Howe-Grant M, Wu K C, Bauer W R, Lippard S J
Biochemistry. 1976 Sep 21;15(19):4339-46. doi: 10.1021/bi00664a031.
The interaction of platinum and palladium complexes with closed and nicked circular and linear DNAs was investigated by a variety of methods. Cationic metal complexes containing flat, aromatic ligands, such as 2,2',2''-terpyridine, o-phenanthroline, and 2,2'-bipyridine, interfere with the usual fluorescence enhancement of ethidium bromide by competing for intercalation sites on calf-thymus DNA. Metal complexes having kinetically exchangable ligands, including the antitumor drugs cis-[(NH3)2PtCl2] and [(en)PtC12], inhibit noncompetitively the DNA-associated ethidium fluorescence enhancement by binding covalently to the bases and blocking potential intercalation sites. Only the metallointercalators were capable of altering the DNA duplex winding, as judged by the effects of these reagents upon the electrophoretic mobility and sedimentation behavior of PM-2 DNAs. Long-term (t greater than 120 h) interactions of metal complexes with PM-2 DNAs I, I0, and II, corresponding to superhelical, closed relaxed, and nicked circles, respectively, showed that covalent binding occurs the most readily to DNA I, possibly because of the presence of underwound duplex regions in this tightly wound superhelical DNA. The active antitumor drugs cis-[(NH3)2PtC12] and [(en)PtC12] bind covalently to DNA I under conditions where the inactive trans- [(NH3)2PtC12] does not. Most of the complexes studied were capable of producing chain scissions in PM-2DNA I. Exceptions are the kinetically inert complexes [(bipy)Pt(en)]2+ and (terpy)Pt(SCH2CH2OH)]+, suggesting that covalent binding might be a prerequisite for nicking.
采用多种方法研究了铂和钯配合物与闭环、带切口的环状及线性DNA的相互作用。含有扁平芳香配体（如2,2',2''-三联吡啶、邻菲啰啉和2,2'-联吡啶）的阳离子金属配合物，通过竞争小牛胸腺DNA上的嵌入位点，干扰溴化乙锭通常的荧光增强。具有动力学可交换配体的金属配合物，包括抗肿瘤药物顺式-[(NH₃)₂PtCl₂]和[(en)PtCl₂]，通过与碱基共价结合并阻断潜在的嵌入位点，非竞争性地抑制与DNA相关的溴化乙锭荧光增强。根据这些试剂对PM - 2 DNA的电泳迁移率和沉降行为的影响判断，只有金属嵌入剂能够改变DNA双链的缠绕。金属配合物与分别对应超螺旋、闭环松弛和带切口环状的PM - 2 DNAs I、I₀和II的长期（t大于120小时）相互作用表明，共价结合最容易发生在DNA I上，这可能是因为在这种紧密缠绕的超螺旋DNA中存在欠缠绕的双链区域。活性抗肿瘤药物顺式-[(NH₃)₂PtCl₂]和[(en)PtCl₂]在非活性反式-[(NH₃)₂PtCl₂]不发生结合的条件下与DNA I共价结合。所研究的大多数配合物能够在PM - 2 DNA I中产生链断裂。例外的是动力学惰性配合物[(bipy)Pt(en)]²⁺和(terpy)Pt(SCH₂CH₂OH)]⁺，这表明共价结合可能是切口形成的前提条件。
