Docking Studies and Antiproliferative Activities of 6-(3-aryl-2-propenoyl)-2(3H)- benzoxazolone Derivatives as Novel Inhibitors of Phosphatidylinositol 3-Kinase (PI3Kα)

Sinan       Bilginer; Sanaa    K.    Bardaweel; Dima    A.    Sabbah; Halise    Inci    Gul

doi:10.2174/1871520620666200807221731

Abstract

Background: Cancer is a life-threatening group of diseases and universally, the second main cause of death. The design and development of new scaffolds targeting selective cancer cells are considered a promising goal for cancer treatment.

Aims and Objective: Chalcone derivatives; 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolone, were previously prepared and evaluated against the oral cavity squamous cell carcinoma cell line, HSC-2, and were reported to have remarkably high tumor selectivity. The aim of this study was to further investigate the anticancer activities of the chalcone derivatives against human colon cancer cells with a possible elucidation of their mechanism of action.

Methods: Computational studies were conducted to explore the potential interaction of the synthesized molecules with the phosphatidylinositol-4,5-bisphosphate 3-kinaseα (PI3Kα). Biological evaluation of the antiproliferative activities associated with compounds 1-23 was carried out against the colon cancer cell line, HCT116. Lactate Dehydrogenase (LDH) activity was measured to study necrosis, while the caspase-3 activation and DNA measurements were used to evaluate apoptosis in the treated cells.

Results: Glide studies against PI3Kα kinase domain demonstrated that the 6-(3-aryl-2-propenoyl)-2(3H)- benzoxazolone scaffold forms H-bond with K802, Y836, E849, V851, N853, Q859, and D933, and it fits the fingerprint of PI3Kα active inhibitors. Biological evaluation of the reported compounds in HCT116 cell line confirmed that the series inhibited PI3Kα activity and induced apoptosis via activation of caspase-3 and reduction of DNA content.

Conclusion: The recently developed compounds might be employed as lead structures for the design of new antitumor drugs targeting PI3Kα.

Keywords: Molecular docking, PI3Kα, colon cancer, apoptosis, chalcone, LDH.

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DOI https://dx.doi.org/10.2174/1871520620666200807221731	Print ISSN 1871-5206
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Anti-Cancer Agents in Medicinal Chemistry

Docking Studies and Antiproliferative Activities of 6-(3-aryl-2-propenoyl)-2(3H)- benzoxazolone Derivatives as Novel Inhibitors of Phosphatidylinositol 3-Kinase (PI3Kα)

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