of superagonistic activity: Syntheses, biological activities and interaction with the receptor. J. Med. Chem. 2007, 50, 932–939. [Google Scholar] [CrossRef] [PubMed]
  249. Gregorio, C.; Eduardo, S.; Rodrigues, L.C.; Regueira, M.; Fraga, R.; Riveiros, R.; Maestro, M.; Mouriño, A. Synthesis of two carboxylic haptens for raising antibodies to 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3. J. St. Biochem. Mol. Biol. 2007, 103, 227–230. [Google Scholar] [CrossRef] [PubMed]
  250. Glebocka, A.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F. 2-(3’-Hydroxypropylidene)-1α-hydroxy-19-norvitamin D compounds with truncated side chain. J. St. Biochem. Mol. Biol. 2007, 103, 310–315. [Google Scholar] [CrossRef]
  251. Kobayashi, E.; Shimazaki, M.; Miyamoto, Y.; Masuno, H.; Yamamoto, K.; DeLuca, H.F.; Yamada, S.; Shimizu, M. Structure-activity relationships of 19-norvitamin D analogs having a fluoroethylene group at the C-2 position. Bioorg. Med. Chem. 2007, 15, 1475–1482. [Google Scholar] [CrossRef]
  252. Inaba, Y.; Yamamoto, K.; Yoshimoto, N.; Matsunawa, M.; Uno, S.; Yamada, S.; Makishima, M. Vitamin D3 derivatives with adamantane or lactone ring side chains are cell type-selective vitamin D receptor modulators. Mol. Pharm. 2007, 71, 1298–1311. [Google Scholar] [CrossRef]
  253. Chiellini, G.; Grzywack, P.; Plum, L.A.; Barycki, R.; Clagett-Dame, M.; DeLuca, H.F. Synthesis and biological properties of 2-methylene-19-nor-25-dehydro-1α-hydroxyvitamin D3-26,26-lactones-weak agonists. Bioorg. Med. Chem. 2008, 16, 8563–8573. [Google Scholar] [CrossRef] [Green Version]
  254. Takaku, H.; Miyamoto, Y.; Asami, S.; Shimazaki, M.; Yamada, S.; Yamamoto, K.; Udagawa, N.; DeLuca, H.F.; Shimizu, M. Synthesis and structure-activity relationships of 16-ene-22-thia-1α,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs having side chains of different sizes. Bioorg. Med. Chem. 2008, 16, 1796–1815. [Google Scholar] [CrossRef]
  255. Shimizu, M.; Miyamoto, Y.; Takaku, H.; Matsuo, M.; Nakabayashi, M.; Masuno, H.; Udagawa, N.; DeLuca, H.F.; Ikura, T.; Ito, N. 2-Substituted-16-ene-22-thia-1α,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs: Synthesis, biological evaluation and crystal structure. Bioorg. Med. Chem. 2008, 16, 6949–6964. [Google Scholar] [CrossRef] [PubMed]
  256. Sánchez-Abella, L.; Fernández, S.; Verstuyf, A.; Verlinden, L.; Gotor, V. Synthesis and biological activity of previtamin D3 analogues with A-ring modifications. Bioorg. Med. Chem. 2008, 16, 10244–10250. [Google Scholar] [CrossRef] [PubMed]
  257. Nakabayashi, M.; Yamada, S.; Yoshimoto, N.; Tanaka, T.; Igarashi, M.; Ikura, T.; Ito, N.; Makishima, M.; Tokiwa, H.; DeLuca, H.F.; et al. Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs: Structural basis for vitamin D receptor antagonism and partial agonism. J. Med. Chem. 2008, 51, 5320–5329. [Google Scholar] [CrossRef] [PubMed]
  258. Hourai, S.; Rodrigues, L.C.; Antony, P.; Reina-San-Martin, B.; Ciesielski, F.; Magnier, B.C.; Schoonjans, K.; Mouriño, A.; Rochel, N.; Moras, D. Structure-based design of a superagonist ligand for the vitamin D nuclear receptor. Chem. Biol. 2008, 15, 383–392. [Google Scholar] [CrossRef] [PubMed]
  259. Saito, T.; Okamoto, R.; Haritunians, T.; O’Kelly, J.; Uskokovic, M.; Maehr, H.; Marczak, S.; Jankowski, P.; Badr, R.; Koeffler, H.P. Novel Gemini vitamin D3 analogs have potent antitumor activity. J. St. Biochem. Mol. Biol. 2008, 112, 151–156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  260. Williams, K.B.; DeLuca, H.F. 2-Methylene-19-nor-20(S)-1α-hydroxy-bishomopregnacalciferol [(20S)-2MbisP], an analog of vitamin D3 [1,25(OH)2D3], does not stimulate intestinal phosphate absorption at levels previously shown to suppress parathyroid hormone. Steroids 2008, 73, 1277–1284. [Google Scholar] [CrossRef]
  261. Usera, A.R.; Dolan, P.; Kensler, T.W.; Posner, G.H. Novel alkyl chain sulfone 1α,25-dihydroxyvitamin D3 analogs: A comparison of in vitro antiproliferative and in vivo calcemic activities. Bioorg. Med. Chem. 2009, 17, 5627–5631. [Google Scholar] [CrossRef] [Green Version]
  262. Plonska-Ocypa, K.; Sicinski, R.R.; Plum, L.A.; Grzywacz, P.; Frelek, J.; Clagett-Dame, M.; DeLuca, H.F. 13-Methyl-substituted des-CD analogs of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (2MD): Synthesis and biological evaluation. Bioorg. Med. Chem. 2009, 17, 1747–1763. [Google Scholar] [CrossRef]
  263. Barycki, R.; Sicinski, R.R.; Plum, L.A.; Grzywacz, P.; Clagett-Dame, M.; DeLuca, H.F. Removal of the 20-methyl group from 2-methylene-19-nor-20(S)-1α-hydroxyvitamin D3 (2MD) selectively eliminates bone calcium mobilization activity. Bioorg. Med. Chem. 2009, 17, 7658–7669. [Google Scholar] [CrossRef] [Green Version]
  264. Inaba, Y.; Yoshimoto, N.; Sakamaki, N.; Nakabayashi, T.; Ikura, T.; Tamamura, H.; Ito, N.; Shimizu, M.; Yamamoto, K. A new class of vitamin D analogues that induce structural rearrangement of the ligand-binding pocket of the receptor. J. Med. Chem. 2009, 52, 1438–1449. [Google Scholar] [CrossRef]
