Piperlongumine (piplartine) and analogues: Antiproliferative microtubule-destabilising agents
Piperlongumine (piplartine) and analogues: Antiproliferative microtubule-destabilising agents
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DOI：
10.1016/j.ejmech.2016.09.048
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发表时间：
2017-01-05
影响因子：
6.7
通讯作者：
O'Boyle, Niamh M.
中科院分区：
文献类型：
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作者：
Meegan, Mary J.;Nathwani, Seema;O'Boyle, Niamh M.
Piperlongumine (piplartine, 1) 是一种小分子生物碱，因其抗增殖和抗癌活性而受到广泛关注。我们研究了 1 对微管蛋白和微管的影响。使用分离的微管蛋白测定以及沉降和蛋白质印迹的组合，我们证明 1 是一种微管蛋白不稳定剂。这一结果得到了免疫荧光和共聚焦显微镜的证实，结果显示MCF-7乳腺癌细胞中的微管在用1处理时解聚。我们合成了许多1的类似物来探索构效关系。化合物 13 具有该系列中最好的细胞毒性，对人乳腺癌 MCF-7 细胞显示出有效的作用，同时对非致瘤性 MCF-10a 细胞相对无毒。这些化合物将被进一步开发为治疗乳腺癌的潜在临床候选药物。 (C) 2016 Elsevier Masson SAS。版权所有。
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. (C) 2016 Elsevier Masson SAS. All rights reserved.