Non-covalent interactions in adducts of platinum drugs with nucleobases in nucleotides and DNA as revealed by using chiral substrates

Selective binding of coordinating agents (cisplatin) to target molecules (DNA) and the contribution of H-bonding, electrostatic interactions, and steric effects in such binding are fundamentally important subjects. To address some of these questions, simple models of the platinum–DNA cross-links, such as cis-(NH3)2PtG2 (G = detached or tethered guanine bases) complexes, have been investigated extensively. The fast interconversion between possible conformers on the NMR time scale led us to construct analogs of cisplatin with bulky ligands designed to reduce the dynamic motion by destabilizing the transition state for Pt-G rotation. The term “retro modeling” was introduced to emphasize that the models are more complicated than the relevant molecule, cisplatin. Retro models have been proved to be particularly useful in unraveling the existence of different conformations, and in the most favorable cases have also allowed the full characterization of the stereochemistry of single conformers. Moreover, several interligand interactions that escaped detection for a long time have been identified and grouped into three categories: First-to-First, First-to-Second, and Second-to-Second sphere Communication. A hierarchy ranking these interactions has been established. The new analysis has allowed us to rationalize computational, solution-state, and solid-state results on cross-linked oligonucleotides directly relevant to the cis-(NH3)2Pt adducts themselves.