Combinatorial Biosynthesis of Novel Bioreductive Agents

新型生物还原剂的组合生物合成

• 批准号: 6486231
• 负责人: YINGQING MAO
• 金额: $ 14.84万
• 依托单位: ACERA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2003-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6486231
• 关键词: alkylation; antineoplastic antibiotics; biosynthesis; biotherapeutic agent; combinatorial chemistry; drug design /synthesis /production; gene expression; mitomycins; molecular cloning; quinones; reducing agents

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.

描述（由申请人提供）：FR900482与抗肿瘤抗生素丝裂霉素（MC）组的结构和生物合成相似性使其成为