Copper-nuclease efficiency correlates with cytotoxicity for the 4-methoxypyrrolic natural products
Copper-nuclease efficiency correlates with cytotoxicity for the 4-methoxypyrrolic natural products
复制标题
DOI：
10.1016/s0162-0134(01)00338-5
复制
发表时间：
2001-12-01
影响因子：
3.9
通讯作者：
Manderville, RA
中科院分区：
文献类型：
--
作者：
Melvin, MS;Wooton, KE;Manderville, RA
包括灵菌红素在内的4-甲氧基吡咯类天然产物的DNA靶向活性（1）。坦比胺E（2）和蓝色素（3）已经使用荧光光谱法进行比较以研究DNA结合和琼脂糖凝胶电泳以评估它们促进氧化铜促进的DNA切割的能力。用小牛胸腺DNA（CT-DNA）对3进行荧光发射滴定，结果表明，天然产物占据的位点大小（n）约为100。两个碱基对，亲和常数（K）约为6 × 10（5）M-1。与灵菌红素（1）类似，发现蓝色色素3在不借助外部还原剂的情况下促进氧化双链DNA（dsDNA）切割。ds-（n（2））和ss-（n（1））断裂的定量提供了类似于8 - 12的n（1）：n（2）比率，其显著大于ss-断裂累积的预期数量（类似于120）。这与tambjamine E（2）的切口活性形成对比，tambjamine E（2）仅在铜的存在下产生ss-断裂。1和3的优异的铜核酸酶活性也与它们对白血病（HL-60）细胞的优异的抗癌性质相关。这些结果进行了讨论，相对于由4-甲氧基吡咯的天然产物的细胞毒性的模式。(C)2001爱思唯尔科技有限公司。保留所有权利。
The DNA-targeting activities of the 4-methoxypyrrolic natural products, that include prodigiosin (1). tambjamine E (2), and the blue pigment (3), have been compared using fluorescence spectroscopy to study DNA binding and agarose gel electrophoresis to assess their ability to facilitate oxidative copper-promoted DNA cleavage. Fluorescence emission titration of 3 with calf-thymus DNA (CT-DNA) shows that the natural product occupies a site size (n) of ca. two base pairs and possesses an affinity constant (K) of similar to6 x 10(5) M-1. Similar to prodigiosin (1), the blue pigment 3 was found to facilitate oxidative double-strand DNA (dsDNA) cleavage without the aid of an external reducing agent. Quantitation of ds- (n(2)) and ss- (n(1)) breaks provided n(1):n(2) ratios of similar to8-12, which were significantly greater than the number expected from the accumulation of ss-breaks (similar to 120). This was contrasted by the nicking activity of tambjamine E (2), which only generates ss-breaks in the presence of copper. The superior copper-nuclease activity of 1 and 3 also correlated with their superior anticancer properties against leukemia (HL-60) cells. These results are discussed with respect to the mode of cytotoxicity by the 4-methoxypyrrolic natural products. (C) 2001 Elsevier Science B.V. All rights reserved.