Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11541, Saudi Arabia.
Molecules. 2023 Jul 20;28(14):5548. doi: 10.3390/molecules28145548.
The discovery of multi-targeted kinase inhibitors emerged as a potential strategy in the therapy of multi-genic diseases, such as cancer, that cannot be effectively treated by modulating a single biological function or pathway. The current work presents an extension of our effort to design and synthesize a series of new quinazolin-4-one derivatives based on their established anti-cancer activities as inhibitors of multiple protein kinases. The cytotoxicity of the new derivatives was evaluated against a normal human cell line (WI-38) and four cancer lines, including HepG2, MCF-7, MDA-231, and HeLa. The most active compound, , showed broad-spectrum anti-cancer activities against all tested cell lines (IC = 1.94-7.1 µM) in comparison to doxorubicin (IC = 3.18-5.57 µM). Interestingly, compound exhibited lower toxicity in the normal WI-38 cells (IC = 40.85 µM) than doxorubicin (IC = 6.72 µM), indicating a good safety profile. Additionally, the potential of compound as a multi-targeted kinase inhibitor was examined against different protein kinases, including VEGFR2, EGFR, HER2, and CDK2. In comparison to the corresponding positive controls, compound exhibited comparable activities in nanomolar ranges against HER2, EGFR, and VEGFR2. However, compound was the least active against CDK2 (2.097 ± 0.126 µM) when compared to the positive control roscovitine (0.32 ± 0.019 µM). The apoptotic activity investigation in HepG2 cells demonstrated that compound arrested the cell cycle at the S phase and induced early and late apoptosis. Furthermore, the results demonstrated that the apoptosis pathway was provoked due to an upregulation in the expression of the proapoptotic genes caspase-3, caspase-9, and Bax and the downregulation of the Bcl-2 anti-apoptotic gene. For the in silico docking studies, compound showed relative binding interactions, including hydrogen, hydrophobic, and halogen bindings, with protein kinases that are similar to the reference inhibitors.
多靶点激酶抑制剂的发现成为治疗多基因疾病（如癌症）的一种潜在策略，这些疾病不能通过调节单一的生物学功能或途径来有效治疗。目前的工作是我们努力的延伸，旨在设计和合成一系列新的喹唑啉-4-酮衍生物，这些衍生物作为多种蛋白激酶的抑制剂具有抗癌活性。新衍生物的细胞毒性通过对正常人类细胞系（WI-38）和四种癌细胞系（HepG2、MCF-7、MDA-231 和 HeLa）进行评估。最活跃的化合物 ，与多柔比星（IC = 3.18-5.57 µM）相比，对所有测试的细胞系均表现出广谱抗癌活性（IC = 1.94-7.1 µM）。有趣的是，与多柔比星（IC = 6.72 µM）相比，化合物 在正常 WI-38 细胞中的毒性较低（IC = 40.85 µM），表明安全性良好。此外，还研究了化合物 作为多靶点激酶抑制剂的潜力，针对不同的蛋白激酶，包括 VEGFR2、EGFR、HER2 和 CDK2。与相应的阳性对照相比，化合物 在纳摩尔范围内对 HER2、EGFR 和 VEGFR2 表现出相当的活性。然而，与阳性对照罗西维亭（0.32 ± 0.019 µM）相比，化合物 对 CDK2 的活性最低（2.097 ± 0.126 µM）。在 HepG2 细胞中的凋亡活性研究表明，化合物 使细胞周期停滞在 S 期，并诱导早期和晚期凋亡。此外，结果表明，凋亡途径是由于促凋亡基因 caspase-3、caspase-9 和 Bax 的表达上调和抗凋亡基因 Bcl-2 的下调而引发的。对于计算机对接研究，化合物 与蛋白激酶表现出相对的结合相互作用，包括氢键、疏水性和卤素键，与参考抑制剂相似。
