Design, synthesis and biological studies of new isoxazole compounds as potent Hsp90 inhibitors.

Autor: Keshavarzipour F; Pharmaceutical Sciences Research Centre, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, 81746-7346, Isfahan, Iran., Abbasi M; Department of Medicinal Chemistry, Faculty of Pharmacy, Hormozgan University of Medical Sciences, 791969-1982, Bandar Abbas, Iran., Khorsandi Z; Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746- 7346, Isfahan, Iran., Ardestani M; Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746- 7346, Isfahan, Iran., Sadeghi-Aliabadi H; Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746- 7346, Isfahan, Iran. sadeghi@pharm.mui.ac.ir.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Nov 14; Vol. 14 (1), pp. 28017. Date of Electronic Publication: 2024 Nov 14.
DOI: 10.1038/s41598-024-79051-5
Abstrakt: Heat shock protein 90 (Hsp90), a molecular chaperone, contributes to the preservation of folding, structure, stability, and function proteins. In this study, novel compounds comprising isoxazole structure were designed, synthesized and their potential ability as Hsp90 inhibitors was validated through docking studies. The active site-based compounds were prepared through a multi-step synthesis process and their chemical structures were characterized employing FT-IR, NMR, and mass spectrometry analysis. Cytotoxic and Hsp90 inhibition activities of synthesized compounds were assessed by MTT assay and ELISA kit, respectively. Based on the obtained results, compound 5 exhibited the highest cytotoxicity (IC 50 ; 14 µM) against cancer cells and reduced Hsp90 expression from 5.54 ng/mL in untreated (normal cells) to 1.56 ng/mL in cancer cells. Moreover, molecular dynamics (MD) simulation results indicated its high affinity to target protein and approved its excellent stability which is essential for exerting an inhibitory effect on cancer cell proliferation.
Competing Interests: Declarations Competing interests The authors declare no competing interests. Institutional review board statement The project was found to be in accordance to the ethical principle and national norms and standards for conducting medical research in Iran (Approval ID IR.MUI.RESEARCH.REC.1398.425 and Approval date 2019-11-02).
(© 2024. The Author(s).)
Databáze: MEDLINE
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