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首页> 外文期刊>Biochemistry >DNA sequence recognition by bispyrazinonaphthalimides antitumor agents
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DNA sequence recognition by bispyrazinonaphthalimides antitumor agents

机译：双吡嗪基萘二甲酰亚胺抗肿瘤剂识别DNA序列

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Bifunctional DNA intercalating agents have long attracted considerable attention as anticancer agents. One of the lead compounds in this category is the dimeric antitumor drug elinafide, composed of two tricyclic naphthalimide chromophores separated by an aminoalkyl linker chain optimally designed to permit bisintercalation of the drug into DNA. In an effort to optimize the DNA recognition capacity, different series of elinafide analogues have been prepared by extending the surface of the planar drug chromophore which is important for DNA sequence recognition. We report here a detailed investigation of the DNA sequence preference of three tetracyclic monomeric or dimeric pyrazinonaphthalimide derivatives. Melting temperature measurements and surface plasmon resonance (SPR) studies indicate that the dimerization of the tetracyclic planar chromophore considerably augments the affinity of the drug for DNA, polynucleotides, or hairpin oligonucleotides and promotes selective interaction with G-C sites. The (CH2)(2)NH(CH2)(3)NH(CH2)(2) connector stabilizes the drug-DNA complexes. The methylation of the two nitrogen atoms of this linker chain reduces the binding affinity and increases the dissociation rates of the drug-DNA complexes by a factor of 10. DNase I footprinting experiments were used to investigate the sequence selectivity of the drugs, demonstrating highly preferential binding to G-C-rich sequences. It also served to select a high-affinity site encompassing the sequence 5'-GACGGCCAG which was then introduced into a biotin-labeled hairpin oligonucleotide to accurately measure the binding parameters by SPR. The affinity constant of the unmethylated dimer for this sequence is 500 times higher than that of the monomer compound and similar to10 times higher than that of the methylated dimer. The DNA groove accessibility was also probed with three related oligonucleotides carrying G --> c(7)G, G --> I, and C --> M substitutions. The level of drug binding to the two hairpin oligonucleotides containing 7-deazaguanine (c(7)G) or 5-methylcytosine (M) residues is unchanged or only slightly reduced compared to that of the unmodified target. In contrast, incorporation of inosine (1) residues considerably decreases the extent of drug binding or even abolishes the interaction as is the case with the monomer. The pyrazinonaphthalimide derivatives are thus much more sensitive to the deletion of the exocyclic guanine 2-amino group exposed in the minor groove of the duplex than to the modification of the major groove elements. The complementary SPR footprinting methodology combining site selection and quantitative DNA affinity analysis constitutes a reliable method for dissecting the DNA sequence selectivity profile of reversible DNA binding small molecules. [References: 61]
机译：长久以来，双功能DNA嵌入剂作为抗癌剂已引起了广泛的关注。该类别中的先导化合物之一是二聚体抗肿瘤药物依那那肽，其由两个三环萘二甲酰亚胺发色团组成，该发色团被一个氨基烷基接头链分开，该氨基烷基接头链经优化设计以允许将该药物双嵌入到DNA中。为了优化DNA识别能力，已经通过扩展对于DNA序列识别重要的平面药物发色团的表面来制备不同系列的依拉那肽类似物。我们在这里报告了三个四环单体或二聚吡嗪并萘邻苯二甲酰亚胺衍生物的DNA序列偏好的详细研究。熔解温度测量和表面等离振子共振（SPR）研究表明，四环平面发色团的二聚化大大提高了药物对DNA，多核苷酸或发夹寡核苷酸的亲和力，并促进了与G-C位点的选择性相互作用。 （CH2）（2）NH（CH2）（3）NH（CH2）（2）连接器可稳定药物-DNA复合物。该连接链上两个氮原子的甲基化作用降低了结合亲和力，并使药物-DNA复合物的解离速率提高了10倍。使用DNase I足迹实验研究了药物的序列选择性，证明了其高度优先性。与富含GC的序列结合。它还用于选择包含序列5'-GACGGCCAG的高亲和力位点，然后将其引入生物素标记的发夹寡核苷酸以通过SPR准确测量结合参数。该序列的未甲基化二聚体的亲和常数比单体化合物高500倍，并且与甲基化二聚体的亲和常数相近10倍。 DNA凹槽可及性也用三个相关的寡核苷酸进行了探测，这些寡核苷酸带有G-> c（7）G，G-> I和C-> M取代。与未修饰靶标相比，与包含7-脱氮鸟嘌呤（c（7）G）或5-甲基胞嘧啶（M）残基的两个发夹寡核苷酸结合的药物水平不变或仅略有降低。相反，肌苷（1）残基的掺入大大降低了药物结合的程度，甚至消除了与单体的情况下的相互作用。因此，吡嗪并萘邻苯二甲酰亚胺衍生物对暴露于双链体小沟中的环鸟嘌呤2-氨基的缺失比对大沟元素的修饰更敏感。互补的SPR足迹方法论结合了位点选择和定量DNA亲和力分析，构成了剖析可逆性DNA结合小分子的DNA序列选择性谱的可靠方法。 [参考：61]

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