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特定烯基二芳基甲烷对微管蛋白聚合的抑制作用

Inhibition of tubulin polymerization by select alkenyldiarylmethanes.

作者信息

Cullen Matthew D, Sarkar Taradas, Hamel Ernest, Hartman Tracy L, Watson Karen M, Buckheit Robert W, Pannecouque Christophe, De Clercq Erik, Cushman Mark

机构信息

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and Purdue Cancer Center, Purdue University, West Lafayette, IN 47907, USA.

出版信息

Bioorg Med Chem Lett. 2008 Jan 15;18(2):469-73. doi: 10.1016/j.bmcl.2007.11.114. Epub 2007 Dec 4.

DOI:10.1016/j.bmcl.2007.11.114
PMID:18083556
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2255563/
Abstract

During studies on the alkenyldiarylmethane (ADAM) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), analogues were discovered that exhibit low micromolar and submicromolar cytotoxicities. Since the ADAMs are structurally related to the tubulin polymerization inhibitor CC-5079, a set of 14 ADAMs were tested for inhibition of tubulin polymerization in an attempt to identify the biological target responsible for their cytotoxicity. The results indicate that, overall, the ADAMs are poor inhibitors of tubulin polymerization. However, the two most cytotoxic compounds, 15 and 16, are in fact active as inhibitors of tubulin assembly with IC(50) values of 3.7+/-0.3 and 2.8+/-0.2 microM, respectively, and they both inhibit the binding of colchicine to tubulin. Both compounds were investigated for anticancer activity in the National Cancer Institute's panel of 60 human cancer cell lines, and both compounds consistently displayed submicromolar cytotoxicities with mean-graph midpoint (MGM) values of 0.31+/-0.08 and 0.47+/-0.09 microM, respectively.

摘要

在对烯基二芳基甲烷（ADAM）类非核苷逆转录酶抑制剂（NNRTIs）的研究过程中，发现了一些具有低微摩尔和亚微摩尔细胞毒性的类似物。由于ADAMs在结构上与微管蛋白聚合抑制剂CC-5079相关，因此测试了一组14种ADAMs对微管蛋白聚合的抑制作用，以试图确定导致其细胞毒性的生物学靶点。结果表明，总体而言，ADAMs对微管蛋白聚合的抑制作用较差。然而，两种细胞毒性最强的化合物15和16实际上作为微管蛋白组装的抑制剂具有活性，其IC（50）值分别为3.7±0.3和2.8±0.2微摩尔，并且它们都抑制秋水仙碱与微管蛋白的结合。在国立癌症研究所的60种人类癌细胞系中对这两种化合物的抗癌活性进行了研究，这两种化合物均始终表现出亚微摩尔细胞毒性，平均图形中点（MGM）值分别为0.31±0.08和0.47±0.09微摩尔。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23b0/2255563/906d47629537/nihms39752f1.jpg

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