Bioisosteric ferrocenyl 1,3-thiazolidine-4-carboxylic acid derivatives: In vitro antiproliferative and antimicrobial evaluations.

Autor: Aksić JM; Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia., Genčić MS; Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia. Electronic address: denijum@yahoo.com., Radulović NS; Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia. Electronic address: nikoradulovic@yahoo.com., Dimitrijević MV; Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia., Stojanović-Radić ZZ; Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia., Ilic Tomic T; Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11010 Belgrade, Serbia., Rodić MV; Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Oct; Vol. 139, pp. 106708. Date of Electronic Publication: 2023 Jul 03.
DOI: 10.1016/j.bioorg.2023.106708
Abstrakt: To improve the antiproliferative effect of ALC67 (diastereomeric mixture of ethyl 2-phenyl-3-propioloyl-1,3-thiazolidine-4-carboxylate), its structure was modified via (i) bioisosteric substitution of the phenyl ring by the ferrocene unit and (ii) replacing the propiolamide side-chain in ACL67 with other acyl groups having differing electrophilicities. In this way, a small library of methyl N-acyl-2-ferrocenyl-1,3-thiazolidine-4-carboxylates (13 compounds in total) was created and characterized by spectral and crystallographic means. The last N-acylation step was highly diastereoselective toward the cis-diastereomer. In solution, most of the obtained compounds existed as a mixture of two rotamers and displayed a preference for the syn-orientation around the CN bond. A twisted 5 T 4 envelope conformation was adopted by the derivative containing the N-phenoxyacetyl group in the crystalline state. Two derivatives with chloroacetyl and bromoacetyl groups in the N-3 side chain were cytotoxic to fibroblasts and hepatocellular cancer cells in the low micromolar range (IC 50 (MRC5) = 9.0 and 11.8 μM, respectively, and IC 50 (HepG2) = 10.6 and 18.4 μM, respectively) causing an effect similar to the lead compound (IC 50 (HepG2) = 10.0 μM) and cisplatin (IC 50 (MRC5) = 4.0 μM and IC 50 (HepG2) = 7.7 μM). Several derivatives also manifested modest antimicrobial effects against the studied microbial strains (MICs in the range from 0.44 to 4.0 μmol/mL). Our findings demonstrated that the introduction of a ferrocene core facilitated the preparation of optically pure analogs of ALC67 and that the cytotoxicity of compounds may be enhanced by adding proper electrophilic centers to the N-acyl side-chain.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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