Brabec V, Neplechova K, Kasparkova J, Farrell N
Academy of Sciences of the Czech Republic, Brno.
J Biol Inorg Chem. 2000 Jun;5(3):364-8. doi: 10.1007/pl00010665.
Recent findings that novel trans-dichloroplatinum(II) complexes exhibit antitumor activity violate the classical structure-activity relationships of platinum(II) complexes. These novel "nonclassical" trans platinum complexes also comprise those containing planar aromatic amines. Initial studies have shown that these compounds form a considerable amount of DNA interstrand cross-links (up to approximately 30%) with a rate markedly higher than clinically ineffective transplatin. The present work has shown, using Maxam-Gilbert footprinting, that trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(NH3)(thiazole)], representatives of the group of new antitumor trans-dichloroplatinum complexes containing planar amines, preferentially form DNA interstrand cross-links between guanine residues at the 5'-GC-3' sites. Thus, DNA interstrand cross-linking by trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(NH3)(thiazole)] is formally equivalent to that by antitumor cisplatin, but different from clinically ineffective transplatin which preferentially forms these adducts between complementary guanine and cytosine residues. This result shows for the first time that simple chemical modification of the structure of an inactive compound alters its DNA binding site into a DNA adduct of an active drug.
最近的研究发现，新型二氯铂（II）配合物具有抗肿瘤活性，这违背了铂（II）配合物的经典构效关系。这些新型“非经典”反式铂配合物还包括含有平面芳香胺的配合物。初步研究表明，这些化合物能形成相当数量的DNA链间交联（高达约30%），其速率明显高于临床上无效的反式铂。目前的研究工作表明，通过Maxam-Gilbert足迹法，含有平面胺的新型抗肿瘤二氯铂配合物组中的代表物反式-[PtCl2(NH3)(喹啉)]和反式-[PtCl2(NH3)(噻唑)]，优先在5'-GC-3'位点的鸟嘌呤残基之间形成DNA链间交联。因此，反式-[PtCl2(NH3)(喹啉)]和反式-[PtCl2(NH3)(噻唑)]引起的DNA链间交联在形式上等同于抗肿瘤顺铂引起的交联，但不同于临床上无效的反式铂，后者优先在互补的鸟嘌呤和胞嘧啶残基之间形成这些加合物。这一结果首次表明，对无活性化合物结构进行简单的化学修饰会将其DNA结合位点改变为活性药物的DNA加合物。
