The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs
Open accessAbstract
Piperlongumine is a naturally occurring small molecule recently identified to be toxic selectively to cancer cells in vitro and in vivo. This compound was found to elevate cellular levels of reactive oxygen species (ROS) selectively in cancer cell lines. The synthesis of 80 piperlongumine analogs has revealed structural modifications that retain, enhance, and ablate key piperlongumine-associated effects on cells, including elevation of ROS, cancer cell death, and selectivity for cancer cells over nontransformed cell types. Structure/activity relationships suggest that the electrophilicity of the C2-C3 olefin is critical for the observed effects on cells. Furthermore, we show that analogs lacking a reactive C7-C8 olefin can elevate ROS to levels observed with piperlongumine but show markedly reduced cell death, suggesting that ROS-independent mechanisms, including cellular cross-linking events, may also contribute to piperlongumine’s induction of apoptosis. In particular, we have identified irreversible protein glutathionylation as a process associated with cellular toxicity. We propose a mechanism of action for piperlongumine that may be relevant to other small molecules having two sites of reactivity, one with greater and the other with lesser electrophilicity.
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Cites
Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?
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Ras Proteins Induce Senescence by Altering the Intracellular Levels of Reactive Oxygen Species
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“Cancer cells have been reported to harbor higher levels of ROS than nontransformed cells, and in some cases activation of a specific oncogene (for example, HRAS) is sufficient to elevate levels of ROS (1, 2).”
BackgroundRedox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities
Wondrak, G. T. (2009) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2541 · Cited by 462
Proteomics Analysis of Cellular Response to Oxidative Stress
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Cited by
Reactive oxygen species and cancer paradox: To promote or to suppress?
Galadari, S., Rahman, A., Pallichankandy, S., & Thayyullathil, F. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.01.004 · Cited by 893
Overview of the therapeutic potential of piplartine (piperlongumine)
Bezerra, D. P., Pessoa, C., de Moraes, M. O., Saker-Neto, N., Silveira, E. R., & Costa-Lotufo, L. V. (2013) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2012.12.003 · Cited by 324
Discovery of piperlongumine as a potential novel lead for the development of senolytic agents
Wang, Y., Chang, J., Liu, X., Zhang, X., Zhang, S., Zhang, X., Zhou, D., & Zheng, G. (2016) · Aging · doi:10.18632/aging.101100 · Cited by 274
Small molecules regulating reactive oxygen species homeostasis for cancer therapy
Zhang, J., Duan, D., Song, Z., Liu, T., Hou, Y., & Fang, J. (2021) · Medicinal Research Reviews · doi:10.1002/med.21734 · Cited by 184
Lozano-Torres, B., Estepa-Fernández, A., Rovira, M., Orzáez, M., Serrano, M., Martínez-Máñez, R., & Sancenón, F. (2019) · Nature Reviews Chemistry · doi:10.1038/s41570-019-0108-0 · Cited by 140
Metadata
- Authors
- Adams, D. J., Dai, M., Pellegrino, G., Wagner, B. K., Stern, A. M., Shamji, A. F., & Schreiber, S. L.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2012-09-04
- Volume
- 109
- Issue
- 38
- Pages
- 15115-15120
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1968351045
- Cited by
- 228
- References
- 7
- FWCI
- 18.35
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Adams, D. J., Dai, M., Pellegrino, G., Wagner, B. K., Stern, A. M., Shamji, A. F., & Schreiber, S. L. (2012). Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1212802109
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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