Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf Province, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Molecules. 2021 Jan 14;26(2):412. doi: 10.3390/molecules26020412.
Cyclin-dependent kinases (CDKs) regulate mammalian cell cycle progression and RNA transcription. Based on the structural analysis of previously reported CDK2 inhibitors, a new compound with 3-hydrazonoindolin-2-one scaffold () was well designed, synthesized, and biologically evaluated as a promising anti-breast cancer hit compound.
The potential anti-cancerous effect of was evaluated using cytotoxicity assay, flow cytometric analysis of apoptosis and cell cycle distribution, ELISA immunoassay, in vitro CDK2/cyclin A2 activity, and molecular operating environment (MOE) virtual docking studies.
The results revealed that exhibits pronounced CDK2 inhibitory activity and cytotoxicity in human breast cancer MCF-7 cell line. The cytotoxicity of was found to be intrinsically mediated apoptosis, which in turn, is associated with low Bcl-2 expression and high activation of caspase 3 and p53. Besides, blocked the proliferation of the MCF-7 cell line and arrested the cell cycle at the G2/M phase. The docking studies did not confirm which one of geometric isomers ( and ) is responsible for binding affinity and intrinsic activity of . However, the molecular dynamic studies have confirmed that the -isomer has more favorable binding interaction and thus is responsible for CDK2 inhibitory activity.
These findings displayed a substantial basis of synthesizing further derivatives based on the 3-hydrazonoindolin-2-one scaffold for favorable targeting of breast cancer.
细胞周期蛋白依赖性激酶（CDKs）调节哺乳动物细胞周期进程和 RNA 转录。基于先前报道的 CDK2 抑制剂的结构分析，我们精心设计、合成了一种具有 3-腙基吲哚啉-2-酮骨架的新型化合物（），并将其作为有前途的抗乳腺癌命中化合物进行了生物学评价。
采用细胞毒性测定法、细胞凋亡和细胞周期分布流式细胞术分析、ELISA 免疫测定法、体外 CDK2/细胞周期蛋白 A2 活性测定法和分子操作环境（MOE）虚拟对接研究评估了的潜在抗癌作用。
结果表明，在人乳腺癌 MCF-7 细胞系中，表现出明显的 CDK2 抑制活性和细胞毒性。发现的细胞毒性是内在介导的细胞凋亡，进而与低 Bcl-2 表达和高激活 caspase 3 和 p53 相关。此外，还阻断了 MCF-7 细胞系的增殖并将细胞周期阻滞在 G2/M 期。对接研究不能确定几何异构体（和）中的哪一个负责结合亲和力和的内在活性。然而，分子动力学研究已经证实 -异构体具有更有利的结合相互作用，因此负责 CDK2 抑制活性。
这些发现为进一步基于 3-腙基吲哚啉-2-酮骨架合成衍生物提供了重要依据，以有利于针对乳腺癌进行靶向治疗。