  265. Laverny, G.; Penna, G.; Uskokovic, M.; Marczak, S.; Maehr, H.; Jankowski, P.; Ceailles, C.; Vouros, P.; Smith, B.; Robinson, M.; et al. Synthesis and anti-inflammatory properties of 1α,25-dihydroxy-16-ene-20-cyclopropyl-24-oxovitamin D3, a hypocalcemic, stable metabolite of 1α,25-dihydroxy-16-ene-20-cyclopropylvitamin D3. J. Med. Chem. 2009, 52, 2204–2213. [Google Scholar] [CrossRef] [PubMed]
  266. Sánchez-Abella, L.; Fernández, S.; Verstuyf, A.; Verlinden, L.; Gotor, V.; Ferrero, M. Synthesis, conformational analysis and biological evaluation of 19-nor-vitamin D3 analogues with A-ring modifications. J. Med. Chem. 2009, 52, 6158–6162. [Google Scholar] [CrossRef] [PubMed]
  267. Minne, G.; Verlinden, L.; Verstuyf, A.; De Clercq, P.J. Synthesis of 1α,25-dihydroxyvitamin D analogues featuring a S2-symmetric CD-ring core. Molecules 2009, 14, 894–903. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  268. De Brysser, F.; Verlinden, L.; Verstuyf, A.; De Clercq, P.J. Synthesis of 22-oxaspiro[4.5]decane CD-ring modified analogs of 1α,25-dihydroxyvitamin D3. Tet. Lett. 2009, 50, 4174–4177. [Google Scholar] [CrossRef]
  269. Gándara, Z.; Pérez, M.; Pérez-García, X.; Gómez, G.; Fall, Y. Stereoselective synthesis of (22Z)-25-hydroxyvitamin D2 and (22Z)-1α,25-dihydroxyvitamin D2. Tet. Lett. 2009, 50, 4874–4877. [Google Scholar] [CrossRef]
  270. Lambin, M.; Dabbas, B.; Spingarn, R.; Mendoza-Sanchez, R.; Wang, T.-T.; An, B.-S.; Huang, D.C.; Kremer, R.; White, J.H.; Gleason, J.L. Vitamin D receptor agonist/histone deacetylase inhibitor molecular hybrids. Bioorg. Med. Chem. 2010, 18, 4119–4137. [Google Scholar] [CrossRef]
  271. Honzawa, S.; Takahashi, N.; Yamashita, A.; Sugiura, T.; Kurihara, M.; Arai, M.A.; Kato, S.; Kittaka, A. Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D3: Interaction with the mutant vitamin D receptor Arg274Leu. Tetahedron 2009, 65, 7135–7147. [Google Scholar] [CrossRef]
  272. Ben Shabat, S.; Sintov, A. Substituted Cyclohexylidene-Ethylidene-Octahydro-Indene Compounds. World Patent Organization. WO2009153782 A1, 23 December 2009. [Google Scholar]
  273. Maehr, H.; Lee, H.J.; Perry, B.; Suh, N.; Uskokovic, M.R. Calcitriol derivatives with two different side chain at C-20. V. Potent inhibitors of mammary carcinogenesis and inducers of leukemia differentiation. J. Med. Chem. 2009, 52, 5505–5519. [Google Scholar] [CrossRef]
  274. Gogoi, P.; Sigüeiro, R.; Eduardo, S.; Mouriño, A. An expeditious route to 1α,25-dihydroxyvitamin D3 and its analogues by an aqueous tandem palladium-catalyzed A-ring closure and Suzuki coupling to the C/D unit. Chem. Eur. J. 2010, 16, 1432–1435. [Google Scholar] [CrossRef]
  275. Sakamaki, Y.; Inaba, Y.; Yoshimoto, N.; Yamamoto, K. Potent antagonist for the vitamin D receptor: Vitamin D analogues with simple side chain structure. J. Med. Chem. 2010, 53, 5813–5826. [Google Scholar] [CrossRef]
  276. Yoshino, M.; Eto, K.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.; Ono, Y.; Saito, H.; Kubodera, N. Synthesis of 20-epi-eldecalcitol [20-epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-epi-ED-71]. Heterocycles 2010, 81, 381–394. [Google Scholar] [CrossRef]
  277. Grzywacz, P.; Chiellini, G.; Plum, L.A.; Clagett-Dame, M.; DeLuca, H.F. Removal of the 26-methyl group from 2-methylene-19-nor-1α,25-dihydroxyvitamin D3 markely reduces in vivo calcemic activity without altering in vitro VDR binding, HL-60 cell differentiation, and transcription. J. Med. Chem. 2010, 53, 8642–8649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  278. Antony, P.; Sigüeiro, R.; Huet, T.; Sato, Y.; Ramalanjaona, N.; Rodrigues, L.C.; Mouriño, A.; Rochel, N.; Moras, D. Structure-function relationships and crystal structures of the vitamin D receptor bound 2α-methyl-(20S,23R)- and 2α-methyl-(20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D3. J. Med. Chem. 2010, 53, 1159–1171. [Google Scholar] [CrossRef] [PubMed]
  279. Sawada, D.; Tsukuda, Y.; Saito, H.; Takagi, K.-i.; Ochiai, E.; Ishizuka, S.; Takenouchi, K.; Kittaka, A. Synthesis of 2β-substituted-14-epi-previtamin D3 and testing its genomic activity. J. St. Biochem. Mol. Biol. 2010, 121, 20–24. [Google Scholar] [CrossRef]
  280. Sokolowska, K.; Mouriño, A.; Sicinski, R.R.; Sigüeiro, R.; Plum, L.A.; DeLuca, H.F. Synthesis and biological evaluation of 6-methyl analog of 1α,25-dihydroxyvitamin D3. J. St. Biochem. Mol. Biol. 2010, 121, 29–33. [Google Scholar] [CrossRef]
  281. Glebocka, A.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F. New 1α,25-dihydroxy-19-nor-vitamin D3 analogs with frozen A-ring conformation. J. St. Biochem. Mol. Biol. 2010, 121, 46–50. [Google Scholar] [CrossRef]
  282. Sibilska, I.; Barycka, K.M.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F. 1-Desoxy analog of 2MD: (20S)-25-hydroxy-2-methylene-19-norvitamin D3. J. St. Biochem. Mol. Biol. 2010, 121, 51–55. [Google Scholar] [CrossRef]
  283. Sawada, D.; Katayama, T.; Tsukuda, Y.; Yamashita, A.; Saito, N.; Saito, H.; Takagi, K.-i.; Ochiai, E.; Ishizuka, S.; Takenouchi, K.; et al. Synthesis of 2α-and 2β-substituted-14-epi-previtamin D3 and their genomic activity. Tetrahedron 2010, 66, 5407–5423. [Google Scholar] [CrossRef]
