Exocyclic C-C Modifications of Aromatic Polyketides

描述（由申请人提供）：芳香族聚酮化合物与其他聚酮化合物的不同之处在于其特征性的多环芳香族结构。这些聚酮化合物广泛分布于细菌、真菌和植物中，其中许多是有临床价值的药物（如四环素类、柔红霉素）或表现出其他迷人的生物活性。虽然芳香族聚酮化合物的基本生物合成原理已被广泛探索，但关于这些代谢物的许多现有独特的环外碳-碳（C-C）连接的构建知之甚少。目前的建议旨在扩大我们对这一现象的理解，通过将两种天然存在的新型芳香族聚酮系统的研究结合在一起，这两种系统有望获得三种不同的环外芳香族聚酮C-C修饰。第一种是来自灰红链霉菌的hedamycin，它提供了仅有的天然存在的二-C-糖基化事件之一以及多环系统的另外的I型PKS-指导的C-烷基链取代。第二，动力霉素从小单孢菌chersina，提供了唯一已知的自然发生的融合之间的烯二炔和芳香族聚酮。预期的研究将为理解这些过程的独特机制以及利用这些工具进行组合生物合成以获得新疗法的潜力奠定基础。这个大规模项目的第一阶段特别旨在i）提供必要的遗传工具和信息，以形成所有三个事件的合理机制假设，ii）启动明确设计用于解决海达霉素/普朗霉素生物合成的C-糖基化和C-烷基化阶段的体内和体外实验，C改性系统，以提高芳香族聚酮化合物结构的多样化。提出的最终多样化策略的一个特别重点将集中在这些高反应性抗肿瘤抗生素与已知的肿瘤导向肽的缀合上。

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.