Andrepont Chase, Pakhomova Svetlana, Marzilli Patricia A, Marzilli Luigi G
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States.
Inorg Chem. 2015 May 18;54(10):4895-908. doi: 10.1021/acs.inorgchem.5b00496. Epub 2015 Apr 24.
Anticancer-active monofunctional Pt(II) complexes have bulky carrier ligands and bind to G residues in DNA, causing structural distortions. To gain fundamental chemical information on such monofunctional adducts, we assessed the 9-ethylguanine (9-EtG) adducts formed by [Pt(N(H)6,6'-Me2dpa)Cl]Cl (N(H)6,6'-Me2dpa = di-(6-methyl-2-picolyl)amine). 9-EtG added to [Pt(N(H)6,6'-Me2dpa)Cl]Cl to form not only the expected Pt(N(H)6,6'-Me2dpa)(9-EtG) monoadduct having syn and anti conformers but also a Pt(N(H)6,6'-Me2dpa)(9-EtG)2 bisadduct consisting of ΛHT and ΔHT conformers (HT = head-to-tail). For both adducts, the two conformers exist as a dynamic equilibrium mixture. Concomitant with formation of the bisadduct, the binding mode of the N(H)6,6'-Me2dpa ligand converts from tridentate to bidentate. A Pt(II)-bound 6-methyl-2-picolyl chain and the secondary amine constitute the bidentate chelate ring. The other 6-methyl-2-picolyl chain is dangling. The secondary nitrogen is an asymmetric center, and each conformer exists as a racemic mixture of two enantiomers. For a given configuration at the secondary amine of the Pt(N(H)6,6'-Me2dpa)(9-EtG)2 adduct, the more abundant HT conformer can form a hydrogen bond between the NH of the bidentate ligand and the cis 9-EtG O6. [Pt(N(H)6,6'-Me2dpa)Cl]Cl forms the monoadduct in ∼1/20 the time for its parent, [Pt(N(H)dpa)Cl]Cl (N(H)dpa = di(2-picolyl)amine), which exhibited typical behavior in forming only a monoadduct. We attribute the unusual new findings for [Pt(N(H)6,6'-Me2dpa)Cl]Cl to Pt-N bond weakening induced by the steric bulk of 6/6'-Me groups. We hypothesize that undetectable intermediates with a dangling 6-methyl-2-picolyl chain facilitate both rapid monoadduct formation and also bisadduct formation. Consistent with the intermediacy of such species with a dangling chain, addition of HCl to a [Pt(N(H)6,6'-Me2dpa)Cl]Cl solution readily produced a dichloro complex with the N(H)6,6'-Me2dpa chelate ligand in the bidentate mode, whereas HCl addition had no effect on [Pt(N(H)dpa)Cl]Cl.
具有抗癌活性的单功能Pt(II)配合物含有庞大的载体配体，可与DNA中的G残基结合，导致结构畸变。为了获取有关此类单功能加合物的基础化学信息，我们评估了由[Pt(N(H)6,6'-Me2dpa)Cl]Cl（N(H)6,6'-Me2dpa = 二-(6-甲基-2-吡啶基)胺）形成的9-乙基鸟嘌呤(9-EtG)加合物。9-EtG与[Pt(N(H)6,6'-Me2dpa)Cl]Cl反应，不仅形成了预期的具有顺式和反式构象的Pt(N(H)6,6'-Me2dpa)(9-EtG)单加合物，还形成了由ΛHT和ΔHT构象（HT = 头对尾）组成的Pt(N(H)6,6'-Me2dpa)(9-EtG)2双加合物。对于这两种加合物，两种构象均以动态平衡混合物的形式存在。伴随双加合物的形成，N(H)6,6'-Me2dpa配体的结合模式从三齿转变为双齿。与Pt(II)配位的6-甲基-2-吡啶基链和仲胺构成双齿螯合环。另一条6-甲基-2-吡啶基链处于游离状态。仲氮是一个不对称中心，每种构象均以两种对映体的外消旋混合物形式存在。对于Pt(N(H)6,6'-Me2dpa)(9-EtG)2加合物仲胺处给定的构型，含量较高的HT构象可在双齿配体NH与顺式9-EtG O6之间形成氢键。[Pt(N(H)6,6'-Me2dpa)Cl]Cl形成单加合物的时间约为其母体[Pt(N(H)dpa)Cl]Cl（N(H)dpa = 二(2-吡啶基)胺）的1/20，后者在形成单加合物时表现出典型行为。我们将[Pt(N(H)6,6'-Me2dpa)Cl]Cl这些不同寻常的新发现归因于6/6'-Me基团的空间位阻导致的Pt-N键减弱。我们推测，具有游离6-甲基-2-吡啶基链的不可检测中间体促进了快速单加合物的形成以及双加合物的形成。与具有游离链的此类物种的中间体作用一致，向[Pt(N(H)6,6'-Me2dpa)Cl]Cl溶液中加入HCl可轻易生成一种二氯配合物，其中N(H)6,6'-Me2dpa螯合配体呈双齿模式，而加入HCl对[Pt(N(H)dpa)Cl]Cl没有影响。
