Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey.
Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan.
Anticancer Agents Med Chem. 2021;21(6):716-724. doi: 10.2174/1871520620666200807221731.
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.
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.
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.
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.
The recently developed compounds might be employed as lead structures for the design of new antitumor drugs targeting PI3Kα.
癌症是一组危及生命的疾病，在全球范围内，是仅次于心脏病的第二大死亡原因。设计和开发针对选择性癌细胞的新型支架被认为是癌症治疗的一个有前途的目标。
先前已经制备了查尔酮衍生物；6-(3-芳基-2-丙烯酰基)-2(3H)-苯并恶唑酮，并对口腔鳞状细胞癌细胞系 HSC-2 进行了评估，结果表明其对肿瘤具有极高的选择性。本研究的目的是进一步研究查尔酮衍生物对人结肠癌细胞的抗癌活性，并可能阐明其作用机制。
进行了计算研究，以探索合成分子与磷酸肌醇-4,5-二磷酸 3-激酶α（PI3Kα）的潜在相互作用。对化合物 1-23 的抗增殖活性进行了生物评估，针对结肠癌细胞系 HCT116。通过测定乳酸脱氢酶（LDH）活性来研究坏死，而通过 caspase-3 激活和 DNA 测量来评估处理细胞中的细胞凋亡。
针对 PI3Kα 激酶结构域的 Glide 研究表明，6-(3-芳基-2-丙烯酰基)-2(3H)-苯并恶唑酮骨架与 K802、Y836、E849、V851、N853、Q859 和 D933 形成氢键，并且它符合 PI3Kα 活性抑制剂的指纹。在 HCT116 细胞系中对报告化合物进行的生物学评估证实，该系列化合物抑制了 PI3Kα 的活性，并通过激活 caspase-3 和减少 DNA 含量诱导细胞凋亡。
新开发的化合物可能被用作针对 PI3Kα 的新型抗肿瘤药物设计的先导结构。
