Etievant C, Schambel P, Guminski Y, Barret J M, Imbert T, Hill B T
Division de Cancérologie Experimentale I, Centre de Recherche Pierre Fabre, Castres, France.
Anticancer Drug Des. 1998 Jun;13(4):317-36.
Podophyllotoxin and epipodophyllotoxin react with tubulin at the same binding site as colchicine, but in contrast to colchicine, do not appear to exert their cytotoxicities by mechanisms dependent on P-glycoprotein (Pgp) expression. To investigate structural requirements for Pgp recognition a series of podophyllotoxin and epipodophyllotoxin derivatives have been synthesized. Their interactions with the multidrug resistance-related protein Pgp have been studied by evaluating their relative cytotoxicities versus P388-sensitive murine leukemic cells and a classic multidrug-resistant (MDR) Pgp-overexpressing subline (P388/ADR), and their relative tubulin polymerization inhibitory activities against microtubular proteins have been determined. Based on tridimensional structure-activity relationships within this series of compounds, structural requirements for Pgp recognition have been identified. Moreover, proposals are made for extending these criteria to other chemical classes of anticancer drugs.
鬼臼毒素和表鬼臼毒素与秋水仙碱在相同的结合位点与微管蛋白发生反应，但与秋水仙碱不同的是，它们似乎并非通过依赖P-糖蛋白（Pgp）表达的机制发挥细胞毒性。为了研究Pgp识别的结构要求，已合成了一系列鬼臼毒素和表鬼臼毒素衍生物。通过评估它们对P388敏感小鼠白血病细胞和经典的多药耐药（MDR）Pgp过表达亚系（P388/ADR）的相对细胞毒性，研究了它们与多药耐药相关蛋白Pgp的相互作用，并测定了它们对微管蛋白的相对微管聚合抑制活性。基于该系列化合物的三维构效关系，已确定了Pgp识别的结构要求。此外，还提出了将这些标准扩展到其他化学类别的抗癌药物的建议。
