Design, synthesis, and biological evaluation of thiazole bioisosteres of goniofufurone through in vitro antiproliferative activity and in vivo toxicity.

Autor: Svirčev M; University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia., Popsavin M; University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia. Electronic address: mirjana.popsavin@dh.uns.ac.rs., Pavić A; University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Laboratory for Microbial Molecular Genetics and Ecology, Vojvode Stepe 444a, 11000 Belgrade, Serbia., Vasiljević B; University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Laboratory for Microbial Molecular Genetics and Ecology, Vojvode Stepe 444a, 11000 Belgrade, Serbia., Rodić MV; University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia., Djokić S; University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia., Kesić J; University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia., Srećo Zelenović B; University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia., Popsavin V; University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia; Serbian Academy of Sciences and Arts, Kneza Mihaila 35, 11000 Belgrade, Serbia. Electronic address: velimir.popsavin@dh.uns.ac.rs., Kojić V; University of Novi Sad, Faculty of Medicine, Oncology Institute of Vojvodina, put Dr. Goldmana 4, 21204 Sremska Kamenica, Serbia.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2022 Apr; Vol. 121, pp. 105691. Date of Electronic Publication: 2022 Feb 18.
DOI: 10.1016/j.bioorg.2022.105691
Abstrakt: The synthesis of several new goniofufurone bioisosteres was achieved in which the phenyl residue was replaced by a thiazole ring. The key steps of the synthesis included the initial condensation of cyanohydrin benzoates with cysteine ethyl ester hydrochloride, followed by the subsequent reaction of resulting C-4' epimeric thiazolines with DBU, to introduce 5-deoxy functionality and to elaborate the thiazole ring in one step. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially bioisostere 4, which in the culture of MCF-7 cells displayed the highest activity (IC 50  = 0.19 nM) of all compounds under evaluation. This molecule exhibited 64474-fold higher antiproliferative activity than lead 2 and was1053-fold more active than the commercial antitumour agent doxorubicin in the culture of MCF-7 cells. The structural features of the tested compounds responsible for their antiproliferative activity have been identified by preliminary SAR analysis. The toxicity of the most active compound 4 was assessed by an in vivo experiment in a zebrafish model (Danio rerio), whereupon it was found non-toxic at any of the tested concentrations up to 125 μM.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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