Discovery and mechanistic study of fluorine biochemistry

描述(由申请人提供) 摘要：氟化药物代表着一类迅速扩大的小分子药物，这些药物在治疗从癌症到高胆固醇等各种人类健康疾病方面变得越来越重要。由于其独特的化学性质，分子与氟的官能化使化学家能够合理地调整小分子的生物活性和药代动力学，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具体结合到分子中的能力，从而限制了我们充分开发氟作为药物设计和发现管道中的设计元素的潜力的能力。尽管人们对合成碳氟键的新方法很感兴趣，但氟化反应在专一性和选择性方面仍然是一个具有挑战性的化学问题。我们团队正在探索生命系统将氟结合到具有特异性的小分子中的能力，长期目标是开发替代合成生物学方法来设计和生产新型含氟天然产品。为了实现这一目标，我们专注于研究卡特莱链霉菌，这是唯一已知的天然有机氟产生生物体，以了解生命系统是如何进化来管理这种独特的元素的。随着对氟生物化学有了更基本的了解，我们可以开始扩大自然界中氟生物化学的狭窄范围，并致力于开发新的药物设计和发现方法。 与公共卫生相关：氟化小分子最近被开发为一类化合物，在治疗人类健康中的各种疾病方面具有很大的实用价值，如癌症、细菌和真菌感染、抑郁症、过敏和高胆固醇。事实上，去年销售的排名前五位的药物中，有一半以上含有氟。我们提议的工作的长期目标是扩大用于将氟结合到新的小分子化合物中的方法，使用生物方法来补充更传统的化学方法。

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.