Imprinting structural information from a GpG ligand into the configurationof a chiral diamine ligand through second-sphere communication in platinum(II) complexes

Cisplatin forms the cis-Pt(NH3)(2)(d(GpG)) cross-link with DNA. We have rec ently created novel d(GpG) conformations by using "retro models'' (complexe s having bulky carrier ligands designed to slow d(GpG) dynamic motion). Our results define four conformer classes: HH1, HH2, Delta HT1, and Delta HT2, with a head-to-head or head-to-tail base orientation and a phosphodiester backbone with a normal (1) or opposite (2) propagation direction. Moreover, each G residue can be syn or anti, and the base canting can be left-handed (L) or right-handed (R). Thus, 32 variants of cis-Pt(NH3)(2)(d(GpG)) are c onceivable, but the adduct is too dynamic to study. Thus far, by using retr o models, we have obtained evidence for five variants with d(GpG) but only four with GpG. We therefore selected Me(2)DAPPt(GpG) complexes for study by H-1 and P-31 NMR spectroscopy, CD spectroscopy, and molecular mechanics an d dynamics (MMD) calculations. Coordinated Me(2)DAP (N,N'-dimethyl-2,4-diam inopentane) has N, C, C, N chiral centers designated, for example, as R,R,R ,R. This ligand has greater flexibility and more readily inverted N centers than ligands used previously in GpG retro models. One goal was to determin e whether the GPG ligand can control the configuration of a carrier ligand. (R,R,R,R)-Me(2)DAPPt(GpG) forms the anti, anti HH1 R variant almost exclus ively. Equal populations of the two possible linkage isomers of (S,R,RR)-Me 2DAPPt(GpG) are formed, both favoring the anti, anti HH1 R variant; however , the isomer with the 5'-G cis to the S nitrogen has sharper signals, sugge sting that interligand interactions are more favorable; Indeed, this linkag e isomer was the major product of isomerization when (R,R,R,R)-Me2DAPPt(GpG ) was kept at pH similar to9.5 to allow N center equilibration. Steric clas hes between the Me2DAP C-Me groups and the G O6 atoms found by MMD calculat ions appear to disfavor the HH1 conformer of (S,S,S,S)-Me(2)DAPPt(GpG) and (S,S,S,R)-Me(2)DAPPt(GpG) complexes. These two complexes have a significant population of the anti, syn Delta HT1 conformer, as indicated by broad H-1 NMR signals and by 31P NMR and CD data. Equilibration of (S,S,S,R)-Me(2)DA BPt(GpG) at PH 9.5 leads to a mixture of (S,S,S,S)-Me2DAPPt(GpG) and at lea st one isomer of (S,S,S,R)-Me(2)DAPPt(GpG). Thus, second-sphere communicati on (hydrogen bonding and steric interligand interactions) influences both G pG conformation and Me2DAP configuration.