抗癌药物卡铂与含硫氨基酸的开环加合物

Ring-Opened Adducts of the Anticancer Drug Carboplatin with Sulfur Amino Acids.

作者信息

Barnham Kevin J., Djuran Milos I., Murdoch Piedad del Socorro, Ranford John D., Sadler Peter J.

机构信息

Gordon House and Christopher Ingold Laboratory, Department of Chemistry, Birkbeck College, University of London, 29 Gordon Square, London WC1H 0PP, U.K., and Department of Chemistry, National University of Singapore, 10 Kent Ridge Crescent, Singapore 0511.

出版信息

Inorg Chem. 1996 Feb 14;35(4):1065-1072. doi: 10.1021/ic950973d.

DOI:10.1021/ic950973d

PMID:11666286

Abstract

Reactions of the anticancer drug carboplatin ("Paraplatin") with a variety of sulfur-containing amino acids have been investigated by (1)H and (15)N NMR spectroscopy and by HPLC. Thiols react very slowly and sulfur-bridged species containing four-membered Pt(2)S(2) rings are the predominant products. In contrast, reactions with thioether ligands are much more rapid, and kinetics for the initial stages of the reaction with L-methionine have been determined (k = 2.7 x 10(-)(3) M(-)(1) s(-)(1)). Surprisingly, very stable ring-opened species are formed such as cis-[Pt(CBDCA-O)(NH(3))(2)(L-HMet-S)] which has a half-life for Met-S,N ring-closure of 28 h at 310 K. A study of the formation of the analogous product for N-acetyl-L-methionine and its subsequent ring closure is reported. Reactions such as these may play a role in the biological activity of carboplatin.

摘要

已通过¹H和¹⁵N核磁共振光谱法以及高效液相色谱法研究了抗癌药物卡铂（“顺铂”）与多种含硫氨基酸的反应。硫醇反应非常缓慢，含四元Pt₂S₂环的硫桥连物种是主要产物。相比之下，与硫醚配体的反应要快得多，并且已确定了与L-蛋氨酸反应初始阶段的动力学（k = 2.7×10⁻³ M⁻¹ s⁻¹）。令人惊讶的是，形成了非常稳定的开环物种，例如顺式-[Pt(CBDCA-O)(NH₃)₂(L-HMet-S)]，其在310 K下Met-S,N环闭合的半衰期为28小时。报道了对N-乙酰-L-蛋氨酸类似产物的形成及其随后环闭合的研究。此类反应可能在卡铂的生物活性中起作用。