Development and Exploitation of New Synthetic Strategies for Tropolones

托酚酮新合成策略的开发和利用

• 批准号: 10614944
• 负责人: Ryan Murelli
• 金额: $ 39.25万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614944
• 关键词: Acids; Air; Anti-Inflammatory Agents; Antimalarials; Antiviral Agents; Architecture; Binding; Biology; C-terminal; Chemicals; Chemistry; Colchicine; Development; Diels Alder reaction; Eligibility Determination; Environment; FDA approved; Funding; Funding Mechanisms; Funding Opportunities; Future; Generations; Goals; Grant; Health; Herpesviridae; Human; Human Herpesvirus 8; Knowledge; Learning; Legal patent; Licensing; Literature; Lytic; Medical; Medicine; Methods; Mission; Modernization; Molecular; Natural Products; Organic Chemistry; Pharmaceutical Chemistry; Pharmaceutical Preparations; Procedures; Process; Property; Public Health; Pyrans; Pyrones; Research; Resources; Route; Science; Scientist; Synthesis Chemistry; Techniques; Testing; Textbooks; Therapeutic; Tropolone; Viral Physiology; Visit; anti-cancer; antiviral drug development; bioactive natural products; career; catalyst; chemical association; chemical reaction; cycloaddition; design; improved; inhibitor; innovation; interest; member; metalloenzyme; novel; oxidation; programs; quinone methide; scaffold; small molecule; tool; undergraduate student; virtual

Project Summary and Abstract Troponoids are naturally occurring aromatic 7-membered rings that, despite being well-known to chem- ists, are highly underexploited in medicinal chemistry studies, and more broadly in the development of func- tional small-molecules. This can be largely tied to the challenges associated with their synthesis, and a lim- ited appreciation for how their unique properties could be leveraged in molecular design. The broader ob- jective of the current proposal is to develop new tools and knowledge related to troponoids, with an empha- sis on their utility biomedically. Aim 1 will exploit the broad herpesvirus antiviral activity of α-hydroxytropolones in a `kick-and-kill' strategy for Kaposi's sarcoma-associated herpesvirus (KSHV). Specifically, we will optimize α-hydroxytropolones as inhibitors of the C-terminal domain of KSHV ORF29. As part of this aim, we will also carry out optimization studies on a newly identified KSHV lytic activator that binds to KSHV PAN ENE. Aim 2 will explore an oxidopyrylium cycloaddition/ring-opening approach to 4-hydroxytropolones. This aim will advance knowledge related to 3-hydroxy-4-pyrone-based oxidopyrylium cycloaddition chemistry, and also provide a new and efficient route to pyran-fused tropolones, which is a structural feature that exists in various bioactive natural products, including the potent anti-cancer molecule pycnidione. Finally, aim 3