Structural Modification and Prodrug Design Based on Natural Stilbene Scaffold for the Discovery of Novel PARP-1 Inhibitors with Improved Antitumor Activity.

Authors

Zhiru Zou, Guoqing Lu, Meixiu Xin, Zhibo Du, Zhuo Cheng, Shaoqiang Wu, Xinwei Chen, Guanbing Chen, Yuchen Cai, Xuejing Zhang, Yong Zou

Published in

Journal of medicinal chemistry. Jul 20, 2026. Epub Jul 20, 2026.

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a critical role in DNA damage repair and has emerged as a synthetic lethal target for BRCA mutant cancers. Herein, we report the discovery of novel PARP-1 inhibitors based on the natural stilbene scaffold through structural modification and ROS-responsive prodrug optimization. A series of stilbene derivatives with ortho-hydroxybenzamide scaffold were designed and synthesized. Among them, compound 24c demonstrated potent antiproliferative activity against BRCA1-deficient cell lines (SUM149PT, MDA-MB-436, and HCC1937) and the BRCA2-deficient cell line (Capan-1). Mechanistic studies revealed that 24c effectively inhibited intracellular PARP-1 activity, exacerbated DNA double-strand breaks, induced ROS generation, and decreased mitochondrial membrane potential, ultimately leading to cell cycle arrest and apoptosis. To enhance in vivo efficacy, ROS-responsive prodrugs were designed and synthesized, with P-24c demonstrating excellent antitumor activity (TGI = 69.3%) and low toxicity in a SUM149PT xenograft model. This work provides a valuable paradigm for developing novel antitumor agents from privileged natural scaffolds.

PMID:
42475630
Bibliographic data and abstract were imported from PubMed on 21 Jul 2026.

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