  284. Glebocka, A.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F. Synthesis and biological activity of 2-(3’-hydroxypropylidene)-1α-hydroxy-19-norvitamin D analogues with shortened alkyl side chains. J. Med. Chem. 2011, 54, 6832–6842. [Google Scholar] [CrossRef]
  285. Kashiwagi, H.; Ono, Y.; Shimizu, K.; Haneishi, T.; Ito, T.; Iijima, S.; Kobayashi, T.; Ichikawa, T.; Harada, S.; Sato, H.; et al. Novel nonsecosteroidal vitamin D3 carboxylic acid analogs for osteoporosis and SAR analysis. Bioorg. Med. Chem. 2011, 19, 4721–4729. [Google Scholar] [CrossRef]
  286. Fujii, S.; Masuno, H.; Taoda, Y.; Kano, A.; Wongmayura, A.; Nakabayashi, M.; Ito, N.; Shimizu, M.; Kawachi, E.; Hirano, T.; et al. Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands: Direct observation of hydrophobic interaction between protein surface and carborane. J. Am. Chem. Soc. 2011, 133, 20933–20941. [Google Scholar] [CrossRef] [PubMed]
  287. Verlinden, L.; Verstuyf, A.; Eelen, G.; Bouillon, R.; Ordóñez-Morán, P.; Larriba, M.J.; Muñoz, A.; Rochel, N.; Sato, Y.; Moras, D.; et al. Synthesis, structure, and biological activity of des-side chain analogues of 1α,25-dihydroxyvitamin D3 with substituents at C18. ChemMedChem 2011, 6, 788–793. [Google Scholar] [CrossRef] [PubMed]
  288. Sawada, D.; Tsukuda, Y.; Saito, H.; Takimoto-Kamimura, M.; Ochiai, E.; Ishizuka, S.; Takenouchi, K.; Kittaka, A. Development of 14-epi-19-nortachysterol and its unprecedented binding configuration for the human vitamin D receptor. J. Am. Chem. Soc. 2011, 133, 7215–7221. [Google Scholar] [CrossRef] [PubMed]
  289. Regueira, M.A.; Samanta, S.; Malloy, P.J.; Ordóñez-Morán, P.; Resende, D.; Sussman, F.; Muñoz, A.; Mouriño, A.; Feldman, D.; Torneiro, M. Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D3 analogues hydroxymethylated at C26. J. Med. Chem. 2011, 54, 3950–3962. [Google Scholar] [CrossRef] [PubMed]
  290. Salomón, D.G.; Grioli, S.M.; Buschiazzo, M.; Mascaró, E.; Vitale, C.; Radivoy, G.; Perez, M.; Fall, Y.; Mesri, E.A.; Curino, A.C.; et al. Novel alkynylphospate analogue of calcitriol with potent antiproliferative effects in cancer cells and lack of calcemic activity. ACS Med. Chem. Lett. 2011, 2, 503–508. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  291. Saito, H.; Chida, T.; Takagi, K.; Horie, K.; Sawai, Y.; Nakamura, Y.; Harada, Y.; Takenouchi, K.; Kittaka, A. Synthesis of C-2 substituted vitamin D derivatives having ringed side chains and their biological evaluation, especially biological effect on bone by modification at the C-2 poistion. Org. Biomol. Chem. 2011, 9, 3954–3964. [Google Scholar] [CrossRef]
  292. Shindo, K.; Kumagai, G.; Takano, M.; Sawada, D.; Saito, N.; Saito, H.; Kakuda, S.; Takagi, K.-i.; Ochiai, E.; Horie, K.; et al. New C15-substituted active vitamin D3. Org. Lett. 2011, 13, 2852–2855. [Google Scholar] [CrossRef]
  293. Molnár, F.; Sigüeiro, R.; Sato, Y.; Araujo, C.; Schuster, I.; Antony, P.; Peluso, J.; Muller, C.; Mouriño, A.; Moras, D.; et al. 1α,25-(OH)2-3-epi-vitamin D3, a natural metabolite of vitamin D3: Its synthesis, biological activity and crystal structure with its receptor. PLoS ONE 2011, 6, e19124. [Google Scholar] [CrossRef]
  294. Wongmayura, A.; Fujii, S.; Ito, S.; Kano, A.; Taoda, Y.; Kawachi, E.; Kagechika, H.; Tanatani, A. Novel vitamin D receptor ligands bearing a spherical hydrophobic core structure-comparison of bicyclic hydrocarbon derivatives with boron cluster derivatives. Bioorg. Med. Chem. Lett. 2012, 22, 1756–1760. [Google Scholar] [CrossRef]
  295. Fischer, J.; Wang, T.-T.; Kaldre, D.; Rochel, N.; Moras, D.; White, J.H.; Gleason, J.L. Synthetically accessible non-secosteroidal hybrid molecules combining vitamin D receptor agonism and histone deacetylase inhibition. Chem. Biol. 2012, 19, 963–971. [Google Scholar] [CrossRef] [Green Version]
  296. Fraga, R.; Zacconi, F.; Sussman, F.; Ordóñez-Morán, P.; Muñoz, A.; Huet, T.; Molnar, F.; Moras, D.; Rochel, N.; Maestro, M.; et al. Design, synthesis, evaluation, and structure of vitamin D analogues with furan side chains. Chem. Eur. J. 2012, 18, 603–612. [Google Scholar] [CrossRef] [PubMed]
  297. Sawada, D.; Tsukuda, Y.; Yasuda, K.; Sakaki, T.; Saito, H.; Kakuda, S.; Takagi, K.-i.; Takenouchi, K.; Chen, T.C.; Reddy, G.S.; et al. Synthesis and biological activities of 1α,4α,25- and 1α,4β,25-trihydroxyvitamin D3 and their metabolism by human CYP24A1 and UDP-glucuronosyltransferase. Chem. Pharm. Bull. 2012, 60, 1343–1346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  298. Sikervar, V.; Fleet, J.C.; Fuchs, P.L. A general approach to the synthesis of enantiopure 19-nor-vitamin D3 and its C-2 phosphate analogs prepared from cyclohexadienyl sulfone. Chem. Comm. 2012, 48, 9077–9079. [Google Scholar] [CrossRef] [PubMed]
  299. Carballa, D.M.; Rumbo, A.; Torneiro, M.; Maestro, M.; Mouriño, A. Synthesis of (1α)-1,25-dihydroxyvitamin D3 with a β-postioned seven-carbon side chain at C(12). Helv. Chim. Acta 2012, 95, 1842–1850. [Google Scholar] [CrossRef]
  300. Flores, A.; Sicinski, R.R.; Grzywacz, P.; Thoden, J.B.; Plum, L.A.; Clagett-Dame, M.; DeLuca, H.F. A 20S Combined with 22R configuration markedly increases both in vivo and in vitro biological activity of 1α,25-dihydroxy-22-methyl-2-methylene-19-norvitamin D3. J. Med. Chem. 2012, 55, 4352–4366. [Google Scholar] [CrossRef] [Green Version]
