1. Effective synthesis of novel dihydrobenzisoxazoles bearing the 2-aminothiazole moiety and evaluation of the antiproliferative activity of their acylated derivatives.
- Author
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Piven YA Dr, Scherbakov AM Dr, Yastrebova MA, Sorokin DV, Shchegolev YY, Matous AE, Zinovich VG Dr, Khlebnicova TS Dr, and Lakhvich FA Dr
- Subjects
- Humans, Cell Line, Tumor, Structure-Activity Relationship, Acylation, HSP90 Heat-Shock Proteins antagonists & inhibitors, HSP90 Heat-Shock Proteins metabolism, Molecular Structure, Dose-Response Relationship, Drug, Molecular Docking Simulation, Cell Proliferation drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Thiazoles pharmacology, Thiazoles chemistry, Thiazoles chemical synthesis, Isoxazoles pharmacology, Isoxazoles chemistry, Isoxazoles chemical synthesis, Drug Screening Assays, Antitumor
- Abstract
An effective method for the synthesis of 8-aryl-4,5-dihydrothiazolo[4',5':3,4]benzo[1,2- c ]isoxazol-2-amines was developed. This method includes the α-keto bromination of 3-aryl-6,7-dihydrobenzo[ c ]isoxazol-4(5 H )-ones followed by the condensation of the obtained bromo derivatives with thiourea in acetonitrile. Using virtual screening, a series of acylated derivatives of the obtained compounds were selected as potential HSP90 inhibitors. These compounds were prepared and evaluated as antiproliferative agents against three cancer cell lines (A431, 22Rv1, and MCF-7). Compounds 8b, 8c and 8q exhibiting high antiproliferative potency against MCF-7 breast cancer cells with IC
50 values ranging from 2.3 to 9.5 μM were chosen for in-depth evaluation. The selected compounds had remarkable effects on HSP90 client proteins, including steroid hormone receptors and the anti-apoptotic factor BCL2. The obtained compounds are of interest for anticancer drug development.- Published
- 2021
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