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Stereoselective Synthesis of Chiral Synthons with Biological or Pharmacological Interest

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 26236

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Prof. Dr. Zsolt Szakonyi

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Institute of Pharmaceutical Chemistry, University of Szeged (SZTE), Szeged, Hungary
Interests: beta-amino acids; aminodiols; heterocyclic chemistry; drug design and synthesis; chiral catalysts; terpenoids
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Special Issue Information

Dear Colleagues,

Nowadays, considerable progress has been made in the synthesis of chiral synthons applied as starting materials in asymmetric syntheses of pharmacologically active drug candidates or as auxiliaries and chiral ligands in enantioselective transformations. In asymmetric syntheses, the growing need for new chiral ligands and building blocks calls for new strategies to obtain the desired enantiopure catalysts. One of the ways to achieve this aim is the incorporation of chirality into ligands by using optically active, naturally occurring compounds widely available as starting materials.

The main aim of the present Special Issue is to collect the results of fundamental studies and applications in a multidisciplinary research area that enrolls chiral compounds. It will bring together novel, unique, and innovative approaches in the field of enantioselective organic synthesis, chiral catalysis, and chiral recognition studies using chiral sources, including results of pharmacological studies. Both original research papers and reviews in these fields are welcome.

It is my sincere hope that this Special Issue will contribute to the development of green methods and semisynthetic processes applying a wide range of natural starting materials.

Prof. Dr. Zsolt Szakonyi
Guest Editor

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Keywords

chiral synthesis
natural source
stereoselective
bioactive compounds
organocatalysis
chiral pools
pharmacological activity
chiral building blocks

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Published Papers (6 papers)

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Research

27 pages, 2582 KiB

Open AccessArticle

Stereoselective Synthesis of Carbon-Sulfur-Bridged Glycomimetics by Photoinitiated Thiol-Ene Coupling Reactions

by Magdolna Csávás, Dániel Eszenyi, Erika Mező, László Lázár, Nóra Debreczeni, Marietta Tóth, László Somsák and Anikó Borbás

Int. J. Mol. Sci. 2020, 21(2), 573; https://doi.org/10.3390/ijms21020573 - 16 Jan 2020

Cited by 6 | Viewed by 3985

Abstract

Oligosaccharides and glycoconjugates are abundant in all living organisms, taking part in a multitude of biological processes. The application of natural O-glycosides in biological studies and drug development is limited by their sensitivity to enzymatic hydrolysis. This issue made it necessary to design hydrolytically stable carbohydrate mimetics, where sulfur, carbon, or longer interglycosidic connections comprising two or three atoms replace the glycosidic oxygen. However, the formation of the interglycosidic linkages between the sugar residues in high diastereoslectivity poses a major challenge. Here, we report on stereoselective synthesis of carbon-sulfur-bridged disaccharide mimetics by the free radical addition of carbohydrate thiols onto the exo-cyclic double bond of unsaturated sugars. A systematic study on UV-light initiated radical mediated hydrothiolation reactions of enoses bearing an exocyclic double bond at C1, C2, C3, C4, C5, and C6 positions of the pyranosyl ring with various sugar thiols was performed. The effect of temperature and structural variations of the alkenes and thiols on the efficacy and stereoselectivity of the reactions was systematically studied and optimized. The reactions proceeded with high efficacy and, in most cases, with complete diastereoselectivity producing a broad array of disaccharide mimetics coupling through an equatorially oriented methylensulfide bridge. Full article

(This article belongs to the Special Issue Stereoselective Synthesis of Chiral Synthons with Biological or Pharmacological Interest)

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17 pages, 2355 KiB

Open AccessArticle

Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpen Aminodiols

by Dániel Ozsvár, Viktória Nagy, István Zupkó and Zsolt Szakonyi

Int. J. Mol. Sci. 2020, 21(1), 184; https://doi.org/10.3390/ijms21010184 - 26 Dec 2019

