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

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.