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)PtG(2)() complexes. We employed the CCC ligand, N,N'-dimethyl-2,3-diaminobutane [Me(2)()DAB with S,R,R,S or R,S,S,R configurations 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 formation of all three possible atropisomers: DeltaHT (head-to-tail), LambdaHT, 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 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, LambdaHT and DeltaHT, and base tilt direction, left- and right-handed, respectively, for the S,R,R,S and R,S,S,R configurations of the Me(2)()DAB ligand. Thus, the chirality of the CCCligand, not hydrogen bonding, is the most important determinant of conformation. For each Me(2)()DABPtG(2) 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(Me(2)()DAB) 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)-Me(2)()DABPtG(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 dominant HT conformer, which has a chirality dictated by the chirality of the CCC ligand and not the N9 substituent.

Features of cisplatin-type anticancer drug adducts with nucleic acids and their constituents are clouded because they exist as a fluxional mixture of conformers. Retro-model adducts containing the specially designed chiral diamine ligand, Bip = 2,2'-bipiperidine, are dramatically less fluxional. Conformers of BipPtG(2) adducts with R,S,S,R and S,R,R,S asymmetric centers at the N, C, C, and N Bip chelate ring atoms and G = 5'-GMP, 5'-dGMP, 3'-GMP, or 9-ethylguanine are amenable to separate characterization. All possible BipPtG(2) atropisomers (one head-to-head (HH) and Delta and Lambda head-to-tail (HT) atropisomers) were observed by NMR spectroscopy. At equilibrium at low pH, one HT atropisomer dominates. CD spectra, G H8 chemical shifts, and low-pH equilibria of BipPtG(2) and Me(2)()DABPtG(2) (Me(2)()DAB = N,N '-dimethyl-2,3-diaminobutane) are similar when the chelate ring atoms have the same stereochemistries; thus, Bip and Me(2)()DAB are termed chirality-controlling chelates (CCC) since these ligands dictate the absolute conformation of the major HT rotamer. In each case, the HT conformer that cannot form G O6-NH(CCC) hydrogen bonds was dominant, and the G H8 chemical shift indicated that this conformer had less tilted bases, allowing favorable base-base dipole-dipole interactions. For both the R,S,S,R and S,R,R,S Bip chiralities of the BipPt(3'-GMP)(2) complexes, the percentage of DeltaHT rotamer increased near pH 7, a probable consequence of phosphate-cis-G hydrogen bonds accompanied by favorable dipole interactions of less tilted bases. For the 5'-GMP complexes, these factors favor the LambdaHT rotamer near pH 7. When G has a 5'-phosphate group, rotamer distribution is also influenced by phosphate-NH(Bip) hydrogen bonds. At high pH, the nature and/or strength of interactions such as G dipole-G dipole interactions and G O6-NH(Bip) and phosphate-cis-G hydrogen bonding are altered by G N(1)H deprotonation. The features of the complexes at high pH can be largely explained as arising from the net result of these interactions. This information from retro models with a CCC ligand lays the foundation for understanding and evaluating the properties of the highly dynamic adducts of anticancer drugs.

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Addition of alcohols (HOR') to the coordinated nitriles (NCR) in the platinum complexes [PtCT/NCR)]-and errand trans-[PtChlNCR^] (R = Me, Et, Ph, Bu') takes place readily under basic conditions. The Z isomer, corresponding to a trans addition of the alcohol to the C=N triple bond, is the first reaction product, subsequently undergoing isomerization to the E form. An increase of the steric bulk of the R group stabilizes the Z isomer with respect to the E isomer; in contrast, an increase of the steric bulk of the R' group stabilizes the E over the Z isomer. The structures of trans-and dr-[PtCl2{E-HN=C(OMe)Me}2] (SEE and 9EE, respectively) have been solved by single-crystal X-ray diffraction. SEE crystallizes in the space group PI (No. 2) with a = 8.491(6) Á, b = 8.603(2) Á, c = 8.973(2) Á, a = 75.56(1)°, ß = 67.52(2)°, = 85.62(2)°, V = 586.4(2) Á3, and Z = 2. 9EE crystallizes in the space group C2Jc (No. 15) with a = 15.854(3) k, b = 8.123(2) k, c = 9.471(2) k, ß -93.72(3)°, V = 1217.1(4) Á3, and Z = 4. In each complex, the Pt atom is linked to two Cl" anions and two imino ether N atoms, the coordination geometry is strictly planar, and the Pt-Cl and Pt-N bond distances have normal values. An unexpected feature resulting from the crystallographic data was the "quasi-planarity" of the imino ether moiety and electron charge delocalization over theN'XX) moiety. As a consequence, all the groups attached to the Nr*Cr*0 skeleton share the same plane, causing considerable steric strain, as indicated by deviations (5°o r even more) of some bond angles from canonical values.

