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

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.