Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation
Open accessAbstract
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 α,β-unsaturated δ-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 α-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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Additional senolytics such as HSP90 inhibitors and piperlongumine have been shown to act selectively on senescent cells.
“Other senolytics, including HSP90 inhibitors213,214 and piperlongumine215,216, have also been demonstrated to be selective towards senescent cells.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [216]
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- Authors
- Liu, X., Wang, Y., Zhang, X., Gao, Z., Zhang, S., Shi, P., Zhang, X., Song, L., Hendrickson, H., Zhou, D., & Zheng, G.
- Affiliations
- University of Arkansas for Medical Sciences (US)
- University of Florida (US)
- Corresponding author
- Zheng, Guangrong
- ORCID
- Venue
- Bioorganic & Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 26
- Issue
- 14
- Pages
- 3925-3938
- ISSN
- 0968-0896 (ISSN-L)
- PMC
- PMC6087492
- OpenAlex
- W2809248765
- Cited by
- 77
- References
- 53
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 10 · 2023: 7 · 2022: 13 · 2021: 9 · 2020: 8 · 2019: 4 · 2018: 2
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Bioorganic & Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01CA122023, R01CA211963, P20GM109005, R56AG056372)
- University of Arkansas
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Piperaceae Chemical and Biological Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- piperlongumine, senolytics, senescent cells, structure-activity relationship, Michael acceptors, reactive oxygen species, WI-38 cells, OXR1, oxidative stress response, age-related diseases, chemotherapy-induced senescence
- MeSH terms
- Dioxolanes, Dose-Response Relationship, Drug, Humans, Infrared Rays, Piperidones, Proteins, Structure-Activity Relationship, Molecular Structure, Cellular Senescence, Apoptosis, Reactive Oxygen Species, Mitochondrial Proteins
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