The long term objective of this proposal is to generate novel anticancer agents which are commercially feasible to prepare by fermentation processes. Epothilone D, a 16-membered polyketide-derived macrolactone, has promising antitumor activity but is produced in low titers by the native organism, Sorangium cellulosum, and is only sparingly soluble in water. Chemical synthesis of epothilones has been achieved but the methods are elaborate and not feasible for scale-up for pharmaceutical applications. The Phase I Specific Aim of this proposal is to generate a number of epothilone analogs by genetic engineering which are more water soluble than and at least as potent as the parent. These analogs will be tested in cell culture (taxol susceptible and resistant lines) and in vitro assays and water solubility measured (octanol-water partition coefficients). Phase II would involve the generation of additional analogs by diketide feeding. The two best compounds in terms of a) potency, b) water solubility and c) economics of production would be carried forward into further testing. Sufficient amounts of each would be produced to use in animal tumor models and in preliminary animal toxicity and pharmacokinetic studies.
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