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

Recent findings that novel trans-dichloroplatinum(II) complexes exhibit ant itumor activity violate the classical structure-activity relationships of p latinum(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 c ross-links (up to similar to 30%) with a rate markedly higher than clinical ly ineffective transplatin. The present work has shown, using Maxam-Gilbert footprinting, that trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(NH3)(thi azole)], representatives of the group of new antitumor trans-dichloroplatin um complexes containing planar amines, preferentially form DNA interstrand cross-links between guanine residues at the 5'-GC-3' sites. Thus, DNA inter strand cross-linking by trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(NH3) (thiazole)] is formally equivalent to that by antitumor cisplatin, but diff erent from clinically ineffective transplatin which preferentially forms th ese adducts between complementary guanine and cytosine residues. This resul t shows for the first time that simple chemical modification of the structu re of an inactive compound alters its DNA binding site into a DNA adduct of an active drug.