  301. Carballa, D.M.; Seoane, S.; Zacconi, F.; Pérez, X.; Rumbo, A.; Álvarez-Díaz, S.; Larriba, M.J.; Pérez-Fernández, R.; Muñoz, A.; Maestro, M.; et al. Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D3 analogues with a long side chain at C12 and short C17 side chains. J. Med. Chem. 2012, 55, 8642–8656. [Google Scholar] [CrossRef]
  302. Lu, Y.; Chen, J.; Janjetovic, Z.; Michaels, P.; Tang, E.K.Y.; Wang, J.; Tuckey, R.; Slominski, A.T.; Li, W.; Miller, D.D. Design, synthesis, and biological action of (20R)-hydroxyvitamin D3. J. Med. Chem. 2012, 55, 3573–3577. [Google Scholar] [CrossRef] [Green Version]
  303. Yoshimoto, N.; Sakamaki, Y.; Haeta, M.; Kato, A.; Inaba, Y.; Itoh, T.; Nakabayashi, M.; Itoh, N.; Yamamoto, K. Butyl pocket formation in the vitamin D receptor strongly affects the agonistic or antagonistic behavior of ligands. J. Med. Chem. 2012, 55, 4373–4381. [Google Scholar] [CrossRef]
  304. Sikervar, V.; Fleet, J.C.; Fuchs, P.L. Fluoride-mediated elimination of allyl sulfones: Application to the synthesis of a 2,4-dimethyl-A-ring vitamin D3 analogue. J. Org. Chem. 2012, 77, 5132–5138. [Google Scholar] [CrossRef]
  305. Ciesielski, F.; Sato, Y.; Chebaro, Y.; Moras, D.; Dejaegere, A.; Rochel, N. Structural basis for the accommodation of bis- and tris-aromatic derivatives in vitamin D nuclear receptor. J. Med. Chem. 2012, 55, 8440–8449. [Google Scholar] [CrossRef]
  306. Chen, B.; Kawai, M.; Wu-Wong, R. Synthesis of VS-105: A novel and potent vitamin receptor agonist with reduced hypercalcemic effects. Bioorg. Med. Chem. Lett. 2013, 23, 5949–5952. [Google Scholar] [CrossRef] [PubMed]
  307. Milczarek, M.; Chodynski, M.; Filip-Psurska, B.; Martowicz, A.; Krup, M.; Krajewski, K.; Kutner, A.; Wietrzyk, J. Synthesis and biological activity of diastereomeric and geometric analogs of calcipotriol, PRI-2202 and PRI-2205, against human HL-60 leukemia and MCF-7 breast cancer cells. Cancers 2013, 5, 1355–1378. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  308. Kashiwagi, H.; Ono, Y.; Ohta, M.; Itoh, S.; Ichikawa, F.; Harada, S.; Takeda, S.; Sekiguchi, N.; Ishigai, M.; Takahashi, T. A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy. Bioorg. Med. Chem. 2013, 21, 1823–1833. [Google Scholar] [CrossRef] [PubMed]
  309. Kashiwagi, H.; Ohta, M.; Ono, Y.; Morikami, K.; Itoh, S.; Sato, H.; Takahashi, T. Effects of fluorines on nonsecosteroidal vitamin D receptor agonists. Bioorg. Med. Chem. 2013, 21, 712–721. [Google Scholar] [CrossRef]
  310. Sibilska, I.S.; Szybinski, M.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F. Highly potent 2-methylene analogs of 1α,25-dihydroxyvitamin D3: Synthesis and biological evaluation. J. St. Biochem. Mol. Biol. 2013, 136, 9–13. [Google Scholar] [CrossRef]
  311. Sibilska, I.S.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F. Synthesis and biological activity of 25-hydroxy-2-methylene-vitamin D3 compounds. J. St. Biochem. Mol. Biol. 2013, 136, 17–22. [Google Scholar] [CrossRef]
  312. Kulezka, U.; Mouriño, A.; Plum, L.A.; DeLuca, H.F.; Sicinski, R.R. Synthesis of 19-norvitamin D3 analogs with unnatural triene system. J. St. Biochem. Mol. Biol. 2013, 136, 23–26. [Google Scholar] [CrossRef]
  313. Sokolowska, K.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F.; Mouriño, A. Synthesis and biological evaluation of novel 6-substituted analogs of 1α,25-dihydroxy-19-norvitamin D3. J. St. Biochem. Mol. Biol. 2013, 136, 30–33. [Google Scholar] [CrossRef]
  314. Glebocka, A.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F. Ring-A-seco analogs of 1α,25-dihydroxy-19-norvitamin D3. J. St. Biochem. Mol. Biol. 2013, 136, 39–43. [Google Scholar] [CrossRef] [Green Version]
  315. Yamada, S.; Makishima, M. Structure-activity relationship of nonsecoesteroidal vitamin D receptor modulators. Trends Phar. Sci. 2014, 35, 324–337. [Google Scholar] [CrossRef]
  316. Ferla, S.; Aboraia, A.S.; Brancale, A.; Pepper, C.J.; Zhu, J.; Ochalek, J.T.; DeLuca, H.F.; Simons, C. Small-molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): Synthesis and biological evaluation. J. Med. Chem. 2014, 57, 7702–7715. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  317. Fujii, S.; Kano, A.; Songkram, C.; Masuno, H.; Taoda, Y.; Kawachi, E.; Hirano, T.; Tanatani, A.; Kagechika, H. Synthesis and structure-activity relationship of p-carborane-based non-secosteroidal vitamin D analogs. Bioorg. Med. Chem. 2014, 22, 1227–1235. [Google Scholar] [CrossRef] [PubMed]
  318. Kudo, T.; Ishizawa, M.; Maekawa, K.; Nakabayashi, M.; Watari, Y.; Uchida, H.; Tokiwa, H.; Ikura, T.; Ito, N.; Makishima, M.; et al. Combination of triple bond and adamantane ring on the vitamin D side chain produced partial agonists for vitamin D receptor. J. Med. Chem. 2014, 57, 4073–4087. [Google Scholar] [CrossRef] [PubMed]
  319. Liu, C.; Zhao, G.-D.; Mao, X.; Suenaga, T.; Fujishima, T.; Zhang, C.-M.; Liu, Z.-P. Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D3 analogues with aromatic side chains attached at C-17. Eur. J. Med. Chem. 2014, 85, 569–575. [Google Scholar] [CrossRef]
