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The broad impacts of our research are to expand the frontiers of the understanding of the role and utility of metal complexes in biology and medicine. This topic has been dominated in recent years by the use of platinum complexes in the clinical treatment of cancer but covers a broad field ranging from effects on viruses, bacteria, the historical use of gold complexes in arthritis, and even nitroprusside as a vasodilator. All these uses and effects have their origin in the coordination chemistry of these complexes and their interactions with biological molecules and biological approaches. I have placed this area of research into both a bioinorganic and medicinal chemistry context in the earlier book “Transition Metal Complexes as Drugs and Chemotherapeutic Agents” (Reidel-Kluwer 1990). Research is by definition highly interdisciplinary combining chemical, computational
In platinum antitumor chemistry our objective is to design and develop complexes acting by new discrete mechanisms of action. Platinum-based drugs are an important part of the anticancer drug armamentarium. Polynuclear platinum complexes studied in our laboratory are a discrete structural class distinct from the clinically used mononuclear cisplatin, carboplatin and oxaliplatin. Structurally unique complexes acting by different mechanisms may display an altered spectrum of antitumor activity and especially activity in cisplatin-resistant lines. To achieve this goal it is necessary to design new chemotypes and delineate their biological action through systematic examination of the principal factors controlling platinum drug cytotoxicity and antitumor activity – cellular accumulation, target (DNA) interactions and the extent of metabolizing interactions. Proof of principle of the utility (and success) of this approach is afforded by the advance of BBR3464, a trinuclear, bifunctional DNA binding agent with an overall 4+ charge, to Phase II clinical trials, the first and only non-cisplatin analog to be introduced to humans. With this advance the paradigm of cisplatin-based antitumor agents was altered.
The challenge for coordination chemists is to expand frontiers and to suggest new mechanisms of action and targets for biologically active inorganic compounds. Research provides the scientific groundwork with long-term possibilities for new medicinal applications. Current projects also include the study of the “coordination chemistry” of zinc finger proteins, contributing to understanding of the design of antiviral (specifically HIV) coordination compounds from first principles. The potential application of our research results will demonstrate the linkage between discovery and societal benefit by expanding in a rational and innovative manner the knowledge gained in diverse scientific areas and placing both in new contexts and understanding.
The broad impacts of our research are to expand the frontiers of the understanding of the role and utility of metal complexes in biology and medicine. This topic has been dominated in recent years by the use of platinum complexes in the clinical treatment of cancer but covers a broad field ranging from effects on viruses, bacteria, the historical use of gold complexes in arthritis, and even nitroprusside as a vasodilator. All these uses and effects have their origin in the coordination chemistry of these complexes and their interactions with biological molecules and biological approaches. I have placed this area of research into both a bioinorganic and medicinal chemistry context in the earlier book “Transition Metal Complexes as Drugs and Chemotherapeutic Agents” (Reidel-Kluwer 1990). Research is by definition highly interdisciplinary combining chemical, computational
In platinum antitumor chemistry our objective is to design and develop complexes acting by new discrete mechanisms of action. Platinum-based drugs are an important part of the anticancer drug armamentarium. Polynuclear platinum complexes studied in our laboratory are a discrete structural class distinct from the clinically used mononuclear cisplatin, carboplatin and oxaliplatin. Structurally unique complexes acting by different mechanisms may display an altered spectrum of antitumor activity and especially activity in cisplatin-resistant lines. To achieve this goal it is necessary to design new chemotypes and delineate their biological action through systematic examination of the principal factors controlling platinum drug cytotoxicity and antitumor activity – cellular accumulation, target (DNA) interactions and the extent of metabolizing interactions. Proof of principle of the utility (and success) of this approach is afforded by the advance of BBR3464, a trinuclear, bifunctional DNA binding agent with an overall 4+ charge, to Phase II clinical trials, the first and only non-cisplatin analog to be introduced to humans. With this advance the paradigm of cisplatin-based antitumor agents was altered.
The challenge for coordination chemists is to expand frontiers and to suggest new mechanisms of action and targets for biologically active inorganic compounds. Research provides the scientific groundwork with long-term possibilities for new medicinal applications. Current projects also include the study of the “coordination chemistry” of zinc finger proteins, contributing to understanding of the design of antiviral (specifically HIV) coordination compounds from first principles. The potential application of our research results will demonstrate the linkage between discovery and societal benefit by expanding in a rational and innovative manner the knowledge gained in diverse scientific areas and placing both in new contexts and understanding.
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