Synthesis and Biological Evaluation of 4-Arylcoumarin Analogues of Combretastatins. Part 2
Synthesis and Biological Evaluation of 4-Arylcoumarin Analogues of Combretastatins. Part 2
复制标题
DOI：
10.1021/jm901826e
复制
发表时间：
2011-05-12
影响因子：
7.3
通讯作者：
Peyrot, Vincent
中科院分区：
文献类型：
--
作者：
Combes, Sebastien;Barbier, Pascale;Peyrot, Vincent
通过交叉偶联反应合成了一系列与考布他汀A-4相关的A环不同甲氧基取代的4-（3-羟基-4-甲氧基苯基）香豆素类化合物。细胞毒性研究表明，对HBL 100细胞系的有效活性。A环上的取代模式对抗增殖活性仅有轻微影响。对于大多数细胞毒性化合物，评价了其作为P-gp和BCRP外排泵潜在调节剂的活性。结果显示化合物2和7能够在与环孢菌素A相似的浓度下恢复米托蒽醌积累（BCRP）。化合物7逆转P-gp活性最有效。发现所有化合物在大部分情况下通过亚化学计量作用模式有效地抑制体外微管形成。发现化合物1和2具有与考布他汀A-4相似的表观亲和结合常数，即，1 x 10（6）M-1。香豆素衍生物的分子建模进行7的分子结构的基础上，通过单晶X-射线晶体学测定。计算表明，在色烯酮部分的平面外存在甲氧基是一个重要的空间位阻因素，嵌入微管蛋白上的结合口袋内的那些分子的可及性。
A series of A-ring variously methoxylated 4-(3-hydroxy-4-methoxyphenyl)coumarins related to combretastatin A-4 was prepared by cross-coupling reactions. Cytotoxicity studies indicated a potent activity against HBL100 cell line. Substitution patterns on A-ring had only a slight effect on antiproliferative activity. For most cytotoxic compounds, the activity as potential modulators of P-gp and BCRP efflux pumps was evaluated. The results show that compounds 2 and 7 were able to restore mitoxantrone accumulation (BCRP) at concentrations similar to that of cyclosporine A. Compound 7 was the most efficient to reverse P-gp activity. All compounds were found to potently inhibit in vitro microtubule formation via a substoichiometric mode of action for the most part. Compounds 1 and 2 were found to have an apparent affinity binding constant similar to that of combretastatin A-4, i.e., 1 x 10 (6) M-1. The molecular modeling of coumarin derivatives was performed on the basis of the molecular structure of 7, as determined by single-crystal X-ray crystallography. The calculations suggested that the presence of a methoxy group out of the plane of the chromenone moiety is an important steric hindrance factor embedding the accessibility of those molecules inside the binding pocket on tubulin.