Choi Sunhee, Mahalingaiah Shruthi, Delaney Sarah, Neale Nathan R., Masood Syed
Department of Chemistry and Biochemistry, Middlebury College, Middlebury, Vermont 05753.
Inorg Chem. 1999 Apr 19;38(8):1800-1805. doi: 10.1021/ic9809815.
A series of Pt(IV) anticancer complexes with different reduction potentials has been investigated for their reactivity toward 5'-guanosine monophosphate (5'-GMP). The Pt(IV) complexes studied were Pt(IV)(trans-d,l)(1,2-(NH(2))(2)C(6)H(10))Cl(4) (tetraplatin, Pt(IV)(dach)Cl(4); dach = diaminocyclohexane), cis,trans,cis-[Pt(IV)((CH(3))(2)CHNH(2))(2)(OH)(2)Cl(2)] (iproplatin, Pt(IV)(ipa)(2)(OH)(2)Cl(2); ipa = isopropylamine), cis,trans,cis-[Pt(IV)(en)(OH)(2)Cl(2)] (Pt(IV)(en)(OH)(2)Cl(2); en = ethylenediamine), Pt(IV)(en)Cl(4), and cis,trans,cis-[Pt(IV)(en)(OCOCH(3))(2)Cl(2)] (Pt(IV)(en)(OCOCH(3))(2)Cl(2)). The reactivity was monitored by the decreased (1)H NMR peak intensity at 8.2 ppm due to H8 of free 5'-GMP and the increased intensity of a new peak around 8.6 ppm due to H8 of 5'-GMP bound to Pt(II). The reactivity followed the order of cathodic reduction potentials of the Pt(IV) complexes: Pt(IV)(dach)Cl(4) (-90 mV) >> Pt(IV)(en)Cl(4) (-160 mV) > Pt(IV)(en)(OCOCH(3))(2)Cl(2) (-546 mV) > Pt(IV)(ipa)(2)(OH)(2)Cl(2) (-730 mV). The most reactive complex, Pt(IV)(dach)Cl(4), showed an additional weak peak at 9.2 ppm due to H8 of the 5'-GMP bound to the Pt(IV) complex, indicating the existence of a Pt(IV) intermediate. (1)H NMR, UV/visible absorption spectra, and high-performance liquid chromatograms suggest that the final product is Pt(II)(dach)(5'-GMP)(ox5'-GMP), where ox5'-GMP is oxidized 5'-GMP. A plausible mechanism is that there is an initial substitution of one Pt(IV)/ligand by a 5'-GMP molecule, followed by a two-electron reduction, and finally a second substitution by another 5'-GMP. In the presence of excess 5'-GMP (at least 20-fold), ox5'-GMP seems to be replaced by 5'-GMP to form Pt(II)(dach)(5'-GMP)(2). UV/visible absorption spectroscopy shows that the formation of the Pt(IV) intermediate by substitution is a very slow process followed by reduction. The reduction is characterized by a relatively fast exponential decay. The addition of a small amount of cis-[Pt(II)(NH(3))(2)Cl(2)] shortened the slow formation time of the intermediate, implicating the occurrence of a Pt(II)-assisted substitution reaction. These reactions may lead to a better understanding of the anticancer activity of Pt(IV) complexes.
一系列具有不同还原电位的铂（IV）抗癌配合物针对其与5'-鸟苷单磷酸（5'-GMP）的反应活性进行了研究。所研究的铂（IV）配合物有Pt(IV)(trans-d,l)(1,2-(NH(2))(2)C(6)H(10))Cl(4)（四铂，Pt(IV)(dach)Cl(4)；dach = 二氨基环己烷）、顺式，反式，顺式-[Pt(IV)((CH(3))(2)CHNH(2))(2)(OH)(2)Cl(2)]（异丙铂，Pt(IV)(ipa)(2)(OH)(2)Cl(2)；ipa = 异丙胺）、顺式，反式，顺式-[Pt(IV)(en)(OH)(2)Cl(2)]（Pt(IV)(en)(OH)(2)Cl(2)；en = 乙二胺）、Pt(IV)(en)Cl(4)以及顺式，反式，顺式-[Pt(IV)(en)(OCOCH(3))(2)Cl(2)]（Pt(IV)(en)(OCOCH(3))(2)Cl(2)）。通过游离5'-GMP的H8在8.2 ppm处的（1）H NMR峰强度降低以及与铂（II）结合的5'-GMP的H8在8.6 ppm左右新峰强度增加来监测反应活性。反应活性遵循铂（IV）配合物的阴极还原电位顺序：Pt(IV)(dach)Cl(4)（-90 mV）>> Pt(IV)(en)Cl(4)（-160 mV）> Pt(IV)(en)(OCOCH(3))(2)Cl(2)（-546 mV）> Pt(IV)(ipa)(2)(OH)(2)Cl(2)（-730 mV）。反应活性最高的配合物Pt(IV)(dach)Cl(4)在9.2 ppm处显示出一个额外的弱峰，这是由于与铂（IV）配合物结合的5'-GMP的H8所致，表明存在铂（IV）中间体。（1）H NMR、紫外/可见吸收光谱和高效液相色谱图表明最终产物是Pt(II)(dach)(5'-GMP)(ox5'-GMP)，其中ox5'-GMP是氧化的5'-GMP。一个合理的机制是首先一个5'-GMP分子取代一个铂（IV）/配体，接着进行双电子还原，最后再被另一个5'-GMP取代。在过量5'-GMP（至少20倍）存在的情况下，ox5'-GMP似乎被5'-GMP取代形成Pt(II)(dach)(5'-GMP)(2)。紫外/可见吸收光谱表明通过取代形成铂（IV）中间体是一个非常缓慢的过程，随后是还原过程。还原的特征是相对快速的指数衰减。加入少量顺式-[Pt(II)(NH(3))(2)Cl(2)]缩短了中间体缓慢形成的时间，这意味着发生了铂（II）辅助的取代反应。这些反应可能有助于更好地理解铂（IV）配合物的抗癌活性。
