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: 7228414
• 负责人: Jurgen T Rohr
• 金额: $ 24.69万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228414
• 关键词: Address; Amino Acids; Anabolism; Antifungal Antibiotics; Antineoplastic Agents; Architecture; Binding; Biological; Brain; Brain Neoplasms; C-glycoside; Class; Colon; Coumarins; DNA; DNA Sequence Rearrangement; Development; Elements; Enzymatic Biochemistry; Enzymes; Family; Figs - dietary; Foundations; Gene Cluster; Generations; Genes; Genetic Recombination; Genus Cola; Goals; Histones; Investigation; Knowledge; Lead; Light; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Modeling; Modification; Molecular; Multienzyme Complexes; Object Attachment; Oxygenases; Pathway interactions; Pharmaceutical Preparations; Production; Property; Prostate; Range; Reaction; Research; Route; Side; Skin; Streptomyces; Streptomyces lividans; Structure; Substrate Interaction; Substrate Specificity; Toxic effect; alpha benzopyrone; analog; anticancer activity; antineoplastic antibiotics; antitumor drug; base; combinatorial; drug biological activity; gilvocarcin V; glycosylation; glycosyltransferase; improved; interest; jadomycin B; leukemia; mutant; novel; 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.

性状（由申请方提供）：Gilvocarcins和jadomycins是具有独特分子框架的angucyclin衍生抗癌药物/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，由各种链霉菌菌株，包括Streptomyces grisebulus Go 3592产生，代表了一个独特的家庭有趣的芳基C-糖苷抗肿瘤药物与香豆素为基础的芳香族核心，促进特定的DNA相互作用时，光激活的近紫外光。这类抗癌药物显示出优异的抗肿瘤活性和显著低的毒性。其前所未有的分子结构及其独特的生物活性使gilvocarcins成为生物合成研究和通过组合生物合成开发新型光活化抗癌药物的绝佳靶标。这些药物可用于治疗特殊癌症，如脑肿瘤、结肠癌、皮肤癌、肺癌和前列腺癌或白血病。Jadomycins是抗生素/抗真菌剂，其结构特征在于在氧化键断裂后不寻常地插入氨基酸构建单元。 先前的生物合成研究表明，对于gilvocarcins和jadomycins，由2型聚酮合酶（PKS）主导的途径，最初导致angucycline型药物中间体，然后氧化重排成最终的分子框架。选择的有趣的后PKS剪裁步骤，即氧化重排（gilvocarcin和jadomycin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，是负责生成结构元件的关键生物合成特征，这是gilvocarcin药物的独特生物活性所必需的。这些级联的后PKS剪裁生物合成的关键反应，发现在jadomycin和gilvocarcin生物合成的调查，是一个主要的研究目标，因为它作为一个有趣的模型后PKS酶复合物，其机制，相互作用，底物结合/通过模式等这个主题从来没有被详细研究，尽管这些剪裁步骤的聚酮药物的生物活性的重要性。对这些生物合成步骤的理解，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。本论文的主要目的是：（1）研究gilvocarcin和jadomycin生物合成的后期步骤;（2）通过选择性PKS后修饰基因的失活和重组来产生新的gilvocarcin类似物;（3）研究gilvocarcin和相关jadomycin生物合成途径的关键酶，以了解它们的作用机制和底物特异性范围，以及它们之间的相互作用;和（4）评价gilvocarcin和新产生的来自特定目标2的类似物的抗肿瘤活性。这项研究的长期目标是开发用于治疗特殊癌症的改良抗癌药物。