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首页> 外文期刊>Biochemistry >DNA binding by antitumor trans[PtCl2(NH3)(thiazole)]. Protein recognition and nucleotide excision repair of monofunctional adductst
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DNA binding by antitumor trans[PtCl2(NH3)(thiazole)]. Protein recognition and nucleotide excision repair of monofunctional adductst

机译：通过抗肿瘤反式[PtCl2（NH3）（噻唑）]与DNA结合。单功能加合物的蛋白质识别和核苷酸切除修复

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Antitumor effects of cis-diamminedichloroplatinum(II) (cisplatin) and the clinical inactivity of its trans isomer (transplatin) have been considered a paradigm for the classical structure-activity relationships of platinum drugs. However, several new analogues of transplatin which exhibit a different spectrum of cytostatic activity including activity in tumor cells resistant to cisplatin have been recently identified. Analogues containing the planar amine ligand of the general structure trans- [PtCl2(NH3)(L)], where L = planar amine, represent an example of such compounds. DNA is believed to be the major pharmacological target of platinum compounds. To contribute to the understanding of mechanisms underlying the activation of trans geometry in transplatin analogues containing planar amine ligands, various biochemical and biophysical methods were employed in previous studies to analyze the global modifications of natural DNA by trans- [PtCl2(NH3)(L)]. These initial studies have revealed some unique features of the DNA binding mode of this class of platinum drugs. As the monofunctional lesions represent a significant fraction of stable adducts formed in DNA by bifunctional antitumor traps-platinum compounds with planar ligands, we analyzed in the present work short DNA duplexes containing the single, site-specific monofunctional adduct of a representative of this class of platinum drugs, antitumor trans-[PtCl2(NH3)(thiazole)]. It has been shown that, in contrast to the adducts of monodentate chlorodiethylenetriamineplatinum(II) chloride or [PtCl(NH3)(3)]Cl, the monofunctional adduct of trans- [PtCl2(NH3)(thiazole)] inhibits DNA synthesis and creates a local conformational distortion similar to that produced in DNA by the major 1,2-GG intrastrand CL of cisplatin, which is considered the lesion most responsible for its anticancer activity. In addition, the monofunctional adducts of trans-[PtCl2(NH3)(thiazole)] are recognized by HMGB1 domain proteins and removed by the nucleotide excision repair system similarly as the 1,2-GG intrastrand CL of cisplatin. The results of the present work further support the view that the simple chemical modification of the structure of an inactive platinum compound alters its DNA binding mode into that of an active drug and that processing of the monofunctional DNA adducts of the traps-platinum analogues in tumor cells may be similar to that of the major bifunctional adducts of "classical" cisplatin. [References: 74]
机译：顺二氨二氯铂（II）（顺铂）的抗肿瘤作用及其反式异构体（transplatin）的临床失活被认为是铂类药物经典结构-活性关系的范例。但是，最近已经发现了几种新的反铂类似物，它们表现出不同的细胞抑制活性谱，包括在对顺铂耐药的肿瘤细胞中的活性。含有一般结构反式[PtCl2（NH3）（L）]的平面胺配体的类似物（其中L =平面胺）代表此类化合物的一个例子。 DNA被认为是铂化合物的主要药理靶标。为了有助于理解含平面胺配体的跨铂类似物中反式几何激活的机理，以前的研究中采用了各种生物化学和生物物理方法来分析反式[PtCl2（NH3）（L）对天然DNA的整体修饰。 ]。这些初步研究揭示了这类铂药物的DNA结合模式的一些独特特征。由于单功能性损伤代表由具有平面配体的双功能抗肿瘤陷阱-铂化合物在DNA中形成的稳定加合物的重要部分，因此在本工作中我们分析了短DNA双链体，其中包含此类代表的单个位点特异性单功能加合物。铂药物，抗肿瘤反式-[PtCl2（NH3）（噻唑）]。已经显示，与单齿氯二亚乙基三胺铂（II）氯化物或[PtCl（NH3）（3）] Cl的加合物相反，反式[PtCl2（NH3）（噻唑）]的单官能加合物抑制DNA合成并产生与顺铂主要的1,2-GG内链CL产生的DNA相似的局部构象变形，被认为是对其抗癌活性最重要的病变。另外，反式-[PtCl2（NH3）（噻唑）]的单官能加合物被HMGB1域蛋白识别，并被核苷酸切除修复系统去除，与顺铂的1,2-GG内链CL相似。本工作的结果进一步支持了以下观点：无活性的铂化合物的结构的简单化学修饰将其DNA结合模式改变为活性药物的模式，并且在肿瘤中捕集器-铂类似物的单功能DNA加合物的加工细胞可能与“经典”顺铂的主要双功能加合物相似。 [参考：74]

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