  320. Okamoto, R.; Gery, S.; Kuwayama, Y.; Borregaard, N.; Ho, Q.; Alvarez, R.; Akagi, T.; Liu, G.Y.; Uskokovic, M.R.; Koeffler, H.P. Novel Gemini vitamin D3 analogs: Large structure/function analysis and ability to induce antimicrobial peptide. Int. J. Cancer 2014, 134, 207–217. [Google Scholar] [CrossRef]
  321. Thomas, E.; Brion, J.-D.; Peyrat, J.-F. Synthesis and preliminary biological evaluation of new antiproliferative aromatic analogues of 1α,25-dihydroxyvitamin D3. Eur. J. Med. Chem. 2014, 86, 381–393. [Google Scholar] [CrossRef]
  322. Takano, M.; Ohya, S.; Yasuda, K.; Nishikawa, M.; Takeguchi, A.; Sawada, D.; Sakaki, T.; Kittaka, A. Synthesis and biological activity of 1α,2α,25-trihydroxyvitamin D3; active metabolite of 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by human CYP3A4. Chem. Pharm. Bull. 2014, 62, 182–184. [Google Scholar] [CrossRef] [Green Version]
  323. Anami, Y.; Itoh, T.; Egawa, D.; Oshimoto, N.; Yamamoto, K. A mixed population of antagonist and agonist binding conformers in a single crystal explains partial agonism against vitamin D receptor: Active vitamin D analogues with 22R-alkyl group. J. Med. Chem. 2014, 57, 4351–4367. [Google Scholar] [CrossRef] [PubMed]
  324. Sibilska, I.S.; Sicinski, R.R.; Ochalek, J.T.; Plum, L.A.; DeLuca, H.F. Synthesis and biological activity of 25-hydroxy-2-methylene-vitamin D3 analogues monohydroxylated in the A-ring. J. Med. Chem. 2014, 57, 8319–8331. [Google Scholar] [CrossRef]
  325. Sigüeiro, R.; Álvarez, A.; Otero, R.; López-Pérez, B.; Carballa, D.; Regueira, T.; González-Berdullas, P.; Seoane, S.; Pérez-Fernández, R.; Mouriño, A.; et al. Synthesis of nonadeuterated 1α,25-dihydroxyvitamin D2. J. St. Biochem. Mol. Biol. 2014, 144, 204–206. [Google Scholar] [CrossRef]
  326. Meyer, D.; Rentsch, L.; Marti, R. Effcient and scalable total synthesis of calcitroic acid and its 13C-labeled derivative. RSC Adv. 2014, 4, 32327–32334. [Google Scholar] [CrossRef]
  327. Banerjee, U.; DeBerardinis, A.M.; Hadden, M.K. Design, synthesis and evaluation of hybrid vitamin D3 side chain analogues as hedgehog pathway inhibitors. Bioorg. Med. Chem. 2015, 23, 548–555. [Google Scholar] [CrossRef] [PubMed]
  328. Anami, Y.; Sakamaki, Y.; Itoh, T.; Inaba, Y.; Nakabayashi, M.; Ikura, T.; Ito, N.; Yamamoto, K. Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-hexyl compound unexpectedly restored agonistic activity. Bioorg. Med. Chem. 2015, 23, 7274–7281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  329. Trynda, J.; Turlej, E.; Milczarek, M.; Pietraszek, A.; Chodynski, M.; Kutner, A.; Wietrzyk, J. Antiproliferative activity and in vivo toxicity of double-point modified analogs of 1,25-dihydroxyergocalciferol. Int. J. Mol. Sci. 2015, 16, 24873–24894. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  330. Misawa, T.; Yorioka, M.; Demizu, Y.; Noguchi-Yachide, T.; Ohoka, N.; Kurashima-Kinoshita, M.; Motoyoshi, H.; Nojiri, H.; Kittaka, A.; Makishima, M.; et al. Effects of the alkyl side chains and terminal hydrophilicity on vitamin D receptor (VDR) agonist activity based on the diphenylpentane skeleton. Bioorg. Med. Chem. Lett. 2015, 25, 5362–5366. [Google Scholar] [CrossRef]
  331. Kulesza, U.; Plum, L.A.; DeLuca, H.F.; Mouriño, A.; Sicinski, R.R. Novel 9-alkyl and 9-alkylidene-substituted 1α,25-dihydroxyvitamin D3 analogues: Synthesis and biological examinations. J. Med. Chem. 2015, 58, 6237–6247. [Google Scholar] [CrossRef]
  332. Lin, Z.; Marepally, S.R.; Ma, D.; Myers, L.; Postlethwaite, A.E.; Tuckey, R.C.; Chen, C.Y.S.; Kim, T.-K.; Yue, J.; Slominski, A.T.; et al. Chemical synthesis and biological activities of 20,24S/R-dihydroxyvitamin D3 epimers and their 1α-hydroxyl derivatives. J. Med. Chem. 2015, 58, 7881–7887. [Google Scholar] [CrossRef] [Green Version]
  333. Sibilska, I.K.; Szybinski, M.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F. Synthesis and biological activity of active 2-methylene analogues of calcitriol and related compounds. J. Med. Chem. 2015, 58, 9653–9662. [Google Scholar] [CrossRef]
  334. Sokolowska, K.; Carballa, D.; Seoane, S.; Pérez-Fernández, R.; Mouriño, A.; Sicinski, R.R. Synthesis and biological activity of two C-7 methyl analogs of vitamin D. J. Org. Chem. 2015, 80, 165–173. [Google Scholar] [CrossRef]
  335. Saitoh, H.; Watanabe, H.; Kakuda, S.; Takimoto-Kamimura, M.; Takagi, K.; Takeuchi, A.; Takenouchi, K. Synthesis and biological activity of vitamin D3 derivatives with cyanoalkyl side chain at C-2 position. J. St. Biochem. Mol. Biol. 2015, 148, 27–30. [Google Scholar] [CrossRef]
  336. Takano, M.; Sawada, D.; Yasuda, K.; Nishikawa, M.; Takeuchi, A.; Takagi, K.-i.; Horie, K.; Reddy, G.S.; Chen, T.C.; Sakaki, T.; et al. Synthesis and metabolic studies of 1α,2α,25-, 1α,4α,25- and 1α,4β,25-trihydroxyvitamin D3. J. St. Biochem. Mol. Biol. 2015, 148, 34–37. [Google Scholar] [CrossRef] [PubMed]
  337. Ferronato, M.J.; Salomón, D.G.; Fermento, M.E.; Gandini, N.A.; López Romero, A.; Rivadulla, M.L.; Pérez-García, X.; Gómez, G.; Pérez, M.; Fall, Y.; et al. Vitamin D analogue: Potent antiproliferative effects on cancer cell lines and lack of hypercalcemic activity. Arch. Pharm. Chem. Life Sci. 2015, 348, 315–329. [Google Scholar] [CrossRef] [PubMed]