Cited by 10 | Viewed by 3385

Abstract

A library of steviol-based trifunctional chiral ligands was developed from commercially available natural stevisoide and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The key intermediate steviol methyl ester was prepared according to literature procedure. Depending on the epoxidation process, both cis- and trans-epoxyalcohols were obtained. Subsequent oxirane ring opening with primary and secondary amines afforded 3-amino-1,2-diols. The ring opening with sodium azide followed by a “click” reaction with alkynes resulted in dihydroxytriazoles. The regioselective ring closure of N-substituted aminodiols with formaldehyde was also investigated. The resulting steviol-type aminodiols were tested against a panel of human adherent cancer cell lines (A2780, SiHa, HeLa, and MDA-MB-231). It was consistently found that the N-benzyl substituent is an essential part within the molecule and the ring closure towards N-benzyl substituted oxazolidine ring system increased the antiproliferative activity to a level comparable with that of cisplatine. In addition, structure–activity relationships were examined by assessing substituent effects on the aminodiol systems. Full article

(This article belongs to the Special Issue Stereoselective Synthesis of Chiral Synthons with Biological or Pharmacological Interest)

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16 pages, 2020 KiB

Open AccessArticle

Unexpected Racemization in the Course of the Acetalization of (+)-(S)-5-Methyl-Wieland–Miescher Ketone with 1,2-Ethanediol and TsOH under Classical Experimental Conditions

by Francesca Leonelli, Irene Piergentili, Giulio Lucarelli, Luisa Maria Migneco and Rinaldo Marini Bettolo

Int. J. Mol. Sci. 2019, 20(24), 6147; https://doi.org/10.3390/ijms20246147 - 5 Dec 2019

Viewed by 5435

Abstract

(+)-(S) and (−)-(R)-5-methyl-Wieland-Miescher ketone (+)-1 and (−)-1, are important synthons in the diastereo and enantioselective syntheses of biological and/or pharmacological interesting compounds. A key step in these syntheses is the chemoselective C(1)O acetalization to (+)-5 and (−)-5, respectively. Various procedures for this transformation have been described in the literature. Among them, the classical procedure based on the use of 1,2-ethanediol and TsOH in refluxing benzene in the presence of a Dean-Stark apparatus. Within our work on bioactive natural products, it occurred to us to observe the partial racemization of (+)-5 in the course of the acetalization of (+)-1 by means of the latter methodology. Aiming to investigate this drawback, which, to our best knowledge, has no precedents in the literature, we acetalized with 1,2-ethanediol and TsOH in refluxing benzene and in the presence of a Dean–Stark apparatus under various experimental conditions, enantiomerically pure (+)-1. It was found that the extent of racemization depends on the TsOH/(+)-1 and 1,2-ethanediol/(+)-1 ratios. Mechanism hypotheses for this partial and unexpected racemization are provided. Full article

(This article belongs to the Special Issue Stereoselective Synthesis of Chiral Synthons with Biological or Pharmacological Interest)

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13 pages, 1139 KiB

Open AccessArticle

Cyclobutane-Containing Scaffolds as Useful Intermediates in the Stereoselective Synthesis of Suitable Candidates for Biomedical Purposes: Surfactants, Gelators and Metal Cation Ligands

by Ona Illa, Albert Serra, Agustí Ardiaca, Xavier Herrero, Guillem Closa and Rosa M. Ortuño

Int. J. Mol. Sci. 2019, 20(18), 4333; https://doi.org/10.3390/ijms20184333 - 4 Sep 2019

Cited by 3 | Viewed by 3121

Abstract

Efficient and versatile synthetic methodologies are reported for the preparation of products that are suitable candidates to be used as surfactants, gelators for hydroxylic solvents or metal cation ligands, with potential use in several fields including biomedical applications. The common structural feature of all the synthesized products is the presence of a cis or trans-1,2- or cis-1,3-difunctionalized cyclobutane ring. In the two first cases, the key intermediates including enantiomerically pure 1,3-diamines and 1,3-amino alcohols have been prepared from β-amino acid derivatives obtained, in turn, from a chiral half-ester. This compound is also precursor of γ-amino esters. Furthermore, two kind of polydentate ligands have also been synthesized from a symmetric 1,5-diamine obtained from norpinic acid, which was easily prepared from commercial verbenone. Full article

