The objective of this Phase II proposal is the development of an efficient means of producing 14-normethyl discodermolide, a totally synthetic analog of the sponge metabolite (+)-discodermolide 3ossessing exciting anticancer activity. The natural product is available only in minute quantities from its endogenous source, and costly total synthesis is, at present, the only effective means of obtaining this compound or a biologically and commercially attractive analog such as 14-normethyl discodermolide. We have developed (Phase I) a synthesis of key precursors used in an established synthesis of (+)-discodermolide using genetically engineered polyketide synthase (PKS) genes operating on functionalized substrates to furnish functionally and stereochemically rich materials that were converted to the desired intermediates. Phase II builds on the successful discoveries of Phase I but avoids the need for the use of precursor directed biosynthesis. Phase II will provide large polyketide fragments that may be disassembled and then reassembled via very short sequences to gain access to 14-normethyl discodermolide.
The specific aims of Phase II are: 1. We will produce in Myxococcus xanthus a truncated and modified analog of soraphen A that will be used for the synthesis of an advanced precursor of 14-normethyl discodermolide. 2. We will produce in Streptomyces coelicolor (2R,3S,4R,5S)-2,4-dimethyl-3,5-dihydroxyhexoate lactone at high titers. 3. We will use the products of Aims 1 and 2 to produce 14-normethyl discodermolide. Successful development of this methodology will reduce the extent, difficulty, and cost of the synthetic chemistry required, making large-scale commercial production of 14-normethyl discodermolide feasible and affordable.
