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Synthesis of Bioactive Compounds from the Chiral Pool

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (15 June 2016) | Viewed by 49033

Special Issue Editors


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Guest Editor
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, I-87036 Arcavacata di Rende, Italy
Interests: high-resolution instrumental analysis of complex vegetable and animal matrices; synthesis of biomolecules and their analogues; amino acid and peptide chemistry; modification of natural amino acids; chiral templates; design and synthesis of protease inhibitors
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Chemistry, University of Patras, GR-26504 Rion, Patras, Greece
Interests: discovery and development of small organic molecules and of natural product analogues or derivatives with anticancer, antibacterial and antiparasitic activity; synthesis of multitarget inhibitors and of hybrids or bioconjugates aiming at improvement of the pharmacological profile of one or more bioactive molecules
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chiral pool synthesis is a well-known and widespread approach for the design and preparation of chiral compounds of biological and pharmacological interest. This particularly important and versatile strategy employs, as starting materials, simple and complex enantiopure compounds readily available from the arsenal of natural sources. The most common components of the chiral pool are monosaccharides and amino acids. The use of these cheap starting materials is of great importance and helpful if the synthetic target compounds display strong similarities to the structure of the enantiopure natural precursors. Moreover, the use of the chiral pool is especially noticeable and fruitful when meandering multistep approaches to enantiopure bioactive compounds may be required. The strategy based on natural sources of chiral compounds is also of great aid in all cases of synthetic procedures characterized by considerable losses in total yields, and when suitable enantiopure scaffolds may be difficult to achieve. The aim of this Special Issue is to gather an inspiring anthology for the dissemination of the most recent acquisitions in the field of design, preparation, and characterization of enantiopure compounds starting from the chiral pool. Reviews, feature articles, and original research papers that focus on new divergent and convergent total syntheses of bioactive natural compounds and their analogues starting from the chiral pool are all welcomed.

Prof. Dr. Carlo Siciliano
Dr. Constantinos M. Athanassopoulos
Guest Editors

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Keywords

  • asymmetric synthesis
  • enantiopure chiral templates
  • total synthesis
  • bioactive compounds

Published Papers (7 papers)

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Research

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771 KiB  
Article
Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition
by Attila Hunyadi, József Csábi, Ana Martins, Joseph Molnár, Attila Balázs and Gábor Tóth
Molecules 2017, 22(2), 199; https://doi.org/10.3390/molecules22020199 - 25 Jan 2017
Cited by 23 | Viewed by 4817
Abstract
P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild [...] Read more.
P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild to moderate inhibition of P-gp function. Here we report the preparation of a set of substituted 2,3-dioxolane derivatives of poststerone, a known in vivo metabolite of 20-hydroxyecdysone (20E). In contrast with previously studied ecdysteroid dioxolanes, the majority of the new compounds did not inhibit the efflux function of P-gp. Nevertheless, a strong, dose dependent sensitization to doxorubicin was observed on a P-gp transfected cancer cell line and on its susceptible counterpart. We also observed that the MDR cell line was more sensitive to the compounds’ effect than the non-MDR. Our results showed for the first time that the chemo-sensitizing activity of ecdysteroids can be fully independent of functional efflux pump inhibition, and suggest these compounds as favorable leads against MDR cancer. Full article
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
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1880 KiB  
Communication
Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists
by Nuno A. L. Pereira, Francesc X. Sureda, Maria Pérez, Mercedes Amat and Maria M. M. Santos
Molecules 2016, 21(8), 1027; https://doi.org/10.3390/molecules21081027 - 6 Aug 2016
Cited by 4 | Viewed by 5660
Abstract
Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the [...] Read more.
Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl d-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic δ-oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson’s disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors. Full article
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
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931 KiB  
Article
A New Class of Glucosyl Thioureas: Synthesis and Larvicidal Activities
by Ping-An Wang, Jun-Tao Feng, Xing-Zi Wang and Mu-Qiong Li
Molecules 2016, 21(7), 925; https://doi.org/10.3390/molecules21070925 - 16 Jul 2016
Cited by 4 | Viewed by 4678
Abstract
A novel series of glucosyl thioureas were synthesized in good overall yields (up to 37% over four steps) from d-glucose and primary amines, and their larvicidal activities toward Mythimna separata Walker were also investigated. This new class of glucosyl thioureas demonstrated low [...] Read more.
A novel series of glucosyl thioureas were synthesized in good overall yields (up to 37% over four steps) from d-glucose and primary amines, and their larvicidal activities toward Mythimna separata Walker were also investigated. This new class of glucosyl thioureas demonstrated low to moderate growth inhibition activity of Mythiman separata Walker, with a growth inhibitory rate of up to 47.5% at a concentration of 100.0 mg/L in acetone. Full article
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
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4150 KiB  
Article
Synthesis of Chiral, Enantiopure Allylic Amines by the Julia Olefination of α-Amino Esters
by Fabio Benedetti, Federico Berti, Lidia Fanfoni, Michele Garbo, Giorgia Regini and Fulvia Felluga
Molecules 2016, 21(6), 805; https://doi.org/10.3390/molecules21060805 - 21 Jun 2016
Cited by 3 | Viewed by 6595
Abstract
The four-step conversion of a series of N-Boc-protected l-amino acid methyl esters into enantiopure N-Boc allylamines by a modified Julia olefination is described. Key steps include the reaction of a lithiated phenylalkylsulfone with amino esters, giving chiral β-ketosulfones, and the [...] Read more.
The four-step conversion of a series of N-Boc-protected l-amino acid methyl esters into enantiopure N-Boc allylamines by a modified Julia olefination is described. Key steps include the reaction of a lithiated phenylalkylsulfone with amino esters, giving chiral β-ketosulfones, and the reductive elimination of related α-acetoxysulfones. The overall transformation takes place under mild conditions, with good yields, and without loss of stereochemical integrity, being in this respect superior to the conventional Julia reaction of α-amino aldehydes. Full article
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
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Review