(This article belongs to the Special Issue Stereoselective Synthesis of Chiral Synthons with Biological or Pharmacological Interest)

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19 pages, 1703 KiB

Open AccessArticle

Stereoselective Synthesis and Investigation of Isopulegol-Based Chiral Ligands

by Tam Minh Le, Tamás Szilasi, Bettina Volford, András Szekeres, Ferenc Fülöp and Zsolt Szakonyi

Int. J. Mol. Sci. 2019, 20(16), 4050; https://doi.org/10.3390/ijms20164050 - 19 Aug 2019

Cited by 11 | Viewed by 4331

Abstract

A library of isopulegol-based bi-, tri- and tetrafunctional chiral ligands has been developed from commercially available (−)-isopulegol and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. Michael addition of primary amines towards α-methylene-γ-butyrolactone, followed by reduction, was accomplished to provide aminodiols in highly stereoselective transformations. Stereoselective epoxidation of (+)-neoisopulegol, derived from natural (−)-isopulegol, and subsequent oxirane ring opening with primary amines afforded aminodiols. The regioselective ring closure of N-substituted aminodiols with formaldehyde was also investigated. Hydroxylation of (+)-neoisopulegol resulted in diol, which was then transformed into aminotriols by aminolysis of its epoxides. Dihydroxylation of (+)-neoisopulegol or derivatives with OsO₄/NMO gave neoisopulegol-based di-, tri- and tetraols in highly stereoselective reactions. The antimicrobial activity of aminodiol and aminotriol derivatives as well as di-, tri- and tetraols was also explored. In addition, structure–activity relationships were examined by assessing substituent effects on the aminodiol and aminotriol systems. Full article

(This article belongs to the Special Issue Stereoselective Synthesis of Chiral Synthons with Biological or Pharmacological Interest)

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20 pages, 2913 KiB

Open AccessArticle

Anti-Cancer Activity of Novel Dihydrotestosterone-Derived Ring A-Condensed Pyrazoles on Androgen Non-Responsive Prostate Cancer Cell Lines

by Gergő Mótyán, Mohana Krishna Gopisetty, Réka Eleonóra Kiss-Faludy, Ágnes Kulmány, István Zupkó, Éva Frank and Mónika Kiricsi

Int. J. Mol. Sci. 2019, 20(9), 2170; https://doi.org/10.3390/ijms20092170 - 2 May 2019

Cited by 10 | Viewed by 5431

Abstract

Regioselective synthesis of novel ring A-fused arylpyrazoles of dihydrotestosterone (DHT) was carried out in two steps under facile reaction conditions. Aldol condensation of DHT with acetaldehyde afforded a 2-ethylidene derivative regio- and stereo-selectively, which was reacted with different arylhydrazines in the presence of iodine via microwave-assisted oxidative cyclization reactions. The 17-keto analogs of steroidal pyrazoles were also synthesized by simple oxidation in order to enlarge the compound library available for pharmacological studies and to obtain structure–activity relationship. The antiproliferative activities of the structurally related heteroaromatic compounds were tested in vitro on human cervical and breast adenocarcinoma cell lines (HeLa, MCF-7 and MDA-MB-231) and on two androgen-independent malignant prostate carcinoma cell lines (PC-3 and DU 145). Based on primary cytotoxicity screens and IC₅₀ assessment, a structure-function relationship was identified, as derivatives carrying a hydroxyl group on C-17 exhibit stronger activity compared to the 17-one counterparts. Cancer cell selectivity of the derivatives was also determined using non-cancerous MRC-5 cells. Furthermore, the proapoptotic effects of some selected derivatives were verified on androgen therapy refractive p53-deficient PC-3 cells. The present study concludes that novel DHT-derived arylpyrazoles exert cancer cell specific antiproliferative activity and activate apoptosis in PC-3 cells. Full article

(This article belongs to the Special Issue Stereoselective Synthesis of Chiral Synthons with Biological or Pharmacological Interest)

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