Grant: Discovery Grants Program - Individual

The research described in this proposal is in the area of organic synthesis. This type of research fits broadly under the heading of "advancement of knowledge" (basic research). However, the project is not just a random attempt to synthesize anything new; the target molecules are specifically designed to have potential as pharmaceutical agents, more specifically with antitumour activity. Hence the proposal also fits into the broad area of "medicinal chemistry". The immediate aims of this project are to explore all aspects of the chemistry, and potential medicinal application, of new molecules in the triazene family (viz. R-N=N-NR2). Interest in triazenes stems in large part from the pharmaceutical use of two triazene drugs for the treatment of cancer in humans. DACARBAZINE has been used for many years in the treatment of human malignant melanoma and, more recently, TEMODAL has been used for treating brain tumours. Thus, there is a significant precedent for association of biological activity with the triazene family and there is every reason to be optimistic that new triazenes synthesized in this laboratory may have useful antitumour activity. A main thrust of the proposal is to explore the synthesis of novel bis-triazenes, i.e. compounds with two triazene units in the same molecule. The synthesis of the new triazenes requires investigation of the coupling reaction of a diazonium salt with innovative heterocyclic amines, such as piperazine, imidazolidine and the diazepanes. The compounds prepared in this way fit into the general description of 1,x-diazacycloalkane derivatives. Using this approach we will investigate the synthesis of triazene derivatives of various heterocycles, e.g. piperazines, imidazolidines, hexahydropyrimidines, 1,3-diazepanes and 1,4-diazepanes. An extension of this approach will be to couple a diazonium salt with a mixture of a diaminoalkane and formaldehyde to afford novel bicyclic bis-triazenes. Furthermore, a major effort will be implemented to seek out collaborations with researchers in the pharmaceutical area, who would undertake to test the full library of previously untested triazenes that exist in this laboratory for biological activity, and the implied pharmaceutical application that will follow.