Liu S Y, Hwang B D, Haruna M, Imakura Y, Lee K H, Cheng Y C
Department of Pharmacology, University of North Carolina, Chapel Hill 27599-7365.
Mol Pharmacol. 1989 Jul;36(1):78-82.
Several derivatives of podophyllotoxin with modifications at the C-4 position of ring C, in addition to demethylation at the C-4' position of ring E, were examined for inhibitory activity against DNA topoisomerase II and tubulin polymerization, generation of protein-linked DNA breaks, and cytotoxicity against KB cells and VP-16-resistant KB variants. Substitution of podophyllotoxin with a group in the beta configuration at the C-4 position of ring C resulted in compounds with greater inhibitory activity against DNA topoisomerase II and lower inhibitory activity against tubulin polymerization than those with an alpha configuration. These active analogs exhibited the same mechanism of DNA topoisomerase II inhibition as the epipodophyllotoxin derivative VP-16, which causes protein-linked DNA breaks in vitro as well as in cells. Two analogs selectively inhibited DNA topoisomerases II to a greater extent than tubulin polymerization. These analogs were cytotoxic towards KB cells in addition to VP-16-resistant KB cell lines, which indicated limited cross-resistance with VP-16 in VP-16-resistant KB variants.
除了在环E的C-4'位置去甲基化外，还对在环C的C-4位置有修饰的几种鬼臼毒素衍生物进行了研究，考察其对DNA拓扑异构酶II和微管蛋白聚合的抑制活性、蛋白质连接的DNA断裂的产生以及对KB细胞和对VP-16耐药的KB变体的细胞毒性。在环C的C-4位置用β构型的基团取代鬼臼毒素，得到的化合物对DNA拓扑异构酶II的抑制活性比对微管蛋白聚合的抑制活性更高，而α构型的化合物则相反。这些活性类似物表现出与表鬼臼毒素衍生物VP-16相同的DNA拓扑异构酶II抑制机制，VP-16在体外和细胞内均能导致蛋白质连接的DNA断裂。两种类似物对DNA拓扑异构酶II的选择性抑制作用比对微管蛋白聚合的抑制作用更强。这些类似物除了对VP-16耐药的KB细胞系有细胞毒性外，对KB细胞也有细胞毒性，这表明在对VP-16耐药的KB变体中，与VP-16的交叉耐药性有限。
