Structure–Activity Relationship of FL118 Platform Position 7 Versus Position 9‑Derived Compounds and Their Mechanism of Action and Antitumor Activity

• Published in: Journal of medicinal chemistry 2023-12, Vol.66 (24), p.16888-16916
• Main Authors: Wang, Wenchao, Ling, Xiang, Wang, Ruojiong, Xiong, Haonan, Hu, Liuzhi, Yang, Zhikun, Wang, Hong, Zhang, Yali, Wu, Wenjie, Singh, Prashant K., Wang, Jianmin, Li, Fengzhi, Li, QingYong
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Benzodioxoles - pharmacology; Cell Line, Tumor; Humans; Indolizines - therapeutic use; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01589

Structurally, FL118 is a camptothecin analogue and possesses exceptional antitumor efficacy against human cancer through a novel mechanism of action (MOA). In this report, we have synthesized and characterized 24 FL118 Position 7-substituted and 24 FL118 Position 9-substituted derivatives. The top compounds were further characterized for their MOA in colorectal cancer (CRC) models using CRC patient-derived xenograft (PDX) models and pancreatic cancer PDX models to evaluate their antitumor activities. Four FL118 Position 7-substituted derivatives showed significantly better antitumor efficacy than the FL118 Position 9-substituted derivatives. The four identified compounds also appeared to have better antitumor activity than their parental platform FL118. Interestingly, RNA-Seq analyses indicated that three of the four compounds exerted antitumor effects via an MOA similar to FL118, which provided an intriguing opportunity for follow-up studies. Extended in vivo studies revealed that FL77-6 (7-(4-ethylphenyl)-FL118), FL77-9 (7-(4-methoxylphenyl)-FL118), and FL77-24 (7-(3, 5-dimethoxyphenyl)-FL118) exhibit potential for further development toward clinical trials.