Research

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11 pages, 1791 KiB

Open AccessCommunication

The Synthesis and Initial Evaluation of MerTK Targeted PET Agents

by Li Wang, Yubai Zhou, Xuedan Wu, Xinrui Ma, Bing Li, Ransheng Ding, Michael A. Stashko, Zhanhong Wu, Xiaodong Wang and Zibo Li

Molecules 2022, 27(5), 1460; https://doi.org/10.3390/molecules27051460 - 22 Feb 2022

Viewed by 1914

Abstract

MerTK (Mer tyrosine kinase), a receptor tyrosine kinase, is ectopically or aberrantly expressed in numerous human hematologic and solid malignancies. Although a variety of MerTK targeting therapies are being developed to enhance outcomes for patients with various cancers, the sensitivity of tumors to [...] Read more.

MerTK (Mer tyrosine kinase), a receptor tyrosine kinase, is ectopically or aberrantly expressed in numerous human hematologic and solid malignancies. Although a variety of MerTK targeting therapies are being developed to enhance outcomes for patients with various cancers, the sensitivity of tumors to MerTK suppression may not be uniform due to the heterogeneity of solid tumors and different tumor stages. In this report, we develop a series of radiolabeled agents as potential MerTK PET (positron emission tomography) agents. In our initial in vivo evaluation, [¹⁸F]-MerTK-6 showed prominent uptake rate (4.79 ± 0.24%ID/g) in B16F10 tumor-bearing mice. The tumor to muscle ratio reached 1.86 and 3.09 at 0.5 and 2 h post-injection, respectively. In summary, [¹⁸F]-MerTK-6 is a promising PET agent for MerTK imaging and is worth further evaluation in future studies. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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12 pages, 3053 KiB

Open AccessArticle

Preparation of Deuterium Labeled Compounds by Pd/C-Al-D₂O Facilitated Selective H-D Exchange Reactions

by Anne Kokel, Dora Kadish and Béla Török

Molecules 2022, 27(3), 614; https://doi.org/10.3390/molecules27030614 - 18 Jan 2022

Cited by 3 | Viewed by 2588

Abstract

The chemo/regioselective H-D exchange of amino acids and synthetic building blocks by an environmentally benign Pd/C-Al-D₂O catalytic system is described. Due to the importance of isotope labeled compounds in medicinal chemistry and structural biology, notably their use as improved drug candidates [...] Read more.

The chemo/regioselective H-D exchange of amino acids and synthetic building blocks by an environmentally benign Pd/C-Al-D₂O catalytic system is described. Due to the importance of isotope labeled compounds in medicinal chemistry and structural biology, notably their use as improved drug candidates and biological probes, the efficient and selective deuteration methods are of great interest. The approach is based on selective H-D exchange reactions where the deuterium source is simple D₂O. D₂ gas is generated in situ from the reaction of aluminum and D₂O, while the commercially available palladium catalyst assists the H-D exchange reaction. The high selectivity and efficiency, as well as the simplicity and safe nature of the procedure make this method an environmentally benign alternative to current alternatives. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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10 pages, 990 KiB

Open AccessArticle

Precursor-Directed Biosynthesis of Aminofulvenes: New Chalanilines from Endophytic Fungus Chalara sp.

by Mahsa Khoshbakht, Jason Srey, Donovon A. Adpressa, Annika Jagels and Sandra Loesgen

Molecules 2021, 26(15), 4418; https://doi.org/10.3390/molecules26154418 - 22 Jul 2021

Cited by 2 | Viewed by 2327

Abstract

The plant endophyte Chalara sp. is able to biotransform the epigenetic modifier vorinostat to form unique, aniline-containing polyketides named chalanilines. Here, we sought to expand the chemical diversity of chalaniline A-type molecules by changing the aniline moiety in the precursor vorinostat. In total, [...] Read more.

