This is Project #3 of the Program """"""""Combinatorial Approaches for Novel Anti-cancer Agents."""""""" a multidisciplinary effort to employ chemical diversity, high throughput and smart assays to anti-tumor drug discovery. The overall goal of this Project is to evaluate the biochemical actions of a targeted library of synthetic anti-tubulin agents in order to identify new drugs with activity against solid tumors. The library consists of ca. 1500 novel derivatives of the potent and structurally unique marine natural products (+)- discodermolide and curacin A prepared in Project #1 by novel targeted-array, parallel and combinatorial methods. Thus, this Project seeks lead compound optimization by chemical diversification of potent natural products acting through a proven chemotherapeutic mechanism of action. The working hypothesis is that, since the two lead compounds show certain enhanced properties over agents with similar mechanisms of action, their chemical diversification will provide structurally unique agents with improved chemotherapeutic properties.
The Specific Aims are to: (1) characterize the in vitro tubulin assembly and microtubule stabilizing activity of all novel library compounds, (2) determine the anti-proliferative and cytotoxic effects of the new agents, (3) assess the mitotic blocking and apoptosis inducing actions of highly active lead compounds and, (4) determine the in vivo anti-tumor activities of prioritized lead compounds. This Project should yield important new information on the structure-activity relationships of microtubule- stabilizing and tubulin polymerization inhibitory agents. Furthermore, there is promise that these studies may provide novel chemotherapeutic drugs.
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