Determination by electrospray mass spectrometry of the outersphere association constants of DNA/platinum complexes using 20-mer oligonucleotides and ([Pt(NH3)4]2+, 2Cl-) or ([Pt(py)4]2+, 2Cl-)

被引:25
作者
Carte, N
Legendre, F
Leize, E
Potier, N
Reeder, F
Chottard, JC
Van Dorsselaer, A
机构
[1] Univ Strasbourg 1, CNRS, UMR 7509, Lab Spectrometr Masse BioOrgan, F-67008 Strasbourg, France
[2] Univ Paris 05, CNRS, UMR 8601, Chim & Biochim Pharmacol & Toxicol Lab, F-75270 Paris 06, France
关键词
electrospray mass spectrometry; noncovalent interactions; oligonucleotides; platinum complexes; quantification; affinity constant;
D O I
10.1006/abio.2000.4661
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
The cytotoxic effects of cisplatin, cis-diamminedichloroplatinum(II), are generally ascribed to the formation of DNA adducts, Several in vitro as well as in vivo studies showed that cisplatin binds preferentially to guanines belonging to (G)(n) sequences (n greater than or equal to 2). After mono- or diaquation of cisplatin, giving the cationic complexes cis-[PtCl(NH3)(2)(H2O)](+) and cis-[Pt(NH3)(2)(H2O)(2)](2+), DNA platination occurs in two steps: the cationic complex gives an outersphere association with DNA and the actual coordination then occurs by substitution of one aqua ligand by guanine-N7, For a better understanding of the (G;), selectivity of cisplatin giving the biologically active adducts, also necessary for the conception of new platinum drugs, the respective contribution of the outersphere association and actual guanine platination must be investigated, To check the role of outersphere association In the overall platination process, we used electrospray mass spectrometry (ESMS) to detect and quantify outersphere association between 20-mer oligonucleotides and platinum complexes, The 20-mer oligonucleotides were single- or double-stranded, with the same number of guanines either isolated or adjacent to each other. To deal only with outersphere association and check the influence of platinum ligands, the [Pt(NH3)(4)](2+) and [Pt(py)(4)](2+) complexes were used, We characterized by ESMS all the different outersphere association species formed during titration of each oligonucleotide with the various platinum complexes and evaluated their affinity constants. The ESMS results demonstrate that the outersphere association depends on electrostatic interactions and on the ability of the platinum ligands to participate to hydrogen bonding, particularly within the duplex form, (C) 2000 Academic Press.
引用
收藏
页码:77 / 86
页数:10
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