New Schiff bases derived from dimethylpyridine-1,2,4-triazole hybrid as cytotoxic agents targeting gastrointestinal cancers: Design, synthesis, biological evaluation and molecular docking studies.

Autor: Strzelecka M; Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland. Electronic address: malgorzata.strzelecka@umw.edu.pl., Wiatrak B; Department of Pharmacology, Wroclaw Medical University, J. Mikulicza-Radeckiego 2, 50-345 Wroclaw, Poland., Jawień P; Department of Biostructure and Animal Physiology, Wroclaw University of Environmental and Life Sciences, Norwida 25/27, 50-375 Wroclaw, Poland., Czyżnikowska Ż; Department of Basic Chemical Sciences, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland., Świątek P; Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland. Electronic address: piotr.swiatek@umw.edu.pl.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Oct; Vol. 139, pp. 106758. Date of Electronic Publication: 2023 Jul 31.
DOI: 10.1016/j.bioorg.2023.106758
Abstrakt: In this research, a series of novel hybrid structures of dimethylpyridine-1,2,4-triazole Schiff bases were designed, synthesized, and evaluated for their in vitro cytotoxic potency on several human gastrointestinal cancer cells (EPG, Caco-2, LoVo, LoVo/Dx, HT29) and normal colonic epithelial cells (CCD 841 CoN). Schiff base 4h was the most potent compound against gastric EPG cancer cells (CC 50  = 12.10 ± 3.10 μM), being 9- and 21-fold more cytotoxic than 5-FU and cisplatin, respectively. Moreover, it was not toxic to normal cells. Regarding the cytotoxicity against colorectal cancer cells, compounds 4d and 4l exhibited good activity against HT29 cells (CC 50  = 52.80 ± 2.80 μM and 61.40 ± 10.70 μM, respectively), and were comparable to or more potent than cisplatin and 5-FU. Also, they were less toxic to normal cells with a higher selectivity index (SI, CCD 841 CoN/HT29 = 4.20 and 2.85, respectively) than reference drugs (SI, CCD 841 CoN/HT29 < 1). Selected Schiff bases were subjected to the P-glycoprotein inhibition assay. Schiff bases 4d, 4e, and 4l influenced P-gp efflux function, significantly increasing the accumulation of rhodamine 123 in colon cancer cell lines. Further mechanistic studies showed that compound 4l induced apoptotic cell death through a caspase-dependent mechanism and by regulating the p53-MDM2 signaling pathway in HT29 cells. Also, physicochemical predictions of compounds 4d, 4e, 4h, and 4i were examined in silico. The results revealed that the compounds possessed promising drug-likeness profiles.
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 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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