Classical ruthenium coordination chemistry has recently yielded extraordinary potential health care dividends involving: 1) The rational design of ruthenium complexes as anticancer agents with overall mechanisms of action distinct from other metallo- anticancer drugs. 2) simple Ru complexes that are superbly efficient immunosuppressive agents by inhibiting T-cell proliferation at nanormolar levels. 3) The design of a ruthenium complex that enhances the electrochemical long-term-potentiation response in brain tissue. Work in this laboratory has helped to stimulate research into the development of Ru-containing pharmaceuticals in several laboratories worldwide. We have recently shown that two suggested mechanisms, which were often thought to be competing for the action of ruthenium antitumor agents, probably work in concert to promote selective Ru binding to tumor cell DNA. This points the way to a possible new class of hybrid, metalloprotein complexes as active antitumor agents. A recently disclosed discovery by Procept, Inc., a local biotechnology company, suggests an entirely new approach to drugs that could facilitate the survival of transplanted organs and combat some immune-system based diseases such as psoriasis. While contributory, complexes we provided paved the away to the discovery of the most active agents. Our results with nitrosyl complexes of technetium suggested a means of manipulating the release of coordinating nitrosyls both thermally and following reduction. A collaborative effort has shown that this is possible and has yielded an active Ru agent that promotes LTP in hippocampal slices. Consequently, an investigation of a series of metallonitrosyl complexes involving strongpi-acceptor ligands, particularly those which can act as trans labilizers, will be undertaken to determine how NO release is affected. The ability to control NO loss should yield a new class of agents capable of crossing membrane barriers and releasing NO within the brain and at other strategic locations.