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5451 KiB  
Review
(+)-Podocarpic Acid as Chiral Template in the Synthesis of Aphidicolane, Stemodane and Stemarane Diterpenoids †
by Angela La Bella, Francesca Leonelli, Luisa Maria Migneco and Rinaldo Marini Bettolo
Molecules 2016, 21(9), 1197; https://doi.org/10.3390/molecules21091197 - 8 Sep 2016
Cited by 10 | Viewed by 6661
Abstract
In this review the synthetic work in the field of aphidicolane, stemodane and stemarane diterpenoids, in which readily available (+)-podocarpic acid (4) was used as chiral template for the construction of their polycyclic structures, is described as it developed along the [...] Read more.
In this review the synthetic work in the field of aphidicolane, stemodane and stemarane diterpenoids, in which readily available (+)-podocarpic acid (4) was used as chiral template for the construction of their polycyclic structures, is described as it developed along the years. In the frame of this work (+)-podocarpic acid (4) was a very useful tool in a model study leading to the syntheses of tetracyclic ketones 7 and 8, models of key intermediates 5a and 6 in the syntheses of (+)-aphidicolin (1) and (+)-stemodin (2a), respectively. (+)-Podocarpic acid (4) was also converted into (+)-2-deoxystemodinone (2d), allowing confirmation of the stemodane diterpenoids absolute configuration, into (+)-aphidicol-15-ene (36) and into Stemodia chilensis tetracyclic diterpenoid (+)-19-acetoxystemodan-12-ol (2f), allowing confirmation of its structure. (+)-Podocarpic acid (4) was then extensively used in the work which led to the synthesis of (+)-stemar-13-ene (57) and (+)-18-deoxystemarin (3b). Finally, (+)-4 was converted into (+)-2-deoxyoryzalexin S (66), which made it possible to demonstrate that the structure of (+)-66 could not be attributed to a Chilean Calceolaria isolated diterpenoid to which this structure had been assigned. Full article
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
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3806 KiB  
Review
Recent Advances in Substrate-Controlled Asymmetric Induction Derived from Chiral Pool α-Amino Acids for Natural Product Synthesis
by Seung-Mann Paek, Myeonggyo Jeong, Jeyun Jo, Yu Mi Heo, Young Taek Han and Hwayoung Yun
Molecules 2016, 21(7), 951; https://doi.org/10.3390/molecules21070951 - 21 Jul 2016
Cited by 39 | Viewed by 9584
Abstract
Chiral pool α-amino acids have been used as powerful tools for the total synthesis of structurally diverse natural products. Some common naturally occurring α-amino acids are readily available in both enantiomerically pure forms. The applications of the chiral pool in asymmetric synthesis can [...] Read more.
Chiral pool α-amino acids have been used as powerful tools for the total synthesis of structurally diverse natural products. Some common naturally occurring α-amino acids are readily available in both enantiomerically pure forms. The applications of the chiral pool in asymmetric synthesis can be categorized prudently as chiral sources, devices, and inducers. This review specifically examines recent advances in substrate-controlled asymmetric reactions induced by the chirality of α-amino acid templates in natural product synthesis research and related areas. Full article
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
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4732 KiB  
Review
The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines
by Renato Dalpozzo
Molecules 2016, 21(6), 699; https://doi.org/10.3390/molecules21060699 - 27 May 2016
Cited by 37 | Viewed by 9150
Abstract
The Pictet–Spengler reaction (PSR) is the reaction of a β-arylethylamine with an aldehyde or ketone, followed by ring closure to give an aza-heterocycle. When the β-arylethylamine is tryptamine, the product is a β-carboline, a widespread skeleton in natural alkaloids. In the natural occurrence, [...] Read more.
The Pictet–Spengler reaction (PSR) is the reaction of a β-arylethylamine with an aldehyde or ketone, followed by ring closure to give an aza-heterocycle. When the β-arylethylamine is tryptamine, the product is a β-carboline, a widespread skeleton in natural alkaloids. In the natural occurrence, these compounds are generally enantiopure, thus the asymmetric synthesis of these compounds have been attracting the interest of organic chemists. This review aims to give an overview of the asymmetric PSR, in which the chirality arises from optically pure amines or carbonyl compounds both from natural sources and from asymmetric syntheses to assemble the reaction partners. Full article
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
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