The plant endophyte Chalara sp. is able to biotransform the epigenetic modifier vorinostat to form unique, aniline-containing polyketides named chalanilines. Here, we sought to expand the chemical diversity of chalaniline A-type molecules by changing the aniline moiety in the precursor vorinostat. In total, twenty-three different vorinostat analogs were prepared via two-step synthesis, and nineteen were incorporated by the fungus into polyketides. The highest yielding substrates were selected for large-scale precursor-directed biosynthesis and five novel compounds, including two fluorinated chalanilines, were isolated, purified, and structurally characterized. Structure elucidation relied on 1D and 2D NMR techniques and was supported by low- and high-resolution mass spectrometry. All compounds were tested for their bioactivity but were not active in antimicrobial or cell viability assays. Aminofulvene-containing natural products are rare, and this high-yielding, precursor-directed process allows for the diversification of this class of compounds. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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11 pages, 4336 KiB

Open AccessArticle

A Formal Rearrangement of Allylic Silanols

by Ranjeet A. Dhokale, Frederick J. Seidl and Shyam Sathyamoorthi

Molecules 2021, 26(13), 3829; https://doi.org/10.3390/molecules26133829 - 23 Jun 2021

Cited by 10 | Viewed by 2841

Abstract

We show that 1M aqueous HCl/THF or NaBH₄/DMF allows for demercurative ring-opening of cyclic organomercurial synthons into secondary silanol products bearing terminal alkenes. We had previously demonstrated that primary allylic silanols are readily transformed into cyclic organomercurials using Hg(OTf)₂/NaHCO [...] Read more.

We show that 1M aqueous HCl/THF or NaBH₄/DMF allows for demercurative ring-opening of cyclic organomercurial synthons into secondary silanol products bearing terminal alkenes. We had previously demonstrated that primary allylic silanols are readily transformed into cyclic organomercurials using Hg(OTf)₂/NaHCO₃ in THF. Overall, this amounts to a facile two-step protocol for the rearrangement of primary allylic silanol substrates. Computational investigations suggest that this rearrangement is under thermodynamic control and that the di-tert-butylsilanol protecting group is essential for product selectivity. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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26 pages, 3823 KiB

Open AccessArticle

Synthesis of Carbohydrate Based Macrolactones and Their Applications as Receptors for Ion Recognition and Catalysis

by Surya B. Adhikari, Anji Chen and Guijun Wang

Molecules 2021, 26(11), 3394; https://doi.org/10.3390/molecules26113394 - 03 Jun 2021

Cited by 5 | Viewed by 2690

Abstract

Glycomacrolactones exhibit many interesting biological properties, and they are also important in molecular recognitions and for supramolecular chemistry. Therefore, it is important to be able to access glycomacrocycles with different sizes and functionality. A new series of carbohydrate-based macrocycles containing triazole and lactone [...] Read more.

Glycomacrolactones exhibit many interesting biological properties, and they are also important in molecular recognitions and for supramolecular chemistry. Therefore, it is important to be able to access glycomacrocycles with different sizes and functionality. A new series of carbohydrate-based macrocycles containing triazole and lactone moieties have been designed and synthesized. The synthesis features an intramolecular nucleophilic substitution reaction for the macrocyclization step. In this article, the effect of some common sulfonate leaving groups is evaluated for macrolactonization. Using tosylate gave good selectivity for monolactonization products with good yields. Fourteen different macrocycles have been synthesized and characterized, of which eleven macrocycles are from cyclization of the C1 to C6 positions of N-acetyl D-glucosamine derivatives and three others from C2 to C6 cyclization of functionalized D-glucosamine derivatives. These novel macrolactones have unique structures and demonstrate interesting anion binding properties, especially for chloride. The macrocycles containing two triazoles form complexes with copper sulfate, and they are effective ligands for copper sulfate mediated azide-alkyne cycloaddition reactions (CuAAC). In addition, several macrocycles show some selectivity for different alkynes. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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10 pages, 2960 KiB

Open AccessArticle

Sweet-Tasting Ionic Conjugates of Local Anesthetics and Vasoconstrictors

by John K. Neubert, Alexander A. Oliferenko, Polina V. Oliferenko, Sergey V. Emets, David A. Ostrov, Gary I. Altschuler, Joe Calkins, Jay Wickersham, Robert Hromas and Iryna O. Lebedyeva

Molecules 2021, 26(4), 983; https://doi.org/10.3390/molecules26040983 - 12 Feb 2021

Viewed by 2520

Abstract

Local anesthetics are widely utilized in dentistry, cosmetology, and medicine. Local anesthesia is essential to providing a pain-free experience during dental and local surgeries as well as cosmetic procedures. However, the injection itself may produce discomfort and be a source of aversion. A [...] Read more.

