Exocyclic C-C Modifications of Aromatic Polyketides

描述（由申请人提供）：芳香聚酮与其他聚酮的不同之处在于其特有的多环芳烃结构。这些聚酮广泛分布于细菌、真菌和植物中，其中许多是临床上有价值的药物（如四环素、柔红霉素）或表现出其他迷人的生物活性。虽然芳香族聚酮的基本生物合成原理已经被广泛探索，但对于这些代谢物上许多现有独特的外环碳-碳（C-C）附着物的结构知之甚少。目前的提案旨在通过汇集两种天然存在的新型芳香聚酮体系的研究来扩大我们对这一现象的理解，这两种体系有望获得三种不同的外环芳香聚酮C-C修饰。第一种是来自灰色链霉菌的海霉素，它提供了唯一自然发生的二c -糖基化事件之一，以及多环体系中额外的I型pks导向的c -烷基链取代。第二种是来自chersina小单孢子菌的动力蛋白，它提供了唯一已知的在烯二酮和芳香聚酮之间自然发生的融合。预期的研究将为理解这些过程的独特机制奠定基础，并为利用这些工具进行组合生物合成以获得新的治疗方法奠定基础。这个庞大项目的第一阶段专门用于i)提供必要的遗传工具和信息，为这三个事件形成合理的机制假设；ii)启动明确设计的体内和体外实验，以解决海霉素/多霉素生物合成的c -糖基化和c -烷基化阶段；Hi)尝试结合所有三种芳香族C-C修饰系统的各个方面，以增强芳香族聚酮结构的多样化。最后提出的多样化策略的一个特别焦点将集中在这些高活性抗肿瘤抗生素与已知肿瘤导向肽的偶联上。

DESCRIPTION (provided by applicant): Aromatic polyketides differ from other polyketides by their characteristic polycyclic aromatic structures. These polyketides are widely distributed in bacteria, fungi and plants, and many of them are clinically valuable agents (e.g. tetracyclines, daunorubicin) or exhibit other fascinating biological activities. While the fundamental biosynthetic principles of aromatic polyketides has been extensively explored, little is known regarding the construction of many existing unique exocyclic carbon-carbon (C-C) attachments to these metabolites. The current proposal is designed to expand our understanding of this phenomenon by bringing together the study of two naturally occurring novel aromatic polyketide systems, which promise access to three distinct exocyclic aromatic polyketide C-C modifications. The first, hedamycin from Streptomyces griseoruber, offers one of the only naturally occurring di-C-glycosylation events as well as an additional type I PKS-directed C-alkyl chain substitution of the polycyclic ring system. The second, dynemicin from Micromonospora chersina, offers the only known naturally occurring fusion between an enediyne and aromatic polyketide. The intended studies are expected to lay a foundation to understand the unique mechanisms of these processes and also the potential to utilize these tools for combinatorial biosynthesis toward novel therapeutics. The first phase of this massive project is specifically intended to i) provide the necessary genetic tools and information to form reasonable mechanistic hypotheses for all three events, ii) to initiate in vivo and in vitro experiments explicitly designed to address the C-glycosylation and C-alkylation stages of hedamycin/pluramycin biosynthesis and Hi) attempt to combine aspects of all three aromatic C-C modification systems toward enhancing the diversification of aromatic polyketide structures. A particular focus of the final diversification strategies presented will be focused upon conjugation of these highly reactive antitumor antibiotics with known tumor-directing peptides.