title: Modification of second-sphere communication, leading to an unusually high abundance of the head-to-head conformer of cisplatin cross-link retro models.
abstract: Rapid atropisomerization of cisplatin-DNA cross-link models, cis-PtA(2)G(2) (A(2) = two amines or a diamine, G = guanine derivative, bold font indicating a guanine not linked to another guanine), makes their NMR spectra uninformative. The conformers [two head-to-tail (DeltaHT and LambdaHT) conformers, one head-to-head (HH) conformer] are detected in (CCC)PtG(2) retro models (CCC = chirality-controlling chelates designed to reduce rotation around the G N7 to Pt bond by destabilizing the transition state). Clear trends are found with four CCC ligands, 2,2'-bipiperidine (Bip) and N,N'-dimethyl-2,3-diaminobutane (each with S,R,R,S and R,S,S,R configurations at the chelate ring N, C, C, and N atoms, respectively). S,R,R,S ligands favor left-handed G base canting and the LambdaHT form; R,S,S,R ligands favor right-handed canting and the DeltaHT form. The HH conformer is normally negligible unless G = 5'-GMP. However, understanding this 5'-phosphate effect is complicated by possible interligand interactions of the 5'-phosphate with the N1H of the cis-5'-GMP and a CCC NH; these interactions are referred to as second-sphere (SSC) and first-to-second-sphere (FSC) communication, respectively. We now investigate the four (CCC)PtG(2) models with 1-Me-5'-GMP, a G lacking the N1H needed for SSC. The phosphate location makes FSC possible in the major but not the minor HT form. The major form should increase from pH 3 to pH 7 because the phosphate is deprotonated at pH 7. However, the major DeltaHT form for the R,S,S,R pair did not change in abundance, and the major LambdaHT form for the S,R,R,S pair actually decreased. Thus, FSC is weak. At pH approximately 7 the HH conformer of the S,R,R,S pair had an abundance (40-44%) higher than that in any reported cis-PtA(2)G(2) adduct. FSC involving one 1-Me-5'-GMP could play a role. The high HH abundance and use of a pH jump experiment with (S,R,R,S)-BipPt(1-Me-5'-GMP)(2) allowed us to obtain the first deconvoluted CD spectrum for a cis-PtA(2)G(2) HH conformer. The CD features for the HH conformer are much weaker than for the HT conformers. Our findings are best interpreted to indicate that FSC is not important in aqueous solution, especially for the HT form. Weak FSC is consistent with recent models of the cross-link in duplexes. In contrast, crystals of fluxional models often reveal FSC, but not the more important SSC. SSC was unrecognized until our retro model studies, and the new results reinforce the value of studying retro models for identifying interactions in solution.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jamil S
authors.initials: JS
authors.lastname: Saad
authors.forename: Tommaso
authors.initials: T
authors.lastname: Scarcia
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shinozuka
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.forename: Luigi G
authors.initials: LG
authors.lastname: Marzilli
mesh_terms: D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002942:Circular Dichroism; D002945:Cisplatin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D003432:Cross-Linking Reagents; D004247:DNA / Q000138:chemical synthesis / Q000737:chemistry; D018736:DNA Adducts / Q000138:chemical synthesis* / Q000737:chemistry; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism
chemical_list: D003432:Cross-Linking Reagents; D018736:DNA Adducts; D008024:Ligands; D006157:Guanosine Monophosphate; D004247:DNA; D002945:Cisplatin