Design, synthesis, and biological evaluation of sorafenib derivatives containing indole (ketone) semicarbazide analogs as antitumor agents

• Published in: Journal of heterocyclic chemistry Vol. 57; no. 6; pp. 2548 - 2560
• Main Authors: Li, Wen, Qi, Ya‐Yun, Wang, Yuan‐Yuan, Gan, Yi‐Yuan, Shao, Li‐Hui, Zhang, Li‐Qiong, Tang, Zhen‐Hua, Zhu, Mei, Tang, Si‐Yu, Wang, Zhen‐Chao, Ouyang, Gui‐Ping
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Inc 01.06.2020; Wiley; Wiley Subscription Services, Inc
• Subjects: Anticancer properties; Apoptosis; Assaying; Benzene; Cancer; Chemistry; Chemistry, Organic; Derivatives; Leukemia; Physical Sciences; Reagents; Science & Technology; Synthesis; Wound healing; APOPTOSIS; CELLS; HEPATOCELLULAR-CARCINOMA; DOWN-REGULATION; TARGETS; CANCER; MULTIKINASE INHIBITOR; RAF/MEK/ERK PATHWAY; BAY 43-9006; DISCOVERY
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.3972

A series of new sorafenib derivatives was designed and synthesized. The antiproliferative activity of the synthesized compounds against human lung cancer cell (A549), human pancreatic cancer cell (PC‐3), human leukemia cell (K562), and human hepatoma cell (SMMC‐7721) was evaluated by MTT assay. The results revealed that several compounds displayed more significant antitumor activities than commercial anticancer agent sorafenib against SMMC‐7721. In addition, compounds 7a, 7g, 7l, 7m, and 7p represented obvious growth inhibition with IC50 values of 1‐9 μM against four cancer cell lines, demonstrating more predominant activities against cancer cells as compared to sorafenib. Furthermore, some structure‐activity relationships have also been established. Compounds containing indole and benzene ring substituted by halogen showed better activity than sorafenib. Wound healing assay suggested that cells would be targeted on their migratory capacity by 7g, potentially affecting the migration activity of these tumors. The effects of A549 and PC‐3 cell apoptosis induced by compound 7g were significantly increased compared with sorafenib. Importantly, the result of western blot assay showed that 7g inhibited cell growth by suppressing the activity of EGFR, especially the expression of p‐EGFR (Tyr1068).