新型增强水溶性羟乙基类似物 combretastatin A-4 的设计与合成。

Design and synthesis of novel enhanced water soluble hydroxyethyl analogs of combretastatin A-4.

机构信息

Department of Chemistry, Division of Natural and Applied Sciences, Hope College, Holland, MI 49422, USA.

出版信息

Bioorg Med Chem Lett. 2011 Apr 1;21(7):2087-91. doi: 10.1016/j.bmcl.2011.01.136. Epub 2011 Feb 3.

DOI:10.1016/j.bmcl.2011.01.136

Abstract

Thirteen hydroxyethyl- analogs of combretastatin A-4 (CA-4) that contain the 1-(1'-hydroxyethyl)-1-(3",4",5"-trimethoxyphenyl)-2-(substituted phenyl)ethene framework were synthesized. Molecular modeling studies at the DFT level showed that compound 3j adopts a 'twisted' conformation mimicking CA-4. The cytotoxicity of the novel compounds against the growth of murine B16 melanoma and L1210 lymphoma cells in culture was measured using an MTT assay. Three analogs 3f, 3h, and 3j were active. Of these, 3j, which has the same substituents as CA-4 and IC(50) values of 16.1 and 4.1 μM against B16 and L1210 cells, respectively, was selected for further biological evaluation. The activity of 3j was verified by the NCI 60 cell line screen. Compound 3j causes microtubule depolymerization in A-10 cells with an EC(50) of 21.2 μM. Analog 3j, which has excellent water solubility of 479 μM, had antitumor activity in a syngeneic L1210 murine model.

摘要

合成了 13 种含有 1-(1'-羟乙基)-1-(3",4",5"-三甲氧基苯基)-2-(取代苯基)乙稀骨架的考布他汀 A-4（CA-4）的羟乙基类似物。在 DFT 水平的分子建模研究表明，化合物 3j 采用了一种“扭曲”构象，模拟 CA-4。使用 MTT 法测定了新型化合物对培养的鼠 B16 黑色素瘤和 L1210 淋巴瘤细胞生长的细胞毒性。三种类似物 3f、3h 和 3j 具有活性。其中，3j 与 CA-4 具有相同的取代基，对 B16 和 L1210 细胞的 IC50 值分别为 16.1 和 4.1 μM，被选为进一步的生物学评价。3j 的活性通过 NCI 60 细胞系筛选得到验证。化合物 3j 在 A-10 细胞中引起微管解聚，EC50 值为 21.2 μM。类似物 3j 具有出色的水溶性（479 μM），在同种 L1210 鼠模型中具有抗肿瘤活性。