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: 7056070
• 负责人: Jurgen T Rohr
• 金额: $ 25.42万
• 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/7056070
• 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（由申请人提供）：吉尔沃卡菌素和JADOMYCINS是具有独特的分子框架的雌激素衍生的抗癌药/抗生素，其常见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。 由各种链霉菌菌株（包括链霉菌菌）生产的吉尔伏霉素（Gilvocarcins）代表了一个具有基于香豆素的芳族核心的有趣的有趣的芳基C-糖苷抗肿瘤药物的独特家族，该药物是基于Coumarin的芳族核心，该核心在通过近UV Light光化时促进特定的DNA相互作用。这类抗癌药物表现出极好的抗肿瘤活性，并且毒性非常低。它的前所未有的分子结构与其独特的生物学活性结合使用，使吉尔沃卡蛋白成为生物合成研究的绝佳靶标，并通过联合生物合成的新颖，光活化抗癌药物的发展。这些药物可能可用于治疗特殊癌症，例如脑肿瘤，结肠，皮肤，肺和前列腺癌或白血病。 JADOMYCINS是抗生素/抗真菌剂，其结构的特征是在氧化键断裂后不寻常插入氨基酸构建块。 先前的生物合成研究表明，Gilvocarcins和Jadomycins是由2型聚酮化合物合酶（PKS）支配的途径，最初导致Angucycline型药物中间体，然后将其氧化重排入最终分子框架。 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 Gilvocarcin药物的独特生物学活性。在Jadyomycin和Gilvocarcin Biosynthes中发现了这些调整生物合成关键反应的这些后PK的级联反应的研究是研究的主要目标，因为它是对Post-PKS酶复合物的有趣模型，因为它的机制，相互作用/通过了细化的范围，因此，该范围的范围均可进行，但这些范围的范围是限制/通过的细节。聚酮药物。对这些生物合成步骤以及负责其执行的酶的理解最终将为通过组合生物合成方法产生更多潜力和更多选择性药物铺平道路。将解决以下具体目的：（1）表征吉尔沃卡素和贾多霉素生物合成的后期步骤； （2）通过灭活和重组选择后PKS剪裁基因的新吉尔沃卡素类似物的产生； （3）表征吉尔沃查霉素的关键酶和相关的JADOMYCIN生物合成途径，以了解其行动机理和底物特异性范围，以及它们的相互作用； （4）评估吉尔沃卡素的抗肿瘤活性和从特定目标2中产生的类似物。这项研究的长期目标是开发改进的抗癌药物来治疗特殊癌症。