Synthetic and Chemical Biological Studies of the Diazofluorene Antitumor Antibiot

重氮芴抗肿瘤抗生素的合成及化学生物学研究

• 批准号: 8459029
• 负责人: Seth B. Herzon
• 金额: $ 28.71万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459029
• 关键词: Antineoplastic Agents; Area; Bacteria; Bacterial Infections; Biological; Biological Factors; Cancer cell line; Carbohydrates; Cell Line; Chemicals; Complement; Coupled; Coupling; DNA; DNA Damage; Development; Digit structure; Dimerization; Disease; Evaluation; Evaluation Studies; Exhibits; Family; Foundations; Glycosides; Goals; Human; Infection; Investigation; Laboratories; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Mission; Modeling; Mono-S; Ovarian; Pathway interactions; Peripheral; Phase; Preparation; Process; Public Health; Quinones; Reaction; Reporting; Research; Role; Route; Solid; Structure; Structure-Activity Relationship; Study models; Therapeutic; United States National Institutes of Health; Work; analog; anticancer activity; base; cancer cell; cancer therapy; cytotoxicity; functional group; inhibitor/antagonist; insight; kinamycin F; lomaiviticin A; member; method development; microbial; novel; pharmacophore; small molecule; success; synthetic construct; tissue culture

DESCRIPTION (provided by applicant): This proposal describes the synthesis and study of the kinamycins and lomaiviticin A, bacterial metabolites with unprecedented structures and powerful biological activities. These isolates are nanomolar inhibitors of human cancers and microbial infections, which are among the public health issues that are central to the mission of the NIH. Lomaiviticin A is active against ovarian cell lines at single-digit picomolar concentrations, and is approximately 2-5 orders of magnitude more potent than any of the kinamycins. Overall, lomaiviticin may be regarded as a dimeric form of the kinamycins, although other structural dissimilarities exist, most notably four 2, 6-dideoxycarbohydrate residues that are found only in lomaiviticin. Common to all of these metabolites is a unique diazofluorene functional group, which has not been seen before in natural products. This functional group has been established as reactive under reducing conditions, but a clear understanding of the role of this reactivity in the observed biological activity of lomaiviticin A has not been developed. The objective of the proposed research is to complete the synthesis of lomaiviticin A and to elucidate the mechanism of action of this natural product. We hypothesize that the diazofluorene functional group is essential to biological activity, and that peripheral substituents can be used to modulate its reactivity. In order to probe this hypothesis, we will complete the synthesis of lomaiviticin A by developing a method for the dimerization of two "monomeric" precursors. A robust dimerization method will facilitate the preparation of simple dimeric diazofluorenes for chemical biological investigations. In parallel with these synthetic studies, we have initiated, and will continue, chemical biological investigations to elucidate the mechanism of action of lomaiviticin A. Evidence to date suggests lomaiviticin A targets DNA by a unique mode of interaction. Therefore we will focus our efforts on understanding the interaction of lomaiviticin and related analogs with DNA. Additionally, we will seek to understand the influence of substituent effects on the reactivity of the diazofluorene, with the goal of identifying easily-prepared, diazofluorene-based anticancer agents. To achieve this, we will conduct structure-function studies and probe the interaction of our synthetic constructs, and the natural product, with DNA. We expect that our research will enable efficient access to this entire family of natural products and related diazofluorenes, thereby overcoming the synthetic obstacles that have hindered the study of these natural products. These synthetic studies are complemented by our chemical biological investigations, which are aimed at developing a lucid understanding of the mechanism of action of lomaiviticin. These are important contributions that will provide the foundation for detailed evaluation of these natural products as new treatments for cancers and bacterial infections.

描述(申请人提供)：本提案描述了具有前所未有的结构和强大的生物活性的细菌代谢物激动素和洛麦维菌素A的合成和研究。这些分离物是人类癌症和微生物感染的纳米分子抑制剂，这是对NIH的使命至关重要的公共卫生问题之一。洛麦维菌素A在个位数的皮摩尔浓度下对卵巢细胞株具有活性，并且比任何一种激动素的效力大约高2-5个数量级。总体而言，lomaiviticin可以被认为是激动素的一种二聚体形式，尽管存在其他结构上的不同之处，最明显的是四个仅在lomaiviticin中发现的2，6-二脱氧碳水化合物残基。所有这些代谢物的共同之处是一种独特的重氮荧官能团，这是以前在天然产品中从未见过的。该官能团已被确定为还原条件下的反应性，但对这种反应性在观察到的洛麦维菌素A生物活性中的作用还没有形成明确的认识。本研究的目的是完成洛麦维菌素A的合成，并阐明该天然产物的作用机理。我们假设重氮荧官能团对生物活性是必不可少的，外围取代基可以用来调节它的反应活性。为了探索这一假说，我们将通过开发两个单体前体的二聚化方法来完成洛麦维菌素A的合成。一种可靠的二聚方法将有助于制备用于化学生物学研究的简单的二聚重氮荧烯。在这些合成研究的同时，我们已经开始并将继续进行化学生物学研究，以阐明洛麦维菌素A的作用机制。迄今为止的证据表明，洛麦维菌素A通过一种独特的相互作用模式靶向DNA。因此，我们将致力于了解洛麦维星及其相关类似物与DNA的相互作用。此外，我们还将试图了解取代基效应对重氮荧烯反应性的影响，目的是寻找易于制备的重氮荧基抗癌药物。为了实现这一点，我们将进行结构-功能研究，并探索我们的合成结构和天然产物与DNA的相互作用。我们预计，我们的研究将使我们能够有效地获得这一整个天然产品家族和相关的重氮荧烯，从而克服阻碍这些天然产品研究的合成障碍。这些合成研究得到了我们的化学生物学研究的补充，这些研究的目的是为了清楚地了解洛麦维星的作用机制。这些都是重要的贡献，将为详细评估这些天然产品作为癌症和细菌感染的新疗法提供基础。