The key problem obscuring the role of the ammine and primary amine groups in the activity of clinically used Pt anticancer drugs is the dynamic character of adducts with DNA and DNA constituents. To address this problem, we introduced the hybrid ligand approach with the diamine pipen = 2-(aminomethyl)piperidine; the piperidine ring greatly reduces dynamic motion in adducts. We now use NMR and CD methods to investigate (S,R)- and (R,S)-pipenPtG(2) complexes (with S,R and R,S configurations at the N and C pipen asymmetric centers, respectively; G = a guanine derivative). Each pipenPtG(2) complex can have two head-to-head (HH) and two head-to-tail (HT) rotamers. However, only the two HT atropisomers were detected. The Delta or Lambda chirality of each HT rotamer was determined from NOESY/EXSY spectra and/or the sign of the CD signal. Examination of adducts with G = 5'-GMP, 3'-GMP, or 9-EtG (9-ethylguanine) allowed us to assess the effects of different N9 substituents and pipen chirality on the stability and spectral properties of the atropisomers. For the 9-EtG complexes, the HT atropisomers were nearly equally stable, indicating that the pipen configuration has little influence when the N9 substituent lacks a phosphate group. However, for GMP complexes, several factors influence both relative abundance and shifts of the H8 signals of the DeltaHT and LambdaHT forms at neutral pH. The chirality of the major HT form of the (S,R)- and (R,S)-pipenPt(5'-GMP)(2) complexes was Lambda and Delta, respectively. Therefore, the chirality of the pipen ligand is an important determinant of HT chirality for pipenPt(5'-GMP)(2). Since, for 5'-GMP, phosphate-NH(pipen) hydrogen bonding is possible, this interaction probably favors the major atropisomer, in which two such interactions are possible, over the minor atropisomer, in which only one interaction is possible. The DeltaHT form was dominant for both (S,R)- and (R,S)-pipenPt(3'-GMP)(2). The stability arises from the more favorable interactions between the phosphates and the NH's of the cis 3'-GMP's in the DeltaHT vs the LambdaHT form. This hydrogen bonding is more favorable when the G bases have less tilt, and less tilted G's are associated with more favorable dipole-dipole interactions and deshielded H8 signals. We showed that 3'-GMP adducts favor the DeltaHT conformer at pH7; the DeltaHT conformer preference explains the enhanced "Delta" CD signal observed for most 3'-GMP adducts, including the cisplatin adduct.

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NMR and CD spectroscopy and molecular mechanics and dynamics (MMD) calculations were used to characterize (Me2DAP)Pt(G)2 complexes (G = N9-substituted guanine derivative; Me2DAP = 2,4-bis(methylamino)pentane with N, C, C, and N stereochemistries of S,R,S,R, S,R,R,R, and R,R,R,R). NMR and MMD results indicated that the favored Me2DAP chelate ring conformations were chair. There are two possible head-to-tail rotamers (ΔHT and ΛHT) and, depending on the Me2DAP stereochemistry, one or two head-to-head (HH) rotamers. Rotation of the G bases around the Pt−N7 bond was found to be rapid on the NMR time scale for all compounds in D2O at room temperature; in contrast, slow rotation was reported for (Me2DAB)Pt(G)2 (Me2DAB = 2,3-bis(methylamino)butane by Xu et al.) Because of the additional flexibility of the six-membered chelate ring in the Me2DAP systems versus the five-membered ring in Me2DAB, the N-methyl groups of Me2DAP can occupy more pronounced axial positions, allowing a low-energy path to rotation as suggested by MMD calculations. The fast rotation necessitated that the rotamer preference be assessed by CD spectroscopy. For the S,R,S,R complexes, the G N9 substituent strongly influenced which HT rotamer was preferred. The ΛHT rotamer was favored for the R,R,R,R complexes at pH 3 regardless of the G used. MMD calculations on the [(R,R,R,R)-(Me2DAP)Pt(9-EtG)2]2+ complex suggested amine-O6 hydrogen bonding in the ΛHT rotamer and indicated an unfavorable nonbonded interaction between the G O6 and an axial cis C-methyl group in the ΔHT rotamer. This nonbonded interaction was also observed in calculated structures of the [(S,R,R,R)-(Me2DAP)Pt(9-EtG)2]2+ complex, for which experimental data showed a preference for the ΛHT rotamer as well. Thus, the orientations of the N- and C-methyl groups appear to be important in determining both the rate of rotation and the rotamer preference of the (Me2DAP)Pt(G)2 systems.