Combinatorial Biosynthesis of Novel Bioreductive Agents

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DESCRIPTION (provided by applicant): The structural and biosynthetic similaritybetween FR900482 and mitomycin (MC) group of antitumor antibiotics makes it promising to rationally create novel mitomycin/FR900482 hybrids through combinatorial biosynthesis. After successful identification of both MC and FR900482 biosynthetic gene clusters, Acera Biosciences now sets to create such potent bioreductive agents through manipulating these pathways. The long-term goal is to generate large libraries of novel hybrids to eventually find compounds with increased tumor specificity and reduced systemic toxicity. The specific aims in this project include 1). Production of novel C6 methyl FR900482 derivatives by MC carbonyl reduction enzyme Mmcl. 2). Creation of novel chimeric MC/FR900482 hybrids. 3). Development of a multiplasmid system for further biosynthetic pathway design. Dozens of novel MC/FR900482 hybrids are expected to be generated in this proposal. The compounds with MC quinone and FR900482 hemiketal functions will be of special interests for making more potent anticancer agents. PROPOSED COMMERCIAL APPLICATION: This project is to create dozens of novel anticancer antibiotics based on the sequencing data accumulated in Acera Biosciences. More potent mitomycin/FR900482 hybrids are expected to be generated to have stronger anticancer activity and yet unobtainable through chemical synthesis methods.