Cisplatin--DNA cross-link models with an unusual type of chirality-neutral chelate amine carrier ligand, N,N dimethylpiperazine (Me2ppz): Me2ppzPt(guanosine monophosphate)2 adducts that exhibit novel properties.
Most simple cis-PtA2G2 complexes that model the G-G cross-link DNA lesions caused by the clinically used anticancer drug cis-PtCl2(NH3)2 undergo large fluxional motions at a rapid rate (A2 = two amines or a diamine; G = guanine derivative). The carrier amine ligands in active compounds have NH groups, but the fundamental role of the NH groups has been obscured by the dynamic motion. To assess carrier ligand effects, we examine retro models, cis-PtA2G2 complexes, in which dynamic motion has been reduced by the incorporation of steric bulk into the carrier ligands. In this study we introduce a new approach employing the chirality-neutral chelate (CNC) ligand, Me2ppz (N,N'-dimethylpiperazine). Because they lie in the Pt coordination plane, the methyl groups of Me2ppz do not clash with the 06 of the base of G ligands in the ground state, but such clashes sterically hinder dynamic motion. NMR spectroscopy provided conclusive evidence that Me2ppzPt(GMP)2 complexes (GMP = 5'- and 3'-GMP) exist as a slowly interconverting mixture of two dominant head-to-tail (HT) conformers and a head-to-head (HH) conformer. Since the absence of carrier ligand chirality precluded using NMR methods to determine the absolute conformation of the two HT conformers, we used our recently developed CD pH jump method to establish chirality. The most abundant HT Me2ppzPt(5'-GMP)2 form had A chirality. Previously this chirality was shown to be favored by phosphate-cis G NIH hydrogen-bonding interligand interactions; such interactions also favor the HT conformers over the HH conformer. For typical carrier ligands, G O6 and phosphate interactions with the carrier ligand NH groups also favor the HT forms. These latter interactions are absent in Me2ppzPt(GMP)2 complexes, but the HT forms are still dominant. Nevertheless, we do find the first evidence for an HH form of a simple cis-PtA2G2 model with A2 lacking any NH groups. In previous studies, the absence of the HH conformer in cis-PtA2G2 complexes lacking carrier NH groups may be due to the presence of out-of-plane carrier ligand bulk. Such bulk forces both G O6-G O6 and G O6-carrier ligand clashes, thereby disfavoring the HH form. The major DNA cross-link adduct has the HH conformation. Thus, for anticancer activity, the small bulk of the NH group may be more important than the H-bonding interaction.
Sullivan
S T
ST
Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
Ciccarese
A
A
Fanizzi
F P
FP
Marzilli
L G
LG
D000970:Antineoplastic Agents / Q000737:chemistry*; D002942:Circular Dichroism; D002945:Cisplatin / Q000737:chemistry*; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry*; D004337:Drug Carriers; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009944:Organoplatinum Compounds / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D008024:Ligands; C422658:N,N'-dimethylpiperazine; D009944:Organoplatinum Compounds; D010879:Piperazines; C422659:bis(guanosine monophosphate)(N,N'-dimethylpiperazine)platinum(II); D006157:Guanosine Monophosphate; D004247:DNA; D002945:Cisplatin