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首页> 外文期刊>Chemistry: A European journal >Fast Interstrand Cross-linking of Cisplatin-DNA monoadducts Compared with Intratrand Chelation: A Kientic Study Using Hairpin-Stabilized Duplex Oligonucleotides
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Fast Interstrand Cross-linking of Cisplatin-DNA monoadducts Compared with Intratrand Chelation: A Kientic Study Using Hairpin-Stabilized Duplex Oligonucleotides

机译：顺铂-DNA单加合物与链内螯合的快速链间交联：使用发夹稳定双链寡核苷酸的Kentic研究。

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摘要

The antitumor drug cisplatin forms two kinds of guanine-guanine cross-links with DNA: intrastrand, occurring mainly at GG sites, and interstrand, formed at GC sites. The former are generally more abundant than the latter, at least in experiments with linear duplex DNA. The formation of interstrand cross-links requires partial disruption of the Watson-Crick base pairing, and one could therefore expect the cross-linking reaction to be rather slow. In contrast with this expectation, kientic measurements reported here indicate that interstrand cross-linking is as fast as intrastrand, or even faster. We have investigated the reactions between two hairpin-stabilized DNA duplexes, containing either a d(TGCA)_2 sequence (duplex TGCA) or a d(G~1G~2CA)d(TG~3CC0 sequence (duplex GGCA), and the diaqua diaqua form of cisplatin, cis-[Pt(NH_3)_2(H_2)_2]~(2+), in an unbuffered solutin kept at pH 4.5+-0.1 and 20deg C. Using HPLC as the analytical method, we have determined the platination (first step) and chelation (second step) rate constants for these reaction stystems. Duplex TGCA, in which the two guanines are quasi-equivalent, is found to be platinated very slowly (k=0.5+-0.1M~(-1)s~(-1)) and to form the final interstrand cross-link very rapidly (k=13+-3X10~(-3)s~(-1)). For GGCA, we find that G~1 is platinated rapidly (k=32+-5 M~(-1)s~(-1)) to form a long-lieved monoadduct, which is only slowly chelated (k=0.039+-0.001X10~(-3)s~(-1)) by G~2 (intrastrand) while G~2 is platinated one order of magnitude more slowly than G~1 (k=2.0+-0.5 M~(-1)s~(-1)) adn chelated fairly rapidly both by G~1 (intrastrand: k=0.4+-0.1X10~(-3)s~(-1)) and G~3 (interstrand: k=0.02+-0.1X10~(-3)s~(-1); finally, G~3 is platinated at about the same rate as G~2 (k=2.4+-0.5 M~(-1)s~(-1)) and chelated very rapidly by G~2 (interstrand: k=10+-4X10~(-3)s~(-1)). these results suggest that the low occurrence of interstrand cross-links in cisplatinated DNA is due to an extremely slow initial platination of guanines involved in d(GC)_2 sequences, rather than to a slow cross-linking reaction.
机译：抗肿瘤药顺铂与DNA形成两种鸟嘌呤-鸟嘌呤交联键：链内（主要出现在GG位）和链间（形成在GC位）。至少在线性双链DNA实验中，前者通常比后者更丰富。链间交联的形成需要沃森-克里克碱基对的部分破坏，因此人们可以预期交联反应相当慢。与此预期相反，此处报告的千变态测量表明，链间交联与链内一样快，甚至更快。我们已经研究了两个发夹稳定的DNA双链体之间的反应，这些双链体包含ad（TGCA）_2序列（双链TGCA）或ad（G〜1G〜2CA）d（TG〜3CC0序列（双链GGCA）和diadia diaqua形式顺铂[-Pt（NH_3）_2（H_2）_2]〜（2+）在pH 4.5 + -0.1和20°C的无缓冲溶液中的溶解度的测定。使用HPLC作为分析方法，我们确定了铂化（这些反应体系的第一步）和螯合（第二步）速率常数，发现两个鸟嘌呤是准等价的双链TGCA镀铂的速度非常慢（k = 0.5 + -0.1M〜（-1）s 〜（-1））并非常迅速地形成最终的链间交联（k = 13 + -3X10〜（-3）s〜（-1））。对于GGCA，我们发现G〜1被快速铂化（ k = 32 + -5 M〜（-1）s〜（-1））形成长单价加合物，仅缓慢螯合（k = 0.039 + -0.001X10〜（-3）s〜（-1） ））通过G〜2（链内）镀金，而G〜2镀铂的速度比G〜1（k = 2.0 + -0.5 M〜（-1）s〜（-1））慢一个数量级，并且两者都被快速螯合由G〜1（i n链：k = 0.4 + -0.1X10〜（-3）s〜（-1））和G〜3（链：k = 0.02 + -0.1X10〜（-3）s〜（-1）;最后，G〜3的镀铂速率与G〜2大致相同（k = 2.4 + -0.5 M〜（-1）s〜（-1）），并很快被G〜2螯合（链：k = 10 + -4X10〜（-3）s〜（-1））。这些结果表明，顺铂DNA中链间交联的发生率低是由于参与d（GC）_2序列的鸟嘌呤的初始电镀极慢，而不是缓慢的交联反应。

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