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: 8305516
• 负责人: Seth B. Herzon
• 金额: $ 29.75万
• 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/8305516
• 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（由申请人提供）：本申请描述了动力学霉素和洛马维菌素A的合成和研究，这两种细菌代谢产物具有前所未有的结构和强大的生物活性。这些分离物是人类癌症和微生物感染的纳米摩尔抑制剂，这是公共卫生问题之一，是美国国立卫生研究院使命的核心。Lomaiviticin A在个位数皮摩尔浓度下对卵巢细胞系有活性，并且比任何一种动力霉素的效力大约高2-5个数量级。总的来说，罗摩维汀可能被认为是动力霉素的二聚体形式，尽管存在其他结构上的差异，最明显的是只有在罗摩维汀中发现的4个2,6 -二脱氧碳水化合物残基。所有这些代谢物共有的是一种独特的重氮芴官能团，这在以前的天然产物中从未见过。该官能团在还原条件下具有反应性，但对该反应性在洛马维汀a的生物活性中所起的作用尚未有明确的认识。本研究的目的是完成洛马维菌素A的合成，并阐明该天然产物的作用机制。我们假设重氮芴官能团对生物活性至关重要，并且外围取代基可以用来调节其反应性。为了验证这一假设，我们将通过开发两种“单体”前体二聚化的方法来完成洛马维菌素A的合成。一种稳健的二聚化方法将有利于简单二聚重氮芴的制备，用于化学生物学研究。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，以阐明洛马维汀A的作用机制。迄今为止的证据表明，洛马维汀A通过一种独特的相互作用模式靶向DNA。因此，我们将重点研究洛马维菌素及其类似物与DNA的相互作用。此外，我们将试图了解取代基效应对重氮芴反应性的影响，以确定容易制备的重氮芴基抗癌剂。为了实现这一目标，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。我们期望我们的研究将能够有效地获得这整个天然产物家族和相关的重氮芴，从而克服阻碍这些天然产物研究的合成障碍。这些合成研究与我们的化学生物学研究相辅相成，其目的是对洛马维菌素的作用机制有一个清晰的认识。这些重要的贡献将为详细评估这些天然产物作为癌症和细菌感染的新疗法提供基础。