作为有效的衰老细胞清除剂的胡椒碱类似物的设计与优化。

Design and optimization of piperlongumine analogs as potent senolytics.

机构信息

Department of Medicinal Chemistry and University of Florida, Gainesville, FL, 32610, USA.

Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.

出版信息

Bioorg Med Chem Lett. 2024 Jan 15;98:129593. doi: 10.1016/j.bmcl.2023.129593. Epub 2023 Dec 15.

DOI:10.1016/j.bmcl.2023.129593

PMID:38104906

Abstract

Selective removal of senescent cells (SnCs) offers a promising therapeutic strategy to treat chronic and age-related diseases. Our prior investigations led to the discovery of piperlongumine (PL) and its derivatives as senolytic agents. In this study, our medicinal chemistry campaign on both the α,β-unsaturated δ-valerolactam ring and the phenyl ring of PL culminated in the identification of compound 24, which exhibited an impressive 50-fold enhancement in senolytic activity against senescent WI-38 fibroblasts compared to PL.

摘要

选择性清除衰老细胞 (SnCs) 为治疗慢性和与年龄相关的疾病提供了一种有前途的治疗策略。我们之前的研究导致发现了胡椒碱 (PL) 及其衍生物作为衰老细胞裂解剂。在这项研究中，我们对 PL 的α,β-不饱和 δ-戊内酰胺环和苯环进行了药物化学研究，最终确定了化合物 24，它对衰老的 WI-38 成纤维细胞的衰老细胞裂解活性比 PL 提高了 50 倍。