Combinatorial Biosynthesis of Novel Bioreductive Agents

描述（由申请人提供）：FR 900482与抗肿瘤抗生素丝裂霉素（MC）组之间的结构和生物合成相似性使其 有希望通过以下方式合理地产生新的丝裂霉素/FR 900482杂合体： 组合生物合成在成功识别MC和 FR900482生物合成基因簇，Acera Biosciences现在将创建这样的 有效的生物还原剂通过操纵这些途径。长期 我们的目标是产生大量的新型杂交体库， 具有增加的肿瘤特异性和降低的全身毒性的化合物。的 该项目的具体目标包括：1）。新型C6甲基 通过MC羰基还原酶Mmcl的FR 900482衍生物。2）。创建 新型嵌合MC/FR 900482杂合体。3）。多质粒系统的开发 用于进一步的生物合成途径设计。数十种新型MC/FR900482杂交种 预计将在本提案中产生。MC醌类化合物 和FR 900482半缩酮官能团对于制备更多的 有效的抗癌剂。 拟定商业应用：该项目旨在根据Acera Biosciences积累的测序数据创建数十种新型抗癌抗生素。 预计将产生更有效的丝裂霉素/FR 900482杂合体，其具有更强的抗癌活性，但通过化学合成方法无法获得。

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.