Abd Elhameed Alaa A, Ali Ahmed R, Ghabbour Hazem A, Bayomi Said M, El-Gohary Nadia S
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University Mansoura 35516 Egypt
RSC Med Chem. 2025 Jan 22. doi: 10.1039/d4md00754a.
Novel thiazole analogs 3a, 3b, 4, 5, 6a-g, 8a, 8b, 9a-c, 10a-d and 11 were designed and synthesized as molecular mimetics of sunitinib. antitumor activity of the obtained compounds was investigated against HepG2, HCT-116, MCF-7, HeP-2 and HeLa cancer cell lines. The obtained data showed that compounds 3b and 10c are the most potent members toward HepG2, HCT-116, MCF-7 and HeLa cells. Moreover, compounds 3a, 3b, 6g, 8a and 10c were assessed for their VEGFR-2 inhibitory activity. Results proved that compound 10c exhibited outstanding VEGFR-2 inhibition (IC = 0.104 μM) compared to sunitinib. Compound 10c paused the G0-G1 phase of the cell cycle in HCT-116 and MCF-7 cells and the S phase in HeLa cells. Additionally, compound 10c elevated caspase-3/9 levels in HCT-116 and HeLa cells, leading to cancer cell death apoptosis. Furthermore, compound 10c showed a significant reduction in tumor volume in Swiss albino female mice as an breast cancer model. Docking results confirmed the tight binding interactions of compound 10c with the VEGFR-2 binding site, with its binding energy surpassing that of sunitinib. PK studies predicted compound 10c to have good oral bioavailability and a good drug score with low human toxicity risks.
设计并合成了新型噻唑类似物3a、3b、4、5、6a - g、8a、8b、9a - c、10a - d和11作为舒尼替尼的分子模拟物。研究了所得化合物对HepG2、HCT - 116、MCF - 7、HeP - 2和HeLa癌细胞系的抗肿瘤活性。所得数据表明，化合物3b和10c对HepG2、HCT - 116、MCF - 7和HeLa细胞是最有效的成员。此外，评估了化合物3a、3b、6g、8a和10c的VEGFR - 2抑制活性。结果证明，与舒尼替尼相比，化合物10c表现出出色的VEGFR - 2抑制作用（IC = 0.104 μM）。化合物10c使HCT - 116和MCF - 7细胞的细胞周期停滞在G0 - G1期，使HeLa细胞的细胞周期停滞在S期。此外，化合物10c提高了HCT - 116和HeLa细胞中caspase - 3/9的水平，导致癌细胞死亡 凋亡。此外，作为乳腺癌模型，化合物10c在瑞士白化雌性小鼠中显示出肿瘤体积显著减小。对接结果证实了化合物10c与VEGFR - 2结合位点的紧密结合相互作用，其结合能超过了舒尼替尼。PK研究预测化合物10c具有良好的口服生物利用度和良好的药物评分，且人体毒性风险较低。
