Strategies for the Synthesis of Bioactive Molecules

生物活性分子的合成策略

• 批准号: 7988231
• 负责人: NEIL K GARG
• 金额: $ 29.47万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988231
• 关键词: Antiviral Agents; Applications Grants; Bicycling; Biological Factors; Carbon; Chemicals; Clinical Trials; Communities; Complex; Coupling; Cyclization; Development; Exercise; Family member; Generations; Goals; Human; Immunosuppressive Agents; Indole Alkaloids; Indoles; Isothiocyanates; Marketing; Methodology; Methods; Outcome; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Process; Reaction; Reporting; Research; Route; Stem cells; Structure-Activity Relationship; System; Transition Elements; enolate; functional group; improved; inhibitor/antagonist; new technology; novel; nucleophilic addition; public health relevance; scaffold; small molecule; stereochemistry; tool

DESCRIPTION (provided by applicant): The indole heterocycle is ubiquitous amongst bioactive molecules and drug substances. More than 10,000 biologically active indole derivatives have been discovered to date, of which over two hundred are currently marketed as pharmaceuticals or undergoing clinical trials. Despite the development of an impressive array of strategies to synthesize functionalized indoles, methods to selectively substitute the indole benzenoid ring are limited. A new technology that allows for the simultaneous introduction of multiple functional groups on the indole benzenoid ring and the assembly of sterically congested bond systems would be of tremendous value, and would ultimately enable the synthesis of a host of biologically- relevant indole-containing complex molecules that are not accessible by conventional means. Thus, the long-term goal of the proposed research is to develop new tactics for the synthesis of highly functionalized small molecules that possess the privileged indole motif. Our approach, and the focus of this proposal, involves the synthesis and study of highly reactive aryne derivatives of indoles, or "indolynes". These species would function as electrophiles, which lies in contrast to the well-known nucleophilic character of the indole heterocycle. We anticipate that this rare indole 'umpolung' will provide unconventional strategies for the synthesis of functionalized indole-containing natural products, including a number of intriguing targets that possess multiple benzenoid substituents or sterically congested frameworks. If the goals of this proposal are achieved, new chemical methods for preparing biologically active molecules will be developed. Ultimately, this contribution will facilitate the discovery of new medicinal agents for treating human illnesses. PUBLIC HEALTH RELEVANCE: If the goals of this proposal are achieved, new chemical methods for preparing biologically active molecules will be developed. Ultimately, this contribution will facilitate the discovery of new medicinal agents for treating human illnesses.

性状（由申请方提供）：吲哚杂环在生物活性分子和原料药中普遍存在。迄今为止，已经发现了超过10，000种具有生物活性的吲哚衍生物，其中超过200种目前作为药物上市或正在进行临床试验。尽管发展了一系列令人印象深刻的策略来合成官能化吲哚，但选择性取代吲哚苯环的方法是有限的。允许在吲哚苯型环上同时引入多个官能团和组装空间拥挤的键系统的新技术将具有巨大的价值，并且将最终能够合成许多生物相关的含吲哚的复合物分子，这些分子通过常规手段是不可接近的。因此，所提出的研究的长期目标是开发用于合成具有特权吲哚基序的高度官能化的小分子的新策略。 我们的方法，这个建议的重点，涉及高反应性的芳基吲哚衍生物的合成和研究，或“indolynes”。这些物种将作为亲电体发挥作用，这与吲哚杂环的众所周知的亲核特性相反。我们预计，这种罕见的吲哚'umpolung'将提供非常规的策略，合成功能化的吲哚含天然产物，包括一些有趣的目标，拥有多个苯取代基或空间拥挤的框架。如果这一提议的目标得以实现，将开发出制备生物活性分子的新化学方法。最终，这一贡献将有助于发现治疗人类疾病的新药剂。 公共卫生相关性：如果这一提议的目标得以实现，将开发出制备生物活性分子的新化学方法。最终，这一贡献将有助于发现治疗人类疾病的新药剂。