Origins of the distortions in the base pair step adjacent to platinum anticancer drug-DNA adducts. Fundamental NMR solution studies utilizing right-handed cross-link models having 5'- and 3'-flanking residues.
For DNA duplexes, the Lippard laboratory has shown that the XG* base pair (bp) step has a very unusual slide and shift, where G* is a G platinated at N7 by di- or monofunctional platinum anticancer drugs. One approach toward understanding the cause of this important unexpected XG* distortion is to examine single-strand (ss) oligonucleotide (oligo) models. Both duplex and ss XG*G* models of the key G*G* cross-link formed by cisplatin have the HH1 conformation with head-to-head bases. Cross-links have R canting (3'-G* H8 atom toward 5'-G*) in duplexes and L canting (5'-G* H8 atom toward 3'-G*) in ss models. However, dynamic motion in solution makes the ss features difficult to define. Thus, we employ less dynamic cross-link models such as (R,S,S,R)-BipPt(d(TG*G*)) and (R,S,S,R)-BipPt(d(pG*G*TTT)), the first examples of an HH1 conformer with R canting for ss oligos longer than d(GpG) (Bip = 2,2'-bipiperidine). In these, the 5'-T residue decreases R canting (indicating steric clashes with the 5'-G*) and the less bulky 5'-phosphate group forms a H-bond to HN-Pt (indicating that R canting allows H-bonding). We conclude that the 5'-X residue in duplex adducts changes its position from that in B form DNA to avoid steric clashes with the 5'-G* and the carrier ligand and secondarily to form a Watson-Crick base pair. These features, possibly aided by weak carrier-ligand H-bonding, lead to the relatively unusual features distinctive to the "Lippard bp step".
Saad
Jamil S
JS
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
Natile
Giovanni
G
Marzilli
Luigi G
LG
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D020029:Base Pairing / Q000187:drug effects*; D001483:Base Sequence; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry* / Q000494:pharmacology; D018736:DNA Adducts / Q000737:chemistry* / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D012996:Solutions
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D012996:Solutions; D002945:Cisplatin