Steric control of DNA interstrand cross-link sites of trans platinum complexes:: specificity can be dictated by planar nonleaving groups

被引:64
作者
Brabec, V
Neplechova, K
Kasparkova, J
Farrell, N
机构
[1] Acad Sci Czech Republ, Inst Biophys, CS-61265 Brno, Czech Republic
[2] Virginia Commonwealth Univ, Dept Chem, Richmond, VA 23284 USA
来源
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY | 2000年 / 5卷 / 03期
基金
美国国家科学基金会;
关键词
DNA; cisplatin; transplatin; cross-link; dimethyl sulfate;
D O I
10.1007/PL00010665
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Recent findings that novel trans-dichloroplatinum(II) complexes exhibit antitumor activity violate the classical structure-activity relationships of platinum(II) complexes. These novel "nonclassical" trans platinum complexes also comprise those containing planar aromatic amines. initial studies have shown that these compounds form a considerable amount of DNA interstrand cross-links (up to similar to 30%) with a rate markedly higher than clinically ineffective transplatin. The present work has shown, using Maxam-Gilbert footprinting, that trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(NH3)(thiazole)], representatives of the group of new antitumor trans-dichloroplatinum complexes containing planar amines, preferentially form DNA interstrand cross-links between guanine residues at the 5'-GC-3' sites. Thus, DNA interstrand cross-linking by trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(NH3)(thiazole)] is formally equivalent to that by antitumor cisplatin, but different from clinically ineffective transplatin which preferentially forms these adducts between complementary guanine and cytosine residues. This result shows for the first time that simple chemical modification of the structure of an inactive compound alters its DNA binding site into a DNA adduct of an active drug.
引用
收藏
页码:364 / 368
页数:5
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