Diminishing Dynamic Motion Problems of Platinum Anticancer Drug Adducts of Guanine Derivatives with the Hybrid Ligand Approach: Evidence for Cis Interligand Interactions Especially between 3'-GMP's.

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.