REVERSIBILITY OF BINDING OF CISPLATIN METHIONINE IN PROTEINS BY DIETHYLDITHIOCARBAMATE OR THIOUREA - A STUDY WITH MODEL ADDUCTS

被引:104
作者
LEMPERS, ELM [1 ]
REEDIJK, J [1 ]
机构
[1] LEIDEN STATE UNIV,GORLAEUS LABS,DEPT CHEM,POB 9502,2300 RA LEIDEN,NETHERLANDS
关键词
D O I
10.1021/ic00327a014
中图分类号
O61 [无机化学];
学科分类号
070301 ; 081704 ;
摘要
Model adducts for platinum—protein binding, i.e. at cysteine and methionine sites, have been synthesized by starting from [PtCl(dien)]Cl, cis-Pt(NH3)2Cl2, ira,tr-Pt(NH3)2Cl2, and [PtCl(NH3)3]Cl. Glutathione (GSH) and 5-methylglutathione (GS-Me) were used to mimic the sulfur atoms in the proteins. At pH 11 both rrai-Pt(NH3)2Cl2and [PtCl(NH3)3]Cl form trans-Pt-(NH3)2(GS)2upon reaction with 2 equiv of GS−. Only the intermediate [Pt(NH3)3GS]Cl was found to be relatively stable. The Pt-cysteine type bonds in [Pt(dien)GS]+and in trans-Pt(NH3)2(GS)2could not be reversed by sodium diethyldithiocarbamate (Na(ddtc)) and thiourea. On the other hand the Pt-methionine models [Pt(dien)GS-Me]2+and cis-Pt(GS-Me) react fast with Na(ddtc) (t1//2= <2 min) and more slowly with thiourea (t1/2= 30 min−2 h), thereby restoring the original structure of the thioether linkage. The complex formed between Na(ddtc) and the liberated Pt(dien)2+unit proved to be a complex in which the Pt-dien chelate ring is partially opened, leaving one NH2noncoordinated. The ability of the nephrotoxicity inhibitors Na(ddtc) and thiourea to reverse Pt-protein adducts—these adducts are supposed to be the origin of nephrotoxicity of platinum antitumor compounds—is interpreted in terms of removing the platinum from methionine sulfurs only. © 1990, American Chemical Society. All rights reserved.
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页码:217 / 222
页数:6
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