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首页> 外文期刊>Biochemistry >DNA SEQUENCE- AND STRUCTURE-SELECTIVE ALKYLATION OF GUANINE N2 IN THE DNA MINOR GROOVE BY ECTEINASCIDIN 743, A POTENT ANTITUMOR COMPOUND FROM THE CARIBBEAN TUNICATE ECTEINASCIDIN TURBINATA
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DNA SEQUENCE- AND STRUCTURE-SELECTIVE ALKYLATION OF GUANINE N2 IN THE DNA MINOR GROOVE BY ECTEINASCIDIN 743, A POTENT ANTITUMOR COMPOUND FROM THE CARIBBEAN TUNICATE ECTEINASCIDIN TURBINATA

机译：ECTEINASCIDIN 743（一种来自加勒比突缘植物抗癌药-TURBINATA的强效抗原化合物）在DNA细沟中的鸟嘌呤N2的DNA序列和结构选择性烷基化

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摘要

Ecteinascidin 743 is one of several related marine alkaloids isolated from the Caribbean tunicate Ecteinascidia turbinata. It is remarkably active and potent in a variety of in vitro and in vivo systems and has been selected for development as an anticancer agent. The present study investigates the interactions of ecteinascidin 743 with DNA. Ecteinascidin 743 retarded the electrophoretic migration of both supercoiled and relaxed simian virus 40 DNA even in the presence of sodium dodecyl sulfate and after ethanol precipitation, consistent with covalent DNA modifications. Similar results were obtained in a DNA oligonucleotide derived from ribosomal DNA, However, DNA denaturation reversed the DNA modifications. The homopolymeric oligonucleotide dG/dC was modified while neither the dI/dC nor the dA/dT oligonucleotides were, consistent with covalent attachment of ecteinascidin 743 to the exocyclic amino group at position 2 of guanine. Ecteinascidin 743 was then compared to another known DNA minor groove alkylating agent, anthramycin, which has also been shown to alkylate guanine N2. Footprinting analyses with DNase I and 1,10-phenanthroline-copper and exonuclease III digestions showed that ecteinascidin 743 covers three to five bases of DNA and exhibits a different sequence specificity than anthramycin in the Escherichia coli tyrosine tRNA promoter (tyrT DNA). The binding of ecteinascidin to DNA was abolished when guanines were substituted with inosines in this promoter. A band shift assay was designed to evaluate the influence of the bases flanking a centrally located guanine in an oligonucleotide containing inosines in place of guanines elsewhere. Ecteinascidin 743 and anthramycin showed similarities as well as differences in sequence selectivity. Ecteinascidin 743-guanine adducts appeared to require at least one flanking guanine and were strongest when the flanking guanine was 3' to the targeted guanine. These data indicate that ecteinascidin 743 is a novel DNA minor groove, guanine-specific alkylating agent.
机译：Ecteinascidin 743是从加勒比被膜Ecteinascidia turbinata分离的几种相关海洋生物碱之一。它在多种体外和体内系统中均具有显着的活性和效力，并已被选择作为抗癌药进行开发。本研究调查了ecteinascidin 743与DNA的相互作用。 Ecteinascidin 743甚至在十二烷基硫酸钠存在和乙醇沉淀后，也能抑制超螺旋和松弛猿猴病毒40 DNA的电泳迁移，这与共价DNA修饰一致。在衍生自核糖体DNA的DNA寡核苷酸中获得了相似的结果，但是，DNA变性逆转了DNA修饰。均聚寡核苷酸dG / dC进行了修饰，而dI / dC和dA / dT寡核苷酸均未修饰，这与ecteinascidin 743在鸟嘌呤2位的环外氨基上的共价连接相一致。然后将Ecteinascidin 743与另一种已知的DNA小沟烷基化试剂蒽霉素进行了比较，该试剂也被证明可以将鸟嘌呤N2烷基化。用DNase I和1,10-菲咯啉-铜和核酸外切酶III消化进行的足迹分析表明，ecteinascidin 743覆盖了3至5个DNA碱基，并且在大肠杆菌酪氨酸tRNA启动子（tyrT DNA）中与蒽霉素相比具有不同的序列特异性。当鸟嘌呤被该启动子中的肌苷取代时，ecteinascidin与DNA的结合被取消。设计了带移分析，以评估位于含有肌苷的寡核苷酸中取代位于其他位置的鸟嘌呤的寡核苷酸旁侧的鸟嘌呤的碱基的影响。 Ecteinascidin 743和蒽霉素显示出相似性以及序列选择性的差异。依考艾斯汀743-鸟嘌呤加合物似乎需要至少一个侧翼鸟嘌呤，并且当侧翼鸟嘌呤与目标鸟嘌呤3'时最强。这些数据表明，ecteinascidin 743是一种新型的DNA小沟，鸟嘌呤特异性烷基化剂。

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