BIOSYNTHETIC KEY STEPS OF ANGUCYCLINE ANTITUMOR DRUGS

安古环素抗肿瘤药物的生物合成关键步骤

• 批准号: 6928092
• 负责人: Jurgen T Rohr
• 金额: $ 26.03万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928092
• 关键词: aminoglycoside antibiotics; antifungal antibiotics; antineoplastic antibiotics; drug design /synthesis /production; enzyme induction /repression; enzyme structure; gene expression; isoquinolines; microorganism metabolism; pharmacokinetics; polyketide synthase

DESCRIPTION (provided by applicant): Gilvocarcins and jadomycins are angucyclin-derived anticancer drugs/antibiotics possessing unique molecular frames, whose common biosynthetic key step is an oxidative rearrangement catalyzed by a closely related set of enzymes. The gilvocarcins, produced by various Streptomyces strains including Streptomyces griseoflavus Go 3592, represent a distinct family of interesting aryl C-glycoside antitumor drugs with a coumarin-based aromatic core that promote specific DNA interactions when photoactivated by near UV light. This class of anticancer drugs shows excellent antitumor activity and remarkably low toxicity. Its unprecedented molecular architecture in conjunction with its unique biological activity makes the gilvocarcins an excellent target for biosynthetic studies and the development of novel, photoactivatable anticancer drugs through combinatorial biosynthesis. The drugs may be useful for the treatment of special cancers, such as brain tumors, colon, skin, lung, and prostate cancers or leukemia. The jadomycins are antibiotics/antifungals, whose structure is characterized by an unusual insertion of an amino acid building block after an oxidative bond breakage. Previous biosynthetic studies suggest for both, gilvocarcins and jadomycins, a pathway dominated by a type-2 polyketide synthase (PKS), leading initially to an angucycline type drug intermediate, which then oxidatively rearranges into the final molecular frame. Selected intriguing post-PKS tailoring steps, namely the oxidative rearrangement (gilvocarcin and jadomycin biosynthesis), the unusual C-glycosylation step (gilvocarcin biosynthesis), and the formation of the vinyl group side chain of gilvocarcin V, are key biosynthetic features responsible for the generation of structural elements, which are essential for the unique biological activity of the gilvocarcin drugs. The investigation of these cascades of post-PKS tailoring biosynthetic key reactions, found in both the jadomycin and gilvocarcin biosyntheses, is a main goal of the research, since it as an interesting model for post-PKS enzyme complexes, their mechanisms, interactions, substrate binding/passing modes etc. This topic has never been studied in detail despite the importance of such tailoring steps for the biological activity of polyketide drugs. The understanding of these biosynthetic steps, and the enzymes responsible for their execution will ultimately pave the way for the generation of more potential and more selective drugs through combinatorial biosynthetic methods. The following specific aims will be addressed: (1) Characterization of the late steps of the gilvocarcin and jadomycin biosynthesis; (2) Generation of new gilvocarcin analogues by inactivation and recombination of selected post-PKS tailoring genes; (3) Characterization of key enzymes of the gilvocarcin and the related jadomycin biosynthetic pathway to understand their mechanism-of-action and substrate specificity range, their interaction; and (4) assessment of the antitumor activity of gilvocarcin and newly generated analogues from specific aim 2. The long-term goal of this research is to develop improved anticancer drugs for the treatment of special cancers.

描述(申请人提供)：Gilvocarcins和jadmycins是由具有独特分子框架的绞股蓝环素衍生的抗癌药物/抗生素，其共同的生物合成关键步骤是由一组密切相关的酶催化的氧化重排。 Gilvocarcins由包括灰黄链霉菌GO 3592在内的各种链霉菌产生，代表了一个独特的家族，具有基于香豆素的芳香族核心，当被近紫外光光激活时，促进特定的DNA相互作用。这类抗癌药物表现出极好的抗肿瘤活性和极低的毒性。其前所未有的分子结构和独特的生物活性使其成为生物合成研究和通过组合生物合成开发新型光激活抗癌药物的极佳靶点。这些药物可能对特殊癌症的治疗有用，如脑瘤、结肠癌、皮肤癌、肺癌、前列腺癌或白血病。Jadmycins是抗生素/抗真菌药物，其结构的特征是在氧化键断裂后不寻常地插入氨基酸构建块。 先前的生物合成研究表明，对于吉尔沃卡星和杰多霉素，这是一条由2型聚酮合成酶(PKS)主导的途径，最初导致一种绞股蓝素类药物中间体，然后该中间体被氧化重排到最终的分子框架中。选择有趣的PKS后剪裁步骤，即氧化重排(gilvocarcin和jadmycin生物合成)、不寻常的C-糖基化步骤(gilvocarcin生物合成)和gilvocarcin V的乙烯基侧链的形成，是负责产生结构元素的关键生物合成特征，这些结构元素对gilvocarcin药物的独特生物活性至关重要。对这些PKS后生物合成关键反应级联的研究是本研究的主要目标，因为它作为PKS后酶复合体的有趣模型，其机制、相互作用、底物结合/传递模式等。尽管这些定制步骤对于聚酮类药物的生物活性很重要，但这一课题从未被详细研究过。了解这些生物合成步骤，以及负责执行这些步骤的酶，最终将为通过组合生物合成方法产生更具潜力和更具选择性的药物铺平道路。具体目标如下：(1)吉罗卡星和杰多霉素生物合成后期步骤的特征；(2)通过选择PKS后剪裁基因的失活和重组来产生新的吉罗卡星类似物；(3)吉罗卡星的关键酶和相关的杰多霉素生物合成途径的特征，以了解它们的作用机制和底物专一性范围，以及它们之间的相互作用；以及(4)评估吉罗卡星和从特定目的产生的新的类似物的抗肿瘤活性2。这项研究的长期目标是开发用于特殊癌症治疗的改进的抗癌药物。