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LIU, SU-YING,HWANG, BYUNG-DOO,HARUNA, MITSUMASA,IMAKURA, YASUHIRO,LEE, KUO-HSIUNG,CHENG, YUNG-CHI 충남대학교부설 생명공학연구소 1992 생물공학연구지 Vol.2 No.-
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 β 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 α 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.