Ruthenium Chemistry Pertaining to the Design of Anticancer Agents

Abstract

Ruthenium compounds hold particular promise in the design of new anticancer agents, including: a) chemotherapeutic drugs, b) radiopharmaceuticals for diagnostic imaging, and, c) most recently, radiosensitizers for radiotherapy. With regard to chemotherapeutic agents, complexes with nitrogen ligands and anionic leaving groups appear to be the most active as cytotoxic agents, with nuclear DNA usually assumed as the target site. Binding to DNA may occur in a variety of modes with ion-pairing and covalent bonding probably being the most important for active agents, often with the former occurring before the latter. After injection as a Ru(III) prodrug, selective localization in the tumor may take place by in vivo reduction to the more actively binding Ru(II) complex. Transferrin may also mediate the transfer of some ruthenium complexes to the tumor site. At least in the case of [(H₂O)(NH₃)5Ru]^{2 +}, coordination to DNA occurs initially at G⁷ sites in the major groove of the DNA.. However, higher concentrations appear to cause uncoiling with subsequent binding to the exocyclic amines of A and C. On coordination to nucleosides, ammineruthenium ions can migrate between nitrogen sites or exist as rotamers on exocyclic ammines. Such metal ion movements can be choreographed by controlling the pH and electrochemical potential of the media. Square-wave voltammetry promises to be a sensitive method for probing the redox chemistry of ruthenium both on free nucleosides and on DNA, and for monitoring isomerization reactions following electron transfer. At high pH, Ru(III) induces the rapid autoxidation of nucleosides, in a manner reminiscent of xanthine oxidase, to yield 8-keto-purines. The anticancer activities of some selected ruthenium compounds are surveyed as to possible mechanisms consistent with their chemistry.