  338. Biswas, T.; Akagi, Y.; Usuda, K.; Yasui, K.; Shimizu, I.; Okamoto, M.; Uesugi, M.; Hosokawa, S.; Nagasawa, K. Synthesis of 24,24-difluoro-1,3-cis-25-hydroxy-19-norvitamin D3 derivatives and evaluation of their vitamin D receptor-binding affinity. Biol. Pharm. Bull. 2016, 39, 1387–1391. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  339. Usuda, K.; Biswas, T.; Akagi, Y.; Yasui, K.; Uesugi, M.; Shimizu, I.; Hosokawa, S.; Nagasawa, K. Synthesis of diastereomers of 1,3-cis-25-hydroxy-19-norvitamin D3. Chem. Pharm. Bull. 2016, 64, 1190–1195. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  340. Otero, R.; Seoane, S.; Sigüeiro, R.; Belorusova, A.Y.; Maestro, M.A.; Pérez-Fernández, R.; Rochel, N.; Mouriño, A. Carborane-based design of a potent vitamin D receptor agonist. Chem. Sci. 2016, 7, 1033–1037. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  341. Nijenhuis, T.; van der Eerden, B.; Zügel, U.; Steinmeyer, A.; Weinans, H.; Hoenderop, J.G.J.; van Leeuwen, J.P.T.M.; Bindels, R.J.M. The novel vitamin D analog ZK191784 as an intestine-specific vitamin D antagonist. FASEB J. 2016, 20, 2171–2173. [Google Scholar] [CrossRef]
  342. Lin, Z.; Marepally, S.R.; Ma, D.; Kim, T.-K.; Oak, A.S.W.; Myers, L.; Tuckey, R.C.; Slominski, A.T.; Miller, D.D.; Li, W. Synthesis and biological evaluation of vitamin D3 metabolite 20,23S-dihydroxyvitamin D3 and its 23R epimer. J. Med. Chem. 2016, 59, 5102–5108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  343. Bolla, N.R.; Corcoran, A.; Yasuda, K.; Chodynski, M.; Krajewski, K.; Cmoch, P.; Marcinkowska, E.; Brown, G.; Sakaki, T.; Kutner, A. Synthesis and evaluation of geometric analogs of 1α,25-dihydroxyvitamin D2 as potential therapeutics. J. St. Biochem. Mol. Biol. 2016, 164, 50–55. [Google Scholar] [CrossRef]
  344. Loureiro, J.; Maestro, M.A.; Mouriño, A.; Sigüeiro, R. Stereoselective synthesis of 1β,25-dihydroxyvitamin D3 and its 26,27-hexadeuterated derivative. J. St. Biochem. Mol. Biol. 2016, 164, 56–58. [Google Scholar] [CrossRef]
  345. Ahmad, M.I.; Raghuvanshi, D.S.; Singh, S.; John, A.A.; Prakash, R.; Nainwat, K.S.; Singh, D.; Tripathi, S.; Sharma, A.; Gupta, A. Design and synthesis of 3-arylbenzopyran based non-steroidal vitamin D3 mimics as osteogenic agents. Med. Chem. Commun. 2016, 7, 2381–2394. [Google Scholar] [CrossRef]
  346. Sawada, D.; Kakuda, S.; Kamimura-Takimoto, M.; Takeuchi, A.; Matsumoto, Y.; Kittaka, A. Revisiting the 7,8-cis-vitamin D3 derivatives: Synthesis, evaluating the biological activity, and study of the binding configuration. Tetrahedron 2016, 72, 2838–2848. [Google Scholar] [CrossRef]
  347. Kittaka, A.; Takano, M.; Saitoh, H. Vitamin D analogs with nitrogen atom at C2 substitution and effect on bone formation. Vitam. Horm. 2016, 100, 379–394. [Google Scholar] [CrossRef] [PubMed]
  348. Sawada, D.; Ochiai, E.; Takeuchi, A.; Kakuda, S.; Kamimura-Takimoto, M.; Kawagoe, F.; Kittaka, A. Synthesis of 2α- and 2β-(3-hydroxypropyl)-7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3 and their biological activity. J. St. Biochem. Mol. Biol. 2017, 173, 79–82. [Google Scholar] [CrossRef]
  349. Suenaga, T.; Nozaki, T.; Fujishima, T. Synthesis of novel vitamin D3 analogues having a spiro-oxetane structure. Vitamins 2016, 90, 109–114. [Google Scholar]
  350. Hernández-Martín, A.; Fernández, S.; Verstuyf, A.; Verlinden, L.; Ferrero, M. A-Ring-modified 2-hydroxyethylidene previtamin D3 analogues: Synthesis and biological evaluation. Eur. J. Org. Chem. 2017, 2017, 504–513. [Google Scholar] [CrossRef]
  351. Chiellini, G.; Rapposelli, S.; Nesi, G.; Sestito, S.; Sabatini, M.; Zhu, J.; Massarelli, I.; Plum, L.A.; Clagett-Dame, M.; DeLuca, H.F. Synthesis and biological evaluation of cyclopropylamine vitamin D-like CYP24A1 inhibitors. ChemistrySelect 2017, 2, 8346–8353. [Google Scholar] [CrossRef]
  352. Szybinski, M.; Brzeminski, P.; Fabisiak, A.; Berkowska, K.; Marcinkowska, E.; Sicinski, R.R. Seco-B-ring steroidal dienynes with aromatic D ring: Design, synthesis and biological evaluation. Int. J. Mol. Sci. 2017, 18, 2162–2176. [Google Scholar] [CrossRef] [Green Version]
  353. Kato, A.; Yamao, M.; Hashihara, Y.; Ishida, H.; Toh, T.; Yamamoto, K. Vitamin D analogues with a p-hydroxyphenyl group at C25 position: Crystal structure of vitamin D receptor ligand-binding domain complexed with the ligand explains the mechanism underlying full antagonistic action. J. Med. Chem. 2017, 60, 8394–8406. [Google Scholar] [CrossRef]
  354. Szybinski, M.; Sokolowska, K.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F. D-seco-Vitamin D analogs having reversed configurations at C-13 and C-14: Synthesis, dockings studies and biological evaluation. J. St. Biochem. Mol. Biol. 2017, 173, 57–63. [Google Scholar] [CrossRef]
  355. Szybinski, M.; Sektas, K.; Sicinski, R.R.; Plum, L.A.; Frelek, J.; DeLuca, H.F. Design, synthesis and biological properties of seco-D-ring modified 1α,25-dihydroxyvitamin D3 analogues. J. St. Biochem. Mol. Biol. 2017, 171, 144–154. [Google Scholar] [CrossRef]
  356. Kattner, L.; Bernardi, D. An efficient synthesis of 1α,25-dihydroxyvitamin D3 LC-biotin. J. St. Biochem. Mol. Biol. 2017, 173, 89–92. [Google Scholar] [CrossRef] [PubMed]
