Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 26, Issue 14, Pages 3925-3938Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2018.06.013
Keywords
Piperlongumine; Senescent cell; Senolytic agent; ROS; OXR1
Funding
- U.S. National Institutes of Health [R01CA122023, R01CA211963, P20GM109005, R56AG056372]
- UNITY Biotechnology
- University of Arkansas for Medical Sciences
- NATIONAL CANCER INSTITUTE [R01CA122023, R01CA211963] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P20GM109005] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R56AG056372] Funding Source: NIH RePORTER
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Selective clearance of senescent cells (SCs) has emerged as a potential therapeutic approach for age-related diseases, as well as chemotherapy- and radiotherapy-induced adverse effects. Through a cell-based phenotypic screening approach, we recently identified piperlongumine (PL), a dietary natural product, as a novel senolytic agent, referring to small molecules that can selectively kill SCs over normal or non-senescent cells. In an effort to establish the structure-senolytic activity relationships of PL analogues, we performed a series of structural modifications on the trimethoxyphenyl and the alpha,beta-unsaturated delta-valerolactam rings of PL. We show that modifications on the trimethoxyphenyl ring are well tolerated, while the Michael acceptor on the lactam ring is critical for the senolytic activity. Replacing the endocyclic C2-C3 olefin with an exocyclic methylene at C2 render PL analogues 47-49 with increased senolytic activity. These alpha-methylene containing analogues are also more potent than PL in inducing ROS production in WI-38 SCs. Similar to PL, 47-49 reduce the protein levels of oxidation resistance 1 (OXR1), an important oxidative stress response protein that regulates the expression of a variety of antioxidant enzymes, in cells. This study represents a useful starting point toward the discovery of senolytic agents for therapeutic uses.
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