Antitumor agents. 199. Three-dimensional quantitative structure-activity relationship study of the colchicine binding site ligands using comparative molecular field analysis
Antitumor agents. 199. Three-dimensional quantitative structure-activity relationship study of the colchicine binding site ligands using comparative molecular field analysis
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DOI：
10.1021/jm990333a
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发表时间：
2000-01-27
影响因子：
7.3
通讯作者：
Li, KH
中科院分区：
文献类型：
--
作者：
Zhang, SX;Feng, J;Li, KH
在秋水仙碱结合位点相互作用的微管蛋白聚合抑制剂是潜在的抗癌剂。我们参与了许多秋水仙碱位点药物的合成，例如秋水仙碱类似物硫代秋水仙素和别样秋水仙素，以及细胞毒性抗有丝分裂黄酮类化合物的氨基类似物a 2-苯基喹诺酮和2-芳基萘啶酮。后一化合物中最具细胞毒性的化合物强烈抑制放射性标记的秋水仙碱与微管蛋白的结合，因此这些药物可能结合在微管蛋白的秋水仙碱位点上。我们应用传统的 CoMFA 和 q(2)-GRS CoMFA 来确定提高这些化合物形成微管蛋白复合物的能力的基本结构要求。 51 种化合物训练集的 CoMFA 模型得到了交叉验证。传统 CoMFA 的 R-2 (q(2)) 值为 0.637，q(2)-GRS CoMFA 的 R-2 (q(2)) 值为 0.692。该模型的预测能力通过对 53 种具有已知微管蛋白聚合抑制剂效力的化合物测试组的成功活性预测得到证实。 88%的化合物的活性预测残差绝对值小于0.5。传统 CoMFA 的预测 q(2) 值为 0.546，q(2)-GRS CoMFA 的预测 q(2) 值为 0.426。具有最高预测 q(2) (0.546) 的传统 CoMFA 模型根据潜在的结构-活性关系进行了详细分析。
Inhibitors of tubulin polymerization interacting at the colchicine binding site are potential anticancer agents. We have been involved in the synthesis of a number of colchicine site agents, such as thiocolchicinoids and allocolchicinoids, which are colchicine analogues, and 2-phenylquinolones and 2-aryl-naphthyridinones, which are the amino analogue a of cytotoxic antimitotic flavonoids. The most cytotoxic of the latter compounds strongly inhibit binding of radiolabeled colchicine to tubulin, and these agents therefore probably bind in the colchicine site of tubulin. We have applied conventional CoMFA and q(2)-GRS CoMFA to identify the essential structural requirements for increasing the ability of these compounds to form tubulin complexes. The CoMFA model for the training set of 51 compounds yielded cross-validated. R-2 (q(2)) values of 0.637 for conventional CoMFA and 0.692 for q(2)-GRS CoMFA. The predictive power of this model was confirmed by successful activity prediction for a test set of 53 compounds with known potencies as inhibitors of tubulin polymerization. The activities of 88% of the compounds were predicted with absolute value of residuals of less than 0.5. The predictive q(2) values were 0.546 for conventional CoMFA and 0.426 for q(2)-GRS CoMFA. The conventional CoMFA model with the highest predictive q(2) (0.546) was analyzed in detail in terms of underlying structure-activity relationships.