Local anesthetics are widely utilized in dentistry, cosmetology, and medicine. Local anesthesia is essential to providing a pain-free experience during dental and local surgeries as well as cosmetic procedures. However, the injection itself may produce discomfort and be a source of aversion. A novel approach toward the taste modulation of local anesthetics is proposed, in which the anesthetics of the “-caine” family serve as cations and are coupled with anionic sweeteners such as saccharinate and acesulfamate. Ionic conjugates of vasoconstrictor epinephrine such as epinephrine saccharinate and epinephrine acesulfamate have also been synthesized. Novel ionic conjugates were developed using anion exchange techniques. Reported compounds are sweet-tasting and are safe to use both topically and as injections. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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14 pages, 2313 KiB

Open AccessArticle

Development of Second Generation Activity-Based Chemical Probes for Sirtuins

by Alyson M. Curry, Elizabeth Barton, Wenjia Kang, Daniel V. Mongeluzi and Yana Cen

Molecules 2021, 26(1), 11; https://doi.org/10.3390/molecules26010011 - 22 Dec 2020

Cited by 5 | Viewed by 2620

Abstract

NAD⁺ (nicotinamide adenine dinucleotide)-dependent protein deacylases, namely, the sirtuins, are important cell adaptor proteins that alter cell physiology in response to low calorie conditions. They are thought to mediate the beneficial effects of calorie restriction to extend longevity and improve health profiles. [...] Read more.

NAD⁺ (nicotinamide adenine dinucleotide)-dependent protein deacylases, namely, the sirtuins, are important cell adaptor proteins that alter cell physiology in response to low calorie conditions. They are thought to mediate the beneficial effects of calorie restriction to extend longevity and improve health profiles. Novel chemical probes are highly desired for a better understanding of sirtuin’s roles in various biological processes. We developed a group of remarkably simple activity-based chemical probes for the investigation of active sirtuin content in complex native proteomes. These probes harbor a thioacyllysine warhead, a diazirine photoaffinity tag, as well as a terminal alkyne bioorthogonal functional group. Compared to their benzophenone-containing counterparts, these new probes demonstrated improved labeling efficiency and sensitivity, shortened irradiation time, and reduced background signal. They were applied to the labeling of individual recombinant proteins, protein mixtures, and whole cell lysate. These cell permeable small molecule probes also enabled the cellular imaging of sirtuin activity change. Taken together, our study provides new chemical biology tools and future drug discovery strategies for perturbing the activity of different sirtuin isoforms. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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16 pages, 1295 KiB

Open AccessArticle

Conjugate Addition of Grignard Reagents to Thiochromones Catalyzed by Copper Salts: A Unified Approach to Both 2-Alkylthiochroman-4-One and Thioflavanone

by Tania J. Bellinger, Teavian Harvin, Ti’Bran Pickens-Flynn, Nataleigh Austin, Samuel H. Whitaker, Mai Ling C. Tang Yuk Tutein, Dabria T. Hukins, Nichele Deese and Fenghai Guo

Molecules 2020, 25(9), 2128; https://doi.org/10.3390/molecules25092128 - 01 May 2020

Cited by 4 | Viewed by 4036

Abstract

Grignard reagents undergo conjugate addition to thiochromones catalyzed by copper salts to afford 2-substituted-thiochroman-4-ones, both 2-alkylthiochroman-4-ones and thioflavanones (2-arylthiochroman-4-ones), in good yields with trimethylsilyl chloride (TMSCl) as an additive. The best yields of 1,4-adducts can be attained with CuCN∙2LiCl as the copper source. [...] Read more.

Grignard reagents undergo conjugate addition to thiochromones catalyzed by copper salts to afford 2-substituted-thiochroman-4-ones, both 2-alkylthiochroman-4-ones and thioflavanones (2-arylthiochroman-4-ones), in good yields with trimethylsilyl chloride (TMSCl) as an additive. The best yields of 1,4-adducts can be attained with CuCN∙2LiCl as the copper source. Excellent yields of 2-alkyl-substituted thiochroman-4-ones and thioflavanones (2-aryl substituted) are attained with a broad range of Grignard reagents. This approach works well with both alkyl and aromatic Grignard reagents, thus providing a unified synthetic approach to privileged 2-substituted thiochroman-4-ones and a potential valuable precursor for further synthetic applications towards many pharmaceutically active molecules. The use of commercially available and/or readily prepared Grignard reagents will expedite the synthesis of a large library of both 2-alkyl substituted thiochroman-4-ones and thioflavanones for additional synthetic applications. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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7 pages, 1510 KiB

Open AccessCommunication

Synthesis of the C₃ and C₁ Constitutional Isomers of Trifluorosubphthalocyanine and Their Fluorescence within MDA-MB-231 Breast Tumor Cells

by Rosemarie L. Calandrino, Katherine J. McAuliffe, Lauren E. Dolmage and Evan R. Trivedi

Molecules 2019, 24(21), 3832; https://doi.org/10.3390/molecules24213832 - 24 Oct 2019

Cited by 3 | Viewed by 2718

Abstract

Metal tetrapyrrole macrocycles such as porphyrins and chlorins are ubiquitous in nature. Synthetic analogs, including phthalocyanines, have found applications in medicine, particularly as photosensitizers for photodynamic therapy and as fluorescent imaging probes. Tripyrrolic macrocycles, called subphthalocyanines (SPcs) with a smaller boron atom at [...] Read more.

