The proposal covers three related, general goals during the grant period. One goal will be to evaluate the in vitro cytotoxicity of alpha, beta- unsaturated Fischer carbenes against breast, prostate, lung, and colon cancers and melanoma. A series of pentacarbonyl chromium and monophosphinated chromium Fischer carbenes will be synthesized for this purpose and tested against the above cancer cell lines. Phosphination allows for systematic variation of the electronic nature of the carbene moiety and is expected to affect the compound's cytotoxicity. A second goal will be to develop a model for relating this biological activity to the rate of nucleophilic attack on these alpha, beta-unsaturated Fischer carbenes. To this end, the rate of reaction of model thiol nucleophiles, such as cysteine, with the alpha, beta-unsaturated Fischer carbenes will be measured. A third goal will be to develop fundamental synthetic methodologies to increase the utility of phosphinated Fischer carbenes in the synthesis of biologically important molecules. The synthetic studies will include new routes to the alpha, beta-unsaturated Fischer carbenes required for the kinetic and biological studies. In addition, synthetic methodologies associated with a new class of compounds, diphosphinated Fischer carbenes, will be evaluated for their synthetic potential in elaborating carbene functionality. This will include achiral and asymmetric versions of the reactions of the diphosphinated Fischer carbene anions with alkylating agents, aldehydes, epoxides and oxetanes.
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