Chirality-Controlling Chelate (CCC) Ligands in Analogues of Platinum Anticancer Agents. Influence of N9 Substituents of Guanine Derivatives (G) on the Distribution of Chiral Conformers of (CCC)PtG₂ with CCC = N,N‘-Dimethyl-2,3-diaminobutane

Chirality-controlling chelate (CCC) ligands are a class of chiral diamine ligands with one or two chiral secondary amine ligating groups. Analogues of platinum anticancer agents containing CCC ligands exhibit unusual steric and dynamic features. In this study NMR and CD methods were used to evaluate the influence of the N9 substituent in guanine derivatives (G) on conformer distribution in one class of (CCC)PtG₂ complexes. We employed the CCC ligand, N,N‘-dimethyl-2,3-diaminobutane [Me₂DAB with S,R,R,S or R,S,S,R configurations at the four asymmetric centers, N, C, C, and N]. For each Me₂DABPtG₂ complex, the presence of four G H8 signals demonstrated formation of all three possible atropisomers:  ΔHT (head-to-tail), ΛHT, and HH (head-to-head). Different G ligands (5‘-GMP, 3‘-GMP, 1-MeGuo, Guo, or 9-EtG) were chosen to assess the effect of the N9 substituent on the relative stability and spectral properties of the atropisomers. The conformations of the atropisomers of Me₂DABPtG₂ were determined from CD spectra and from NOE cross-peaks (assigned via COSY spectra) between G H8 signals and those for the Me₂DAB protons. Regardless of the N9 substituent, the major form was HT. However, this form had the opposite chirality, ΛHT and ΔHT, and base tilt direction, left- and right-handed, respectively, for the S,R,R,S and R,S,S,R configurations of the Me₂DAB ligand. Thus, the chirality of the CCC ligand, not hydrogen bonding, is the most important determinant of conformation. For each Me₂DABPtG₂ complex, the tilt direction of all three atropisomers is the same and, except for 5‘-GMP, the order of abundance was major HT > minor HT > HH. For 5‘-GMP, the HH atropisomer was three times as abundant as the minor HT species, suggesting that phosphate-NH(Me₂DAB) hydrogen bonds could be present since such bonding is possible only for the 5‘-GMP derivatives. However, if such phosphate-NH hydrogen bonds exist, they are weak since the percentage of the major HT form of 5‘-GMP complexes is similar and indeed can be smaller compared to this percentage for complexes with other G's. The CD spectra of all (S,R,R,S)-Me₂DABPtG₂ complexes were similar and opposite to those of all (R,S,S,R)-Me₂DABPtG₂ complexes, indicating the CD signature is characteristic of the dominant HT conformer, which has a chirality dictated by the chirality of the CCC ligand and not the N9 substituent.