Design and optimization of piperlongumine analogs as potent senolytics

  • Bioorg Med Chem Lett. 2023 Dec 15:98:129593. doi: 10.1016/j.bmcl.2023.129593.
Xuan Zhang  1 ,  Yonghan He  2 ,  Xingui Liu  2 ,  Xin Zhang  2 ,  Peizhong Shi  3 ,  Yingying Wang  3 ,  Daohong Zhou  4 ,  Guangrong Zheng  5
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: [email protected].
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.
Products