Benzothiazole and chromone derivatives as potential ATR kinase inhibitors and anticancer agents

Show simple item record Frasinyuk, Mykhaylo Chhabria, Dimple Kartsev, Victor Dilip, Haritha Sirakanyan, Samvel N. Kirubakaran, Sivapriya Petrou, Anthi Geronikaki, Athina Spinelli, Domenico
dc.coverage.spatial Switzerland 2022-08-02T14:47:37Z 2022-08-02T14:47:37Z 2022-07
dc.identifier.citation Frasinyuk, Mykhaylo; Chhabria, Dimple; Kartsev, Victor; Dilip, Haritha; Sirakanyan, Samvel N.; Kirubakaran, Sivapriya; Petrou, Anthi; Geronikaki, Athina and Spinelli, Domenico, "Benzothiazole and chromone derivatives as potential ATR kinase inhibitors and anticancer agents", Molecules, DOI: 10.3390/molecules27144637, vol. 27, no. 14, Jul. 2022. en_US
dc.identifier.issn 1420-3049
dc.description.abstract Despite extensive studies and the great variety of existing anticancer agents, cancer treatment remains an aggravating and challenging problem. Therefore, the development of novel anticancer drugs with a better therapeutic profile and fewer side effects to combat this persistent disease is still necessary. In this study, we report a novel series of benzothiazole and chromone derivatives that were synthesized and evaluated for their anticancer activity as an inhibitor of ATR kinase, a master regulator of the DDR pathway. The cell viability of a set of 25 compounds was performed using MTT assay in HCT116 and HeLa cell lines, involving 72 h incubation of the compounds at a final concentration of 10 �M. Cells incubated with compounds 2c, 7h and 7l were found to show viability ?50%, and were taken forward for dose-response studies. Among the tested compounds, three of them (2c, 7h and 7l) showed higher potency, with compound 7l exhibiting the best IC50 values in both the cell lines. Compounds 2c and 7l were found to be equally cytotoxic towards both the cell lines, namely, HCT116 and HeLa, while compound 7h showed better cytotoxicity towards HeLa cell line. For these three compounds, an immunoblot assay was carried out in order to analyze the inhibition of phosphorylation of Chk1 at Ser 317 in HeLa and HCT116 cells. Compound 7h showed inhibition of pChk1 at Ser 317 in HeLa cells at a concentration of 3.995 �M. Further analysis for Chk1 and pChk1 expression was carried out in Hela cells by treatment against all the three compounds at a range of concentrations of 2, 5 and 10 �M, wherein compound 7h showed Chk1 inhibition at 2 and 5 �M, while pChk1 expression was observed for compound 7l at a concentration of 5 �M. To support the results, the binding interactions of the compounds with the ATR kinase domain was studied through molecular docking, wherein compounds 2c, 7h and 7l showed binding interactions similar to those of Torin2, a known mTOR/ATR inhibitor. Further studies on this set of molecules is in progress for their specificity towards the ATR pathway.
dc.description.statementofresponsibility by Mykhaylo Frasinyuk, Dimple Chhabria, Victor Kartsev, Haritha Dilip, Samvel N. Sirakanyan, Sivapriya Kirubakaran, Anthi Petrou, Athina Geronikaki and Domenico Spinelli
dc.language.iso en_US en_US
dc.publisher MDPI en_US
dc.subject Benzothiazole en_US
dc.subject Chromone en_US
dc.subject Kinase inhibitor en_US
dc.subject Anticancer en_US
dc.subject DDR en_US
dc.subject ATR en_US
dc.title Benzothiazole and chromone derivatives as potential ATR kinase inhibitors and anticancer agents en_US
dc.type Article en_US
dc.relation.journal Molecules

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