A series of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives (3a₁−3d₆) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activities against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicities against HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results showed that the representative compound 3a₁ exhibited effective inhibition on tumor growth in the HepG2 xenograft mouse model. Mechanistic studies suggested that 3a₁ may exert antitumor activity by the up-regulation of Bax, intracellular Ca²⁺ release, ROS generation, p21, p27 and p53, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, and inhibition of CDK activity.

中文翻译：

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新型 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline 衍生物作为抗肿瘤剂的设计、合成和药理学评价：体外和体内抗肿瘤活性、细胞周期停滞和凋亡反应†

设计并合成了一系列新型2-氯-3-(1 H-苯并[ d ]咪唑-2-基)喹啉衍生物( 3a ₁ -3d _{6 )作为抗肿瘤剂。}体外抗肿瘤试验结果表明，一些化合物对 HepG2、SK-OV-3、NCI-H460 和 BEL-7404 肿瘤细胞系表现出中度至高度抑制活性，与 HL-7702 正常细胞系相比，大多数化合物表现出低得多的细胞毒性对 5-FU 和顺铂。体内抗肿瘤试验结果表明，代表性化合物3a ₁在HepG2异种移植小鼠模型中对肿瘤生长具有有效抑制作用。机理研究表明，3a ₁可能通过上调 Bax、细胞内 Ca ²⁺释放、ROS 生成、p21、p27 和 p53、Bcl-2 下调、caspase-9 和 caspase-3 的激活以及随后的 PARP 裂解来发挥抗肿瘤活性，和抑制 CDK 活性。