Piperlongumine (piplartine) and analogues: Antiproliferative microtubule-destabilising agents.
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.
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
Mary J
MJ
Meegan
School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160, Pearse Street, Trinity College Dublin, Dublin 2, Ireland.
Seema
S
Nathwani
School of Chemistry, Trinity College Dublin, Dublin 2, Ireland.
Brendan
B
Twamley
School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, 152-160, Pearse Street, Trinity College Dublin, Dublin 2, Ireland.
Daniela M
DM
Zisterer
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: oboyleni@tcd.ie.
Niamh M
NM
O'Boyle
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004148:Dioxolanes / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004148:Dioxolanes; D010881:Piperidones; D017382:Reactive Oxygen Species; D014404:Tubulin; D050257:Tubulin Modulators; C498077:piperlongumine
Anticancer; Antiproliferative; Combretastatin A-4; Microtubule-destabilising; Piperlongumine; Tubulin