Design and optimization of piperlongumine analogs as potent senolytics

Xuan Zhang; Yonghan He; Xingui Liu; Xin Zhang; Peizhong Shi; Yingying Wang; Daohong Zhou; Guangrong Zheng

doi:10.1016/j.bmcl.2023.129593

Design and optimization of piperlongumine analogs as potent senolytics

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

Authors

Xuan Zhang¹, Yonghan He², Xingui Liu², Xin Zhang², Peizhong Shi³, Yingying Wang³, Daohong Zhou⁴, Guangrong Zheng⁵

Affiliations

¹ Department of Medicinal Chemistry and University of Florida, Gainesville, FL, 32610, USA.
² Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
³ Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72204, USA.
⁴ Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA; Department of Biochemistry and Structure Biology, Center of Innovative Drug Discovery, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
⁵ Department of Medicinal Chemistry and University of Florida, Gainesville, FL, 32610, USA. Electronic address: zhengg@cop.ufl.edu.

PMID: 38104906
DOI: 10.1016/j.bmcl.2023.129593

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.

Keywords: Cellular senescence; Piperlongumine; Senescent cells; Senolytics; Structure activity relationship.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Benzodioxoles
Cellular Senescence*
Senotherapeutics*

Substances

Senotherapeutics
piperlonguminine
Benzodioxoles

Abstract

Publication types

MeSH terms

Substances

Grants and funding