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Identification and Characterization of Novel Antimitotic Compounds for the Treatment of Breast Cancer

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Annual rept. 15 Jul 1999-15 Jul 2000

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Our goal is to find new antimitotic drugs for the treatment of breast cancer using a novel cell-based assay to screen natural product libraries and guide the purification of their active components. We have completed a screen of over 30,000 extracts of terrestrial plants, algae and marine organisms and obtained 223 positive extracts. To maximize our chance of finding novel and useful compounds, we have carried out a variety of different tests on the positive extracts and prioritized for futher study those that are particularly potent, those that are particularly effective against multidrug-resistant breast cancer cells, those that cause microtubule bundling, those that come from unusual or little-studied organisms, and those that appear to act by unusual mechanisms. We have purified and studied the active compounds from S of these positive extracts and a further 17 are undergoing purification. Our screen also revealed a new source of eleutherobin. This promising compound was discovered in 1997 but lack of material impeded its development. Our source is abundant and may provide sufficient material for preclinical and early phase clinical trials. We also discovered novel eleutherobin analogs, carried out a structure-activity study, and determined the solution and crystal structures of eleutherobin, all of which will be important for drug development. We are confident that year 2 will proceed as scheduled and that of our 223 positive extracts some will yield structurally novel compounds that will be useful lead compounds for therapy.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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