Discovery and mechanistic study of fluorine biochemistry

氟生物化学的发现及其机理研究

• 批准号: 8146802
• 负责人: MICHELLE C CHANG
• 金额: $ 230.25万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146802
• 关键词: Bacterial Infections; Biochemistry; Biological; Biological Factors; Carbon; Chemicals; Cholesterol; Drug Design; Drug Kinetics; Elements; Fluorine; Goals; Hand; Health; Human; Hypersensitivity; Indium; Lead; Malignant Neoplasms; Mental Depression; Methods; Mycoses; Nature; Organism; Pharmaceutical Preparations; Pharmacologic Substance; Production; Specificity; Streptomyces; Work; abstracting; chemical property; design; drug discovery; effective therapy; interest; novel; public health relevance; small molecule; synthetic biology

DESCRIPTION (Provided by the applicant) Abstract: Fluorinated pharmaceuticals represent a rapidly expanding class of small molecule drugs that have become important in the treatment of diverse human health conditions ranging from cancer to high cholesterol. Owing to its unique chemical properties, functionalization of molecules with fluorine has allowed chemists to rationally tune the bioactivity and pharmacokinetics of small molecules and turn a lead compound into an effective treatment. However, these same chemical properties limit our ability to specifically incorporate fluorine into molecules and consequently our ability to fully exploit the potential that fluorine provides as a design element in the pipeline of drug design and discovery. Although much interest has focused on new synthetic methods to make carbon-fluorine bonds, fluorination remains a challenging chemical problem with regard to specificity and selectivity. Our group is exploring the ability of living systems to incorporate fluorine into small molecules with specificity, with the long-term goal of developing alternative synthetic biology approaches for the design and production of novel fluorinated natural products. Towards this goal, we have focused on studying Streptomyces cattleya, the only known native organofluorine-producing organism, to develop a basic picture of how living systems have evolved to manage this unique element. With a more fundamental understanding of fluorine biochemistry in hand, we can begin to expand the narrow scope of fluorine biochemistry in nature and work towards developing new methods for drug design and discovery. Public Health Relevance: Fluorinated small molecules have been tapped relatively recently as a class of compounds with great utility in treating diverse conditions in human health, such as cancer, bacterial and fungal infections, depression, allergies, and high cholesterol. Indeed over half of the top five drugs sold in the last year contain fluorine. The long-term goal of our proposed work is to expand methods used to incorporate fluorine into new small-molecule compounds using biological approaches that are complementary to more traditional chemical methods.

描述（由申请人提供） 摘要：氟化药物代表了一类迅速扩大的小分子药物，在治疗从癌症到高胆固醇的各种人类健康状况方面变得重要。由于其独特的化学性质，用氟对分子进行官能化使化学家能够合理地调节小分子的生物活性和药代动力学，并将先导化合物转化为有效的治疗方法。然而，这些相同的化学性质限制了我们将氟特异性掺入分子中的能力，因此限制了我们充分利用氟作为药物设计和发现管道中的设计元素的潜力的能力。虽然许多兴趣都集中在新的合成方法，使碳氟键，碳氟键仍然是一个具有挑战性的化学问题方面的特异性和选择性。我们的研究小组正在探索生命系统将氟特异性结合到小分子中的能力，长期目标是开发替代合成生物学方法，用于设计和生产新型氟化天然产品。为了实现这一目标，我们专注于研究链霉菌cattleya，唯一已知的天然有机氟生产有机体，开发一个基本的图片如何生活系统已经进化到管理这个独特的元素。有了对氟生物化学更基本的了解，我们可以开始扩大自然界中氟生物化学的狭窄范围，并致力于开发药物设计和发现的新方法。 公共卫生相关性：最近，氟化小分子已被开发为一类在治疗人类健康中的各种病症（诸如癌症、细菌和真菌感染、抑郁症、过敏症和高胆固醇）中具有巨大效用的化合物。事实上，去年销售的前五名药物中有一半以上含有氟。我们提出的工作的长期目标是扩大用于将氟纳入新的小分子化合物的方法，使用与更传统的化学方法互补的生物方法。