  357. Vinhas, S.; Vázquez, S.; Rodríguez-Borges, J.E.; Sigüeiro, R. A convergent approach to the side-chain homologated of 1α,25-dihydroxyergocalciferol. J. St. Biochem. Mol. Biol. 2017, 173, 83–85. [Google Scholar] [CrossRef] [PubMed]
  358. Kang, Z.-S.; Wang, C.; Han, X.-L.; Du, J.-J.; Li, Y.-Y.; Zhang, C. Design, synthesis and biological evaluation of non-secosteroidal vitamin D receptor ligand bearing double side chain for the treatment of chronic pancreatitis. Eur. J. Med. Chem. 2018, 146, 541–553. [Google Scholar] [CrossRef]
  359. Kang, Z.-S.; Wang, C.; Han, X.-L.; Wang, B.; Yuan, H.-L.; Hao, M.; Hou, S.-Y.; Hao, M.-X.; Du, J.-J.; Li, Y.-Y.; et al. Sulfonyl-containing phenyl-pyrrolyl pentane analogues: Novel non-secosteroidal vitamin D receptor modulators with favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity. Eur. J. Med. Chem. 2018, 157, 1174–1191. [Google Scholar] [CrossRef] [PubMed]
  360. Hao, M.; Hou, S.; Xue, L.; Yuan, H.; Zhu, L.; Wang, C.; Wang, B.; Tang, C.; Zhang, C. Further developments of the phenyl-pyrrolyl pentane series of nonsteroidal vitamin D receptor modulators as anticancer agents. J. Med. Chem. 2018, 61, 3059–3075. [Google Scholar] [CrossRef] [PubMed]
  361. Carballa, D.; Sigüeiro, R.; Rodríguez-Docampo, Z.; Zacconi, F.; Maestro, M.A.; Mouriño, A. Stereoselective palladium-catalyzed approach to vitamin D3 derivatives in protic medium. Chem. Eur. J. 2018, 24, 3314–3320. [Google Scholar] [CrossRef] [PubMed]
  362. Yoshizawa, M.; Itoh, T.; Hori, T.; Kato, A.; Anami, Y.; Yoshimoto, N.; Yamamoto, K. Identification of the histidine residue in vitamin D receptor that covalently binds to electrphilic ligands. J. Med. Chem. 2018, 61, 6339–6349. [Google Scholar] [CrossRef] [PubMed]
  363. Gogoi, P.; Seoane, S.; Sigüeiro, R.; Guiberteau, T.; Maestro, M.A.; Pérez-Fernández, R.; Rochel, N.; Mouriño, A. Aromatic-based design of highly active and non calcemic vitamin D receptor agonists. J. Med. Chem. 2018, 61, 4928–4937. [Google Scholar] [CrossRef]
  364. Otero, R.; Ishizawa, M.; Numoto, N.; Ikura, T.; Ito, N.; Tokiwa, H.; Mouriño, A.; Makishima, M.; Yamada, S. 25S-Adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3: Synthesis, tissue selective biological activities, and X-ray crystal structural analysis of its vitamin D complex. J. Med. Chem. 2018, 61, 6658–6673. [Google Scholar] [CrossRef]
  365. Brzeminski, P.; Fabisiak, A.; Sektas, K.; Berkowska, K.; Marcinkowska, E.; Sicinski, R.R. Synthesis of 19-norcalcitriol analogs with elongated side chain. J. St. Biochem. Mol. Biol. 2018, 177, 231–234. [Google Scholar] [CrossRef]
  366. Fabisiak, A.; Brzeminski, P.; Berkowska, K.; Marcinkowska, E.; Sicinski, R.R. Synthesis of 19-norcalcitriol analogs with alkylidene moieties at C-2 based on succinic acid and L-methionine. J. St. Biochem. Mol. Biol. 2018, 177, 235–239. [Google Scholar] [CrossRef] [PubMed]
  367. Sawada, D.; Kakuda, S.; Takeuchi, A.; Kawagoe, F.; Takimoto-Kamimura, M.; Kittaka, A. Effects of 2-substitution on 14-epi-19-nortachysterol-mediated biological events; based on synthesis and X-ray co-crystallographic analysis with the human vitamin D receptor. Org. Biomol. Chem. 2018, 16, 2448–2455. [Google Scholar] [CrossRef] [PubMed]
  368. Sigüeiro, R.; Maestro, M.A.; Mouriño, A. Synthesis of side-chain locked analogs of 1α,25-dihydroxyvitamin D3 bearing a C17 methyl group. Org. Lett. 2018, 20, 2641–2644. [Google Scholar] [CrossRef] [PubMed]
  369. Lin, Z.; Marepally, S.R.; Goh, E.S.Y.; Chen, C.Y.S.; Janjetovic, Z.; Kim, T.-k.; Miller, D.D.; Postlehwaite, A.E.; Slominski, A.T.; Tuckey, R.C.; et al. Investigation of 20S-hydroxyvitamin D3 analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities. Sci. Rep. 2018, 8, 1478–1489. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  370. Kawagoe, F.; Yasuda, K.; Mototani, S.; Sugiyama, T.; Uesugi, M.; Sakaki, T.; Kittaka, A. Synthesis and CYP24A1-dependent metabolism of 23-fluorinated vitamin D3 analogues. ACS Omega 2019, 4, 11332–11337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  371. Maschinot, C.A.; Chau, L.Q.; Wechsler-Reya, R.J.; Hadden, M.K. Synthesis and evaluating of third generation vitamin D3 analogues as inhibitors of Hedgehog signaling. Eur. J. Med. Chem. 2019, 162, 495–506. [Google Scholar] [CrossRef] [PubMed]
  372. Sigüeiro, R.; Loureiro, J.; González-Berdullas, P.; Mouriño, A.; Maestro, M.A. Synthesis of 28,28,28-trideutero-25-hydroxydihydrotachysterol2. J. St. Biochem. Mol. Biol. 2019, 185, 248–250. [Google Scholar] [CrossRef]
  373. Ferronato, M.J.; Obiol, D.J.; Alonso, E.N.; Guevara, J.A.; Grioli, S.M.; Mascaró, M.; Rivadulla, M.L.; Martínez, A.; Gómez, G.; Fall, Y.; et al. Synthesis of a novel analog of calcitriol and its biological evaluation as antitumor agent. J. St. Biochem. Mol. Biol. 2019, 185, 118–136. [Google Scholar] [CrossRef] [Green Version]
  374. Wang, W.; Zhao, G.-D.; Cui, J.-i.; Li, M.-Q.; Liu, Z.-P. Synthesis of 1α,25-dihydroxyvitamin D3 Analogues with α,α-difluorocycloketone at the CD-ring side chains and their biological properties in ovariectomized rats. J. St. Biochem. Mol. Biol. 2019, 186, 66–73. [Google Scholar] [CrossRef]
