Piperlongumine (piplartine) and analogues: Antiproliferative microtubule-destabilising agents

  • Eur J Med Chem. 2017 Jan 5:125:453-463. doi: 10.1016/j.ejmech.2016.09.048.
Mary J Meegan  1 ,  Seema Nathwani  2 ,  Brendan Twamley  3 ,  Daniela M Zisterer  2 ,  Niamh M O'Boyle  4
Affiliations
  • 1. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
  • 2. School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160, Pearse Street, Trinity College Dublin, Dublin 2, Ireland.
  • 3. School of Chemistry, Trinity College Dublin, Dublin 2, Ireland.
  • 4. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160, Pearse Street, Trinity College Dublin, Dublin 2, Ireland. Electronic address: [email protected].
PMID: 27689728 DOI: 10.1016/j.ejmech.2016.09.048
Abstract

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 depolymerized 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.

Keywords
Anticancer; Antiproliferative; Combretastatin A-4; Microtubule-destabilising; Piperlongumine; Tubulin.