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)PtG(2) with CCC = N,N '-dimethyl-2,3-diaminobutane

Chirality-controlling chelate (CCC) ligands are a class of chiral diamine l igands with one or two chiral secondary amine ligating groups. Analogues of platinum anticancer agents containing CCC ligands exhibit unusual steric a nd dynamic features. In this study NMR and CD methods were used to evaluate the influence of the N9 substituent in guanine derivatives (G) on conforme r distribution in one class of (CCC)PtG(2) complexes. We employed the CCC l igand, N,N'-dimethyl-2,3-diaminobutane [Me(2)DAB with S,R,R,S or R,S,S,R co nfigurations at the four asymmetric centers, N, C, C, and N]. For each Me(2 )DABPtG(2) complex, the presence of four G H8 signals demonstrated formatio n of all three possible atropisomers: Delta HT (head-to-tail), Lambda HT, a nd 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 relat ive stability and spectral properties of the atropisomers. The conformation s of the atropisomers of Me(2)DABPtG(2) were determined from CD spectra and from NOE cross-peaks (assigned via COSY spectra) between G H8 signals and those for the Me(2)DAB protons. Regardless of the N9 substituent, the major form was HT. However, this form had the opposite chirality, Lambda HT and Delta HT, and base tilt direction, left- and right-handed, respectively, fo r the S,R,R,S and R,S,S,R configurations of the Me(2)DAB ligand. Thus, the chirality of the CCC ligand, not hydrogen bonding, is the most important de terminant of conformation. For each Me(2)DABPtG(2) complex, the tilt direct ion 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 phosph ate-NH(Me(2)DAB) hydrogen bonds could be present since such bonding is poss ible only for the 5'-GMP derivatives. However, if such phosphate-NH hydroge n 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 perce ntage for complexes with other G's. The CD spectra of all (S,R,R,S)-Me(2)DA BPtG(2) complexes were similar and opposite to those of all (R,S,S,R)-Me(2) DABPtG(2) complexes, indicating the CD signature is characteristic of the d ominant HT conformer, which has a chirality dictated by the chirality of th e CCC ligand and not the N9 substituent.