Exocyclic C-C Modifications of Aromatic Polyketides

说明书(由申请人提供)：芳香族聚酮因其特征的多环芳香族结构而不同于其他聚酮。这些多酮类化合物广泛存在于细菌、真菌和植物中，其中许多是具有临床价值的药物(如四环素、柔红霉素)或表现出其他有趣的生物活性。虽然芳香族聚酮的基本生物合成原理已经得到了广泛的探索，但对于这些代谢物上存在的许多独特的外环碳-碳(C-C)键的结构却知之甚少。目前的提议旨在通过将两个天然存在的新型芳香族聚酮系统的研究结合在一起来扩大我们对这一现象的理解，这两个系统有望获得三种不同的外环芳香族聚酮C-C修饰。第一种是来自灰色链霉菌的海达霉素，它提供了仅有的自然发生的二碳糖基化事件之一，以及额外的I型PKS指导的多环环系统的C-烷基链取代。第二种是来自樱桃小单孢菌的Dynemicin，它提供了已知的唯一一种在烯二炔和芳香族聚酮之间自然发生的融合。这些预期的研究有望为了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走向新的疗法奠定基础。这一庞大计划的第一阶段旨在：i)提供必要的遗传工具和信息，为所有这三个事件形成合理的机制假说；ii)启动体内和体外实验，明确设计用于研究海达霉素/多柔比星生物合成的C-糖基化和C-烷基化阶段；以及hi)尝试结合所有三种芳香族C-C修饰系统的各个方面，以促进芳香族聚酮结构的多样化。最后提出的多样化战略的一个特别重点将集中在这些高活性抗肿瘤抗生素与已知的肿瘤导向肽的结合上。

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.