American Chemical Society
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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

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journal contribution
posted on 1998-12-01, 00:00 authored by Luigi G. Marzilli, Francesco P. Intini, Danita Kiser, Hing C. Wong, Susan O. Ano, Patricia A. Marzilli, Giovanni Natile
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.