期刊
ACS OMEGA
卷 7, 期 3, 页码 2591-2603出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.1c04659
关键词
-
资金
- Deutsche Forschungsgemeinschaft DFG [SCHM 857/18-1]
- Russian Scientific Foundation [19-13-00158]
- Russian Science Foundation [19-13-00158] Funding Source: Russian Science Foundation
The synthesis and investigation of PT-100, a potential anticancer drug, were reported. PT-100 exhibited high antiproliferative and apoptosis-inducing effects, especially in multidrug-resistant cancer cell lines, and showed synergistic effects with vincristine in certain cell lines.
Colchicine, the main active alkaloid from Colchicum autumnale L., is a potent tubulin binder and represents an interesting lead structure for the development of potential anticancer chemotherapeutics. We report on the synthesis and investigation of potentially reactive colchicinoids and their surprising biological activities. In particular, the previously undescribed colchicinoid PT-100, a B-ring contracted 6-exo-methylene colchicinoid, exhibits extraordinarily high antiproliferative and apoptosis-inducing effects on various types of cancer cell lines like acute lymphoblastic leukemia (Nalm6), acute myeloid leukemia (HL-60), Burkitt-like lymphoma (BJAB), human melanoma (MelHO), and human breast adenocarcinoma (MCF7) cells at low nanomolar concentrations. Apoptosis induction proved to be especially high in multidrug-resistant Nalm6-derived cancer cell lines, while healthy human leukocytes and hepatocytes were not affected by the concentration range studied. Furthermore, caspase-independent initiation of apoptosis via an intrinsic pathway was observed. PT-100 also shows strong synergistic effects in combination with vincristine on BJAB and Nalm6 cells. Cocrystallization of PT-100 with tubulin dimers revealed its (noncovalent) binding to the colchicine-binding site of beta-tubulin at the interface to the a-subunit. A pronounced effect of PT-100 on the cytoskeleton morphology was shown by fluorescence microscopy. While the reactivity of PT-100 as a weak Michael acceptor toward thiols was chemically proven, it remains unclear whether this contributes to the remarkable biological properties of this unusual colchicinoid.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据