There are two parallel overall objectives of this proposal. One is to further delineate the molecular mechanisms that give rise to the antitumor efficacy of three groups of agents, of which two are in phase II clinical trials and the third shows promising in vivo activity. The second is to validate and then use differential gene expression technology to guide the course of research that will pinpoint the molecular mechanisms for the antitumor activity of the same three groups of compounds. The specific objectives of the proposed research are to: 1. design and synthesize a series of fluoroquinolones with a dual mechanism of action so that different members of the series are optimized for one or the other of the activities and others have both activities. 2. determine the structural and biochemical effects of Et 743, a DNA-reactive drug with phase II clinical activity. 3. determine the mechanism of action of HMAF, a phase II clinical trial candidate with an unknown mechanism of action. 4. design experiments to interpret patterns of differential gene expression from the agents in specific aim 1 and use this information to guide the course of experiments in Specific Aims 2 and 3. In order to achieve these objectives, a variety of techniques, including design and synthesis of small molecular weight molecules, high-field NMR and molecular modeling, gel electrophoresis, and DNA microchip array analysis, will be used.
