TANNINS AS POTENT INHIBITORS OF DNA TOPOISOMERASE-II INVITRO
TANNINS AS POTENT INHIBITORS OF DNA TOPOISOMERASE-II INVITRO
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DOI：
10.1002/jps.2600820511
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发表时间：
1993-05-01
影响因子：
3.8
通讯作者：
LEE, KH
中科院分区：
文献类型：
--
作者：
KASHIWADA, Y;NONAKA, G;LEE, KH
在体外实验中，60种单宁中有52种是人DNA拓扑异构酶II的抑制剂，包括甘露单宁、鞣木单宁、缩合单宁和复合单宁。通过atp依赖性解结P4噬菌体DNA来评估，36种化合物在500 nM或更低浓度下完全抑制酶活性，其效力至少是临床有用的抗肿瘤药物依托泊苷（VP-16）的100倍。相对抑制活性主要与活性结构中发现的酚羟基（没食子酰基和六羟基二酚基）的数量有关，基团越多，效力越强。与VP-16和一些稳定拓扑异构酶II-DNA切割中间体的DNA插入剂不同，这些活性化合物都不会在培养细胞中诱导蛋白质连接的DNA断裂。一些单宁降低了vp - 16诱导的蛋白质链DNA断裂20%或更多，但其中一种化合物(-)-表儿茶素在体外不是抑制剂。我们的数据表明，一些单宁，如桑金苷H-6，是体外催化双dna链传递的有效抑制剂，可能以类似于已知毒素的方式靶向细胞内酶活性，干扰酶- dna共价中间体的形成。
Fifty-two out of 60 tannins, including gallo-, ellagi-, condensed, and complex tannins, are inhibitors of human DNA topoisomerase II in vitro. Thirty-six compounds that completely inhibited enzyme activity at a concentration of 500 nM or less, as assessed by ATP-dependent unknotting of P4 phage DNA, were at least 100-fold more potent than the clinically useful antitumor agent etoposide (VP-16). Relative inhibitory activity was primarily related to the number of phenolic hydroxyl groups (galloyl and hexahydroxydiphenoyl moieties) found in the active structures, with more groups generally conferring increased potencies. Unlike VP-16 and some DNA intercalative agents that stabilize the topoisomerase II-DNA cleavage intermediate, none of the active compounds induced protein-linked DNA breaks in cultured cells. Some of the tannins reduced VP-1 6-induced protein-linked DNA breaks by 20% or more, but one of these compounds, (-)-epicatechin, was not an inhibitor in vitro. Our data suggest that some tannins, such as sangiin H-6, that are potent inhibitors of catalytic double DNA-strand passage in vitro may target intracellular enzyme activity in a similar fashion to known poisons that interfere with formation of the enzyme-DNA covalent intermediate.