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Hayward, CA, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 750.00K | Year: 2004

DESCRIPTION (provided by applicant): The long-range goal of our research program is to discover novel, more potent water soluble geldanamycin analogs and to develop one of them into a useful antitumor drug. 17-Allylamino-17-desmethoxygeldanamycin (17-


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 750.00K | Year: 2004

DESCRIPTION (provided by applicant): 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 ant


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2004

DESCRIPTION (provided by applicant): The long-range goal of our research program is to discover novel disorazole analogs and to develop one of them into a useful antitumor drug. Although disorazole A is a potent cytotoxic agent, with IC50's below the


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 0.00 | Year: 2004

DESCRIPTION (provided by applicant): 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.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2005

DESCRIPTION (provided by applicant): The incidence of aspergillosis, and other invasive mould infections (IMIs), is increasing in hospitals worldwide at an alarming rate. These infections occur primarily in neutropenic patients undergoing cancer chemotherapy and in transplant centers where patients are undergoing immunosuppressive therapy. The treatments employed for these infections consist of the currently available antifungal drugs, often in combination, with failures approaching 50% and high associated mortality. Where successful, treatments are usually long term and usually prolong the hospitalization of the patient. Aspergillus fumigatus, and other Aspergillus species account for about 70% of IMIs, the remainder caused by Scedosporium, Cryptococcus, Fusarium, Rhizopus and other moulds. Current development of antifungal drugs has always targeted Candida infections and has not focused on Aspergillus and other invasive moulds. The ambruticins, polyketides with unusual structures discovered in the 1970s and 1990s from different strains of the myxobacterium Sorangium cellulosum, have high potencies against a number of Aspergillus strains, good oral bioavailability and excellent safety profiles in laboratory animals. In this Phase I proposal, we will make a number of semisynthetic analogs of ambruticin S and ambruticin VS4 and determine their in vitro potencies against a number of Aspergillus species, Cryptococcus, Rhizopus, Scedosporium and Fusarium species. Other in vitro experiments will include the determination of synergy or antagonism of ambruticin with other antifungal agents, and determination of the post-antibiotic effect of these compounds. We will also determine the pharmacokinetic parameters and LD50 of selected compounds. Results obtained during the one year granting period will allow us to make intelligent and systematic choices of molecules for animal efficacy and IND-enabling studies in subsequent Phase II research.

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