Metal tetrapyrrole macrocycles such as porphyrins and chlorins are ubiquitous in nature. Synthetic analogs, including phthalocyanines, have found applications in medicine, particularly as photosensitizers for photodynamic therapy and as fluorescent imaging probes. Tripyrrolic macrocycles, called subphthalocyanines (SPcs) with a smaller boron atom at their core, have similar potential as optical agents. We have recently reported a series of mixed fluorinated SPcs with varying aromaticity, showing that electronic absorption and emission are synthetically tunable across the far visible region, and that the inclusion of 4–12 peripheral fluorine atoms results in strong fluorescence within MDA-MB-231 breast tumor cells. Further probing this system, we report herein the synthesis and characterization of boron trifluorosubphthalocyanine chloride (F₃SPc). The constitutional isomers F₃SPc(C₃) and F₃SPc(C₁) are readily separable by chromatography, and their identity and purity have been confirmed by ¹H NMR, ¹⁹F NMR, HR APCI-MS, and HPLC. Unsurprisingly, these structurally similar F₃SPcs have identical electronic absorption (λ_max = 557 nm; tetrahydrofuran (THF)) and emission (λ_em = 574 nm; Φ_f = 0.27–0.28; THF). Strong fluorescence from MDA-MB-231 breast tumor cells was observed following treatment with F₃SPc(C₃) and F₃SPc(C₁) (50 µM F₃SPc, 15 min), further highlighting the importance of even a limited number of peripheral fluorine atoms for this type of application. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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Review

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44 pages, 20643 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

by Dianqing Sun

Molecules 2022, 27(3), 1012; https://doi.org/10.3390/molecules27031012 - 02 Feb 2022

Cited by 11 | Viewed by 3900

Abstract

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput [...] Read more.

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C–C and C–heteroatom cross-coupling, copper- or ruthenium-catalyzed azide–alkyne cycloaddition, intramolecular S_NAr or S_N2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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37 pages, 15150 KiB

Open AccessFeature PaperReview

Synthesis of Naphthoquinone Derivatives: Menaquinones, Lipoquinones and Other Vitamin K Derivatives

by Margaret Braasch-Turi and Debbie C. Crans

Molecules 2020, 25(19), 4477; https://doi.org/10.3390/molecules25194477 - 29 Sep 2020

Cited by 15 | Viewed by 5922

Abstract

Menaquinones are a class of isoprenoid molecules that have important roles in human biology and bacterial electron transport, and multiple methods have been developed for their synthesis. These compounds consist of a methylnaphthoquinone (MK) unit and an isoprene side chain, such as found [...] Read more.

Menaquinones are a class of isoprenoid molecules that have important roles in human biology and bacterial electron transport, and multiple methods have been developed for their synthesis. These compounds consist of a methylnaphthoquinone (MK) unit and an isoprene side chain, such as found in vitamin K₁ (phylloquinone), K₂, and other lipoquinones. The most common naturally occurring menaquinones contain multiple isoprene units and are very hydrophobic, rendering it difficult to evaluate the biological activity of these compounds in aqueous assays. One way to overcome this challenge has been the application of truncated MK-derivatives for their moderate solubility in water. The synthesis of such derivatives has been dominated by Friedel-Crafts alkylation with BF₃∙OEt₂. This attractive method occurs over two steps from commercially available starting materials, but it generally produces low yields and a mixture of isomers. In this review, we summarize reported syntheses of both truncated and naturally occurring MK-derivatives that encompass five different synthetic strategies: Nucleophilic ring methods, metal-mediated reactions, electrophilic ring methods, pericyclic reactions, and homologation and side chain extensions. The advantages and disadvantages of each method are discussed, identifying methods with a focus on high yields, regioselectivity, and stereochemistry leading to a detailed overview of the reported chemistry available for preparation of these compounds. Full article

(This article belongs to the Special Issue Organic Chemistry in the USA)

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