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

Mary J. Meegan; Seema Nathwani; Brendan Twamley; Daniela M. Zisterer; Niamh M. O'Boyle

doi:10.1016/j.ejmech.2016.09.048

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

Mary J. Meegan, Seema Nathwani, Brendan Twamley, Daniela M. Zisterer, Niamh M. O'Boyle

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	453-463
Number of pages	11
Journal	European Journal of Medicinal Chemistry
Volume	125
DOIs	https://doi.org/10.1016/j.ejmech.2016.09.048
Publication status	Published - 2017

Keywords

Anticancer
Antiproliferative
Combretastatin A-4
Microtubule-destabilising
Piperlongumine
Tubulin

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@article{cd7de218175e45dab0bcf77699b5772a,

title = "Piperlongumine (piplartine) and analogues: Antiproliferative microtubule-destabilising agents",

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",

author = "Meegan, {Mary J.} and Seema Nathwani and Brendan Twamley and Zisterer, {Daniela M.} and O'Boyle, {Niamh M.}",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Masson SAS",

year = "2017",

doi = "10.1016/j.ejmech.2016.09.048",

language = "English",

volume = "125",

pages = "453--463",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

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TY - JOUR

T1 - Piperlongumine (piplartine) and analogues

T2 - Antiproliferative microtubule-destabilising agents

AU - Meegan, Mary J.

AU - Nathwani, Seema

AU - Twamley, Brendan

AU - Zisterer, Daniela M.

AU - O'Boyle, Niamh M.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Anticancer

KW - Antiproliferative

KW - Combretastatin A-4

KW - Microtubule-destabilising

KW - Piperlongumine

KW - Tubulin

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U2 - 10.1016/j.ejmech.2016.09.048

DO - 10.1016/j.ejmech.2016.09.048

M3 - Article

SN - 0223-5234

VL - 125

SP - 453

EP - 463

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

Abstract

Keywords

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