Kleine Marco, Wolters Dirk, Sheldrick William S
Lehrstuhl für Analytische Chemie, Ruhr-Universität Bochum, D-44780, Bochum, Germany.
J Inorg Biochem. 2003 Dec 1;97(4):354-63. doi: 10.1016/s0162-0134(03)00289-7.
The pH- and time-dependent reaction of the anticancer drug carboplatin, [Pt(cbdca-kappa(2)O,O')(NH(3))(2)] (cbdca=cyclobutane-1,1-dicarboxylate), with the tripeptides H-glyglymet-OH (glycylglycyl-L-methionine) and Ac-glyglymet-OH at 313 K was investigated by high-performance liquid chromatography, NMR and mass spectrometry. The relative stability of the initial ring-opened kappaS complex [Pt(cbdca-kappaO)(Ac-glyglymet-OH-kappaS)(NH(3))(2)] leads to increased formation of the kinetically favoured kappaS:kappaS' bis-adduct Pt(Ac-glyglymet-OH-kappaS)(2)(NH(3))(2) in comparison with cisplatin. As a result a second 1:2 reaction pathway kappaS-->kappaS:kappaS'-->kappa(2)N(M), S:kappaS'-->kappa(3)N(G2),N(M), S:kappaS', where N(M) and N(G2) represent, respectively, metallated methionine and glycine nitrogen atoms, competes with the 1:1 route kappaS-->kappa(2)N(M), S-->kappa(3)N(G2),N(M), S also observed for cisplatin. Cleavage of N-acetylglycine at the backbone C(O)-N bond to the second gly residue (G2) is observed after 100 h for the respective tridentate complexes [Pt(Ac-glyglyH(-1)metH(-1)-OH-kappa(3)N(G2),N(M), S) (Ac-glyglymet-OH-kappaS)] and [Pt(Ac-glyglyH(-1)metH(-1)-OH-kappa(3)N(G2),N(M), S)(NH(3))] at pH <5.2. The longevity of the initial kappaS complex leads to about an eight-fold increase in the rate of formation of the kappaN7:kappaN7' bis-adduct Pt(5'-GMP-kappaN7)(2)(NH(3))(2) for the reaction of carboplatin with 5'-GMP(2-) at pH 7 in the presence of Ac-glyglymet-OH. A mixed-ligand kappaS:kappaN7 species [Pt(5'-GMP-kappaN7)(Ac-glyglymet-OH-kappaS)(NH(3))(2)] provides the major precursor for this 1:2 nucleotide complex and kappaN7 coordination of 5'-GMP(2-) is also observed in the kappa(2)N(M),S:kappaN7 complex Pt(5'-GMP-kappaN7)(Ac-glyglymetH(-1)-OH-kappa(2)N(M),S)(NH(3))(2) formed by substitution of the ammine ligand trans to the methionine sulphur. As the intermediate kappaS:kappaN7 species is formed rapidly within the first 10 h of reaction, these results suggest that the transfer reaction pathway kappaS-->kappaS:kappaN7-->kappaN7:kappaN7' involving kappaS platinated peptides could play an important role in accelerating the rate of DNA binding for carboplatin.
通过高效液相色谱、核磁共振和质谱研究了抗癌药物卡铂[Pt(cbdca - κ(2)O,O')(NH(3))(2)]（cbdca = 环丁烷 - 1,1 - 二羧酸）与三肽H - glyglymet - OH（甘氨酰甘氨酰 - L - 甲硫氨酸）和Ac - glyglymet - OH在313 K时的pH和时间依赖性反应。与顺铂相比，初始开环κS配合物[Pt(cbdca - κO)(Ac - glyglymet - OH - κS)(NH(3))(2)]的相对稳定性导致动力学上有利的κS:κS'双加合物Pt(Ac - glyglymet - OH - κS)(2)(NH(3))(2)形成增加。结果，第二条1:2反应途径κS→κS:κS'→κ(2)N(M), S:κS'→κ(3)N(G2),N(M), S:κS'（其中N(M)和N(G2)分别代表金属化的甲硫氨酸和甘氨酸氮原子）与顺铂也观察到的1:1途径κS→κ(2)N(M), S→κ(3)N(G2),N(M), S竞争。对于各自的三齿配合物[Pt(Ac - glyglyH(-1)metH(-1)-OH - κ(3)N(G2),N(M), S)(Ac - glyglymet - OH - κS)]和[Pt(Ac - glyglyH(-1)metH(-1)-OH - κ(3)N(G2),N(M), S)(NH(3))]，在pH <5.2时，100小时后观察到N - 乙酰甘氨酸在主链C(O)-N键处与第二个甘氨酸残基（G2）的裂解。初始κS配合物的寿命导致卡铂与5'-GMP(2-)在pH 7且存在Ac - glyglymet - OH时，κN7:κN7'双加合物Pt(5'-GMP - κN7)(2)(NH(3))(2)的形成速率增加约八倍。混合配体κS:κN7物种[Pt(5'-GMP - κN7)(Ac - glyglymet - OH - κS)(NH(3))(2)]为这种1:2核苷酸配合物提供了主要前体，并且在由与甲硫氨酸硫反位的氨配体取代形成的κ(2)N(M),S:κN7配合物Pt(5'-GMP - κN7)(Ac - glyglymetH(-1)-OH - κ(2)N(M),S)(NH(3))(2)中也观察到5'-GMP(2-)的κN7配位。由于中间κS:κN7物种在反应的前10小时内迅速形成，这些结果表明涉及κS铂化肽的转移反应途径κS→κS:κN7→κN7:κN7'可能在加速卡铂与DNA结合的速率中起重要作用。
