在这项研究中，我们报道了白杨素衍生物作为一类针对聚（ADP-核糖）聚合酶1（PARP1）的新型抑制剂的发现和构效关系分析。在这些衍生物中，化合物5d成为最有效的基于白杨素的PARP1抑制剂，其IC50值为108 nmol·L-1。该化合物通过诱导 DNA 损伤，显着抑制乳腺癌细胞系 HCC-1937 和 MDA-MB-436 的增殖和迁移。此外，5d 诱导细胞凋亡并导致这些细胞系的 G1/S 期延长。分子对接研究表明5d对PARP1具有很强的结合亲和力。在体内异种移植模型中，5d 通过下调 PARP1 表达有效减少肿瘤生长。总体而言，化合物 5d 显示出作为治疗 BRCA 野生型乳腺癌的潜在治疗剂的前景。版权所有 © 2024 中国药科大学。由 Elsevier B.V. 出版。保留所有权利。

In this study, we reported the discovery and structure-activity relationship analysis of chrysin derivatives as a new class of inhibitors targeting poly (ADP-ribose) polymerase 1 (PARP1). Among these derivatives, compound 5d emerged as the most effective chrysin-based inhibitor of PARP1, with an IC50 value of 108 nmol·L-1. This compound significantly inhibited the proliferation and migration of breast cancer cell lines HCC-1937 and MDA-MB-436 by inducing DNA damage. Furthermore, 5d induced apoptosis and caused an extended G1/S-phase in these cell lines. Molecular docking studies revealed that 5d possesses a strong binding affinity toward PARP1. In vivo, in a xenograft model, 5d effectively reduced tumor growth by downregulating PARP1 expression. Overall, compound 5d shows promise as a potential therapeutic agent for the treatment of BRCA wild-type breast cancer.Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.