Mansour Nayera I, El-Sayed Selwan M, El-Gohary Nadia S, Abdel-Aziz Naglaa I, El-Subbagh Hussein I, Ghaly Mariam A
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt.
Bioorg Chem. 2022 Oct;127:105966. doi: 10.1016/j.bioorg.2022.105966. Epub 2022 Jun 14.
A novel series of phthalimide derivatives was synthesized and evaluated for in vitro antitumor activity against six human cancer cell lines; HepG-2, HCT-116, MCF-7, Hep2, PC3 and Hela.The obtained results revealed that compound 32 was the most potent antitumor, while compounds 33, 22 and 24 showed strong activity against all tested cell lines. Further biological evaluation of the most active compounds was done and their in vitro EGFR-TK inhibition was tested, and the results came in accordance with the results of antitumor testing, where 32 displayed promising inhibitory activity (IC = 0.065 µM) compared to the standard drug erlotinib (IC = 0.067 µM). In addition, compounds 48, 22, 28 and 19 showed strong inhibitory activity (IC = 0.089, 0.093, 0.147 and 0.152 µM respectively). Cell cycle analysis was conducted and the results revealed that 32 induced cell cycle arrest on Hela and MCF-7 at G0-G1 phase and Pre-G1 phase causing cell death mainly via apoptosis. Additionally, in vivo antitumor screening revealed that 32 reduced both body weight and tumor volume in solid tumor utilizing Ehrlich ascites carcinoma (EAC) animal model. Molecular modeling study showed that 32 and 48 have the highest affinity for binding with the active site of EGFR-TK with docking score comparable to erlotinib. Compounds 32 and 48 could be used as template models for further optimization.
合成了一系列新型邻苯二甲酰亚胺衍生物，并对其针对六种人类癌细胞系（HepG-2、HCT-116、MCF-7、Hep2、PC3和Hela）的体外抗肿瘤活性进行了评估。所得结果表明，化合物32具有最强的抗肿瘤活性，而化合物33、22和24对所有测试细胞系均表现出较强的活性。对活性最强的化合物进行了进一步的生物学评估，并测试了它们的体外表皮生长因子受体酪氨酸激酶（EGFR-TK）抑制作用，结果与抗肿瘤测试结果一致，其中化合物32表现出有前景的抑制活性（IC = 0.065 μM），与标准药物厄洛替尼（IC = 0.067 μM）相当。此外，化合物48、22、28和19表现出较强的抑制活性（IC分别为0.089、0.093、0.147和0.152 μM）。进行了细胞周期分析，结果表明，化合物32在Hela和MCF-7细胞系中诱导细胞周期在G0-G1期和前G1期停滞，主要通过凋亡导致细胞死亡。此外，体内抗肿瘤筛选显示，在利用艾氏腹水癌（EAC）动物模型的实体瘤中，化合物32降低了体重和肿瘤体积。分子模拟研究表明，化合物32和48与EGFR-TK活性位点结合的亲和力最高，对接分数与厄洛替尼相当。化合物32和48可作为进一步优化的模板模型。
