Diminishing dynamic motion problems of platinum anticancer drug adducts ofguanine 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 i n the activity of clinically used Pt anticancer drugs is the dynamic charac ter of adducts with DNA and DNA constituents. To address this problem, we i ntroduced the hybrid ligand approach with the diamine pipen = 2-(aminomethy l)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 substitue nts and pipen chirality on the stability and spectral properties of the atr opisomers. 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, sev eral factors influence both relative abundance and shifts of the Ks signals of the Delta HT and Lambda HT forms at neutral pH. The chirality of the ma jor 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 a n important determinant of HT chirality for pipenPt(S'-GMP)a. Since, for 5' -GMP, phosphate-NH-(pipen) hydrogen bonding is possible, this interaction p robably favors the major atropisomer, in which two such interactions are po ssible, over the minor atropisomer, in which only one interaction is possib le. The Delta HT 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 Delta HT vs the Lambda HT 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 HX signals. We showed that 3'-GMP adducts favo r the Delta HT conformer at pH7; the Delta HT conformer preference explains the enhanced "Delta" CD signal observed for most 3'-GMP adducts, including the cisplatin adduct.