  375. Kawagoe, F.; Sugiyama, T.; Yasuda, K.; Uesugi, M.; Sakaki, T.; Kittaka, A. Concise synthesis of 23-hydroxylated vitamin D3 metabolites. J. St. Biochem. Mol. Biol. 2019, 186, 161–168. [Google Scholar] [CrossRef]
  376. Fujishima, T.; Suenaga, T.; Kawahata, M.; Yamaguchi, K. Synthesis and characterization of 20-hydroxyvitamin D3 with the A-ring modification. J. St. Biochem. Mol. Biol. 2019, 187, 27–33. [Google Scholar] [CrossRef] [PubMed]
  377. Kawagoe, F.; Mototani, S.; Yasuda, K.; Nagasawa, K.; Uesugi, M.; Sakaki, T.; Kittaka, A. Introduction of fluorine atoms to vitamin D3 side-chain and synthesis of 24,24-difluoro-25-hydroxyvitamin D3. J. St. Biochem. Mol. Biol. 2019, 195, 105477. [Google Scholar] [CrossRef] [PubMed]
  378. Fabisiak, A.; Brzeminski, P.; Berkowska, K.; Marcinkowska, E.; Sicinski, R.R. Synthesis of 19-norcalcitriol with pegylated alkylidene chains at C-2. J. St. Biochem. Mol. Biol. 2019, 185, 251–255. [Google Scholar] [CrossRef] [PubMed]
  379. Nagata, A.; Akagi, Y.; Asano, L.; Kotake, K.; Kawagoe, F.; Mendoza, A.; Masoud, S.S.; Usuda, K.; Takemoto, Y.; Kittaka, A.; et al. Synthetic chemical probes that dissect vitamin D activities. ACS Chem. Biol. 2019, 14, 2851–2858. [Google Scholar] [CrossRef]
  380. Ibe, K.; Yamada, T.; Okamoto, S. Synthesis and vitamin D receptor affinity of 16-oxavitamin D3 analogues. Org. Biomol. Chem. 2019, 17, 10188–10200. [Google Scholar] [CrossRef]
  381. Fujishima, T.; Komatsu, T.; Takao, Y.; Yonamine, W.; Suenaga, T.; Isono, H.; Morikawa, M.; Takaguchi, K. Design and concise synthesis of novel vitamin D analogues bearing a functionalized aromatic ring on the side chain. Tetrahedron 2019, 75, 1098–1106. [Google Scholar] [CrossRef]
  382. Sibilska-Kaminski, I.K.; Sicinski, R.R.; Plum, L.A.; DeLuca, H.F. Synthesis and biological activity of 2,22-dimethylene analogues of 19-norcalcitriol and related compounds. J. Med. Chem. 2020, 63, 7355–7368. [Google Scholar] [CrossRef]
  383. Katner, L.; Rauch, E. Efficient synthesis of 3-TBDMS-11α,25-dihydroxyvitamin D3 and D2 ethers. J. St. Biochem. Mol. Biol. 2020, 200, 105638. [Google Scholar] [CrossRef]
  384. Brzeminski, P.; Fabisiak, A.; Berkowska, K.; Rárova, L.; Marcinkowska, E.; Sicinski, R.R. Synthesis of Gemini analogs of 19-norcalcitriol and their platinum(II) complexes. Bioorg. Chem. 2020, 100, 103883. [Google Scholar] [CrossRef]
  385. Fabisiak, A.; Brzeminski, P.; Berkowska, K.; Rárova, L.; Marcinkowska, E.; Sicinski, R.R. Design, synthesis and biological evaluation of novel 2-alkylidene 19-norcalcitriol analogs. Bioorg. Chem. 2020, 100, 104013. [Google Scholar] [CrossRef]
  386. Sibilska-Kaminski, I.K.; Fabisiak, A.; Brzeminski, P.; Plum, L.A.; Sicinski, R.R.; DeLuca, H.F. Novel superagonist analogs of 2-methylene calcitriol: Design, molecular docking, synthesis and biological evaluation. Bioorg. Chem. 2022, 118, 105416. [Google Scholar] [CrossRef] [PubMed]
  387. Obelleiro, A.; Gómez-Bouzó, U.; Gómez, G.; Fall, Y.; Santalla, H. Design and efficient synthesis of novel vitamin D analogues bearing an aniline moiety in their side chains. Tet. Lett. 2020, 61, 152493. [Google Scholar] [CrossRef]
  388. Fraga, R.; Len, K.; Lutzing, R.; Laverny, G.; Loureiro, J.; Maestro, M.A.; Rochel, N.; Rodriguez-Borges, E.; Mouriño, A. Design, synthesis, evaluation and structure of allenic 1α,25-dihydroxyvitamin D3 analogs with locked mobility at C17. Chem. Eur. J. 2021, 27, 13384–13389. [Google Scholar] [CrossRef] [PubMed]
  389. Seoane, S.; Gogoi, P.; Zárate-Ruiz, A.; Peluso-Iltis, C.; Peters, S.; Guiberteau, T.; Maestro, M.A.; Pérez-Fernández, R.; Rochel, N.; Mouriño, A. Design, synthesis, biological activity and structural analysis of novel des-C—Ring aromatic-D-ring analogues of 1α,25-dihydroxyvitamin D3. J. Med. Chem. 2022, 65, 13112–13124. [Google Scholar] [CrossRef] [PubMed]
  390. Ibe, K.; Nakada, H.; Ohgami, M.; Yamada, T.; Okamoto, S. Design, synthesis, and properties of des-D-ring interphenylene derivatives of 1α,25-dihydroxyvitamin D3. Eur. J. Med. Chem. 2022, 243, 114795. [Google Scholar] [CrossRef]
  391. Kawagoe, F.; Mendoza, A.; Hayata, Y.; Asano, L.; Kotake, K.; Mototani, S.; Kawamura, S.; Kurosaki, S.; Akagi, Y.; Takemoto, Y.; et al. Discovery of a vitamin D receptor-silent vitamin D derivative that impairs regulatory element-binding protein in vivo. J. Med. Chem. 2021, 64, 5689–5709. [Google Scholar] [CrossRef]
  392. Saito, H.; Horie, K.; Suga, A.; Kaibara, Y.; Mashiko, T. Vitamin D Derivative Having Cyclic Amine in Side Chain. World Patent Organization. WO2022059684A1, 24 March 2022. [Google Scholar]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Maestro, M.A.; Seoane, S. The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands. Nutrients 2022, 14, 4927. https://doi.org/10.3390/nu14224927

AMA Style

Maestro MA, Seoane S. The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands. Nutrients. 2022; 14(22):4927. https://doi.org/10.3390/nu14224927

Chicago/Turabian Style

Maestro, Miguel A., and Samuel Seoane. 2022. "The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands" Nutrients 14, no. 22: 4927. https://doi.org/10.3390/nu14224927

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop