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1. NATURAL SCIENCES, 1.4 CHEMICAL SCIENCES, Organic Chemistry, Biochemistry and molecular biology, Pharmacology and pharmacy, Medicinal chemistry, Oncology
Piperlongumine (piplartine, 1) is a small molecule alkaloid that is receiving intense interest due to its antiproliferative and anticancer activities. We investigated the effects of 1 on tubulin and microtubules. Using both an isolated tubulin assay, and a combination of sedimentation and Western blotting, we demonstrated that 1 is a tubulin-destabilising agent. This result was confirmed by immunofluorescence and confocal microscopy, which showed that microtubules in MCF-7 breast cancer cells were depolymerised when treated with 1. We synthesised a number of analogues of 1 to explore structure-activity relationships. Compound 13 had the best cytotoxic profile of this series, showing potent effects in human breast carcinoma MCF-7 cells whilst being relatively non-toxic to non-tumorigenic MCF-10a cells. These compounds will be further developed as potential clinical candidates for the treatment of breast cancer.
Megan, M. et al (2016). Piperlongumine (piplartine) and analogues: antiproliferative microtubule-destabilising agents. European Journal of Medicinal Chemistry,,Vol. 125, no. 5, pp. 453-463. doi: 10.1016/j.ejmech.2016.09.048
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European Journal of Medicinal Chemistry
Volume 125, 5 January 2017, Pages 453-463