Non-Covalent Polynuclear Platinum Compounds As Polyamine Analogs

Polynuclear platinum compounds (PPCs) represent a discrete class of antitumor agents that bear structural resemblance to polyamines. This chapter reviews developments on the chemistry and biology of polynuclear platinum drugs and especially the recognition that “non-covalent” agents based on this motif represent a further challenge to the structure-activity paradigms for platinum antitumor agents. Pt-DNA bond formation is not a strict requirement for DNA affinity leading to manifestation of promising cytotoxicity and antitumor activity. Non-covalent PPCs bind to DNA in a non-covalent manner through a novel binding motif, the phosphate clamp, analogous to the arginine fork. This binding mode is discrete from “classical” intercalation and minor groove binding. In solution, analysis of 1-D and 2-D 1HNMR data places the compounds in the minor groove of the DNA, spanning several base pairs. A melphalan protection assay indicated that the complex was at least as effective in blocking melphalan access to the minor groove as distamycin. Further biological consequences of the structure are remarkably enhanced cellular accumulation, further distinguishing the non-covalent group as a unique class of agents.