Search

[Display omitted] • ALC67 belongs to a recently discovered family of novel antiproliferative agents. • A synthetic library of optically pure ferrocenyl analogs of ALC67 was prepared. • Two compounds (6c- cis and 6-d) showed similar cytotoxicity to ALC67 and cisplatin. • The cytotoxicity depended on the electrophilicity of the N -acyl side chain group. • Derivative 6c- cis also manifested a selective anti- Bacillus cereus activity. 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 C N 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. [ABSTRACT FROM AUTHOR]