SITE-SPECIFIC DNA CLEAVAGE BY MAMMALIAN DNA TOPOISOMERASE-II INDUCED BY NOVEL FLAVONE AND CATECHIN DERIVATIVES

被引:165
作者
AUSTIN, CA
PATEL, S
ONO, K
NAKANE, H
FISHER, LM
机构
[1] ST GEORGE HOSP,SCH MED,DEPT CELLULAR & MOLEC SCI,MOLEC GENET GRP,CRANMER TERRACE,LONDON SW17 0RE,ENGLAND
[2] AICHI CANC CTR,RES INST,VIRAL ONCOL LAB,NAGOYA,AICHI 464,JAPAN
关键词
D O I
10.1042/bj2820883
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Four naturally occurring flavones (baicalein, quercetin, quercetagetin and myricetin) and two novel catechins [(-)-epicatechin gallate and (-)-epigallocatechin gallate, from the tea plant Camellia sinensis], which are known inhibitors of reverse transcriptase, were shown to induce mammalian topoisomerase II-dependent DNA cleavage in vitro. The flavones differed from the catechins in causing unwinding of duplex DNA, but both classes of compound induced enzymic DNA breakage at the same sites on DNA. Moreover, the cleavage specificity was the same as that for the known intercalator 4'-(acridin-9-ylamino)methanesulphon-m-anisidide, suggesting that these agents trap the same cleavable complex. Analysis of some 30 flavonoid compounds allowed elucidation of the structure-function relationships for topoisomerase II-mediated DNA cleavage. For flavonoid inhibitors an unsaturated double bond between positions 2 and 3 of the pyrone ring and hydroxy groups at the 5, 7, 3' and 4' positions favoured efficient cleavage. Hydroxy substitutions could be tolerated at the 3, 6 and 5 positions. Indeed, the absence of substituents at the 3', 4' and 5' positions could be compensated by a hydroxy group at position 6 (baicalein). Similar requirements have been reported for flavonoid inhibitors of protein kinase C that act competitively with ATP, suggesting interaction with a conserved protein feature. Formation of the cleavable complex is a cytotoxic lesion that may contribute to the growth-inhibitory properties of flavones observed for three human tumour cell lines. These results are discussed in regard to the selectivity of antiviral agents.
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页码:883 / 889
页数:7
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