National Organization for Drug Control and Research, Cairo, Egypt.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
Drug Dev Res. 2024 Nov;85(7):e70007. doi: 10.1002/ddr.70007.
Novel 3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives were synthesized and screened for their antiproliferative activity against a panel of 60 cancer cell lines. Derivatives 5b, 5f, and 9c showed significant antitumor activity at a single dose with mean growth inhibition of 55.62%, 55.79%, and 71.40%, respectively. These compounds were further investigated against HCT-116, colon cancer cell line, and FHC, normal colon cell line. Compound 9c showed the highest activity with IC = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC = 2.556 ± 0.09 µM and SI = 6.19. Compound 9c was also the most potent against B-RAF and mutated B-RAF with IC = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively. The cell cycle analysis showed that 9c increased the cell population and induced an arrest in the cell cycle of HCT-116 cancer cells at the G0-G1 stage with 1.23-fold. Apoptosis evaluation showed that compound 9c displayed an 18.18-fold elevation in total apoptosis of HCT-116 cancer cells in comparison to the control. Compound 9c increased the content of caspase-3 by 3.52-fold versus the control. A molecular modeling study determined the binding profile and interaction of 9c with the B-RAF active site.
新型 3-苯基四氢苯并[4,5]噻吩并[2,3-d]嘧啶衍生物被合成并筛选其对 60 种癌细胞系的抗增殖活性。衍生物 5b、5f 和 9c 在单剂量下表现出显著的抗肿瘤活性，平均生长抑制率分别为 55.62%、55.79%和 71.40%。这些化合物进一步针对 HCT-116（结肠癌细胞系）和 FHC（正常结肠细胞系）进行了研究。化合物 9c 表现出最高的活性，IC = 0.904 ± 0.03 µM，SI = 20.42，优于 doxorubicin，其 IC = 2.556 ± 0.09 µM，SI = 6.19。与 vemurafenib 相比，化合物 9c 对 B-RAF 和突变型 B-RAF 的抑制作用也最强，IC = 0.145 ± 0.005 和 0.042 ± 0.002 µM，而 vemurafenib 的 IC = 0.229 ± 0.008 和 0.038 ± 0.001 µM。细胞周期分析表明，9c 增加了 HCT-116 癌细胞的细胞群体，并诱导细胞周期在 G0-G1 期停滞，细胞群体增加了 1.23 倍。凋亡评估显示，与对照组相比，化合物 9c 使 HCT-116 癌细胞的总凋亡增加了 18.18 倍。与对照组相比，化合物 9c 使 caspase-3 的含量增加了 3.52 倍。分子建模研究确定了 9c 与 B-RAF 活性位点的结合模式和相互作用。
