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: 8655165
• 负责人: Seth B. Herzon
• 金额: $ 29.68万
• 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/8655165
• 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）：该提案描述了Kinamycins和Lomaiviticin A，具有前所未有的结构和强大生物学活性的细菌代谢物的合成和研究。这些分离株是人类癌症和微生物感染的纳摩尔抑制剂，这是NIH使命至关重要的公共卫生问题之一。洛氏素毒素A在单位皮摩尔浓度下针对卵巢细胞系具有活性，并且比任何kinamycins都高约2-5个数量级。总体而言，尽管存在其他结构差异，但洛米霉素可能被认为是kinamycins的一种二聚体形式，但最著名的是仅在lomaiviticin中发现的四种2，6-二氧氧基碳水化合物残基。所有这些代谢产物共有的是独特的二氮氟烯功能组，在天然产物中以前从未见过。在还原条件下，该功能组已被确定为反应性，但是对这种反应性在观察到的洛氏素毒素A的生物学活性中的作用有清晰的理解。 拟议的研究的目的是完成洛氏素素A的合成，并阐明该天然产物的作用机理。我们假设二氮氟烯官能团对于生物活性至关重要，并且外周取代基可用于调节其反应性。为了探究这一假设，我们将通过开发两个“单体”前体的二聚化方法来完成乳霉素A的合成。强大的二聚化方法将有助于制备简单的二聚体二氧氟烯烯，以进行化学生物学研究。 与这些合成研究并行，我们已经开始并将继续进行化学生物学研究，以阐明洛氏素化素A的作用机理。因此，我们将重点放在理解洛氏素养素和相关类似物与DNA的相互作用上。此外，我们将寻求理解取代基作用对二氮氟烯反应性的影响，目的是鉴定易于准备的，二氮氟烷的抗癌剂。为了实现这一目标，我们将进行结构功能研究，并探测合成构建体以及天然产物与DNA的相互作用。 我们希望我们的研究能够有效地访问整个天然产品和相关的二氧氟烯家族，从而克服了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，这些研究旨在发展对洛马氏素毒素作用机理的清晰度理解。这些是重要的贡献，它将为这些天然产品作为癌症和细菌感染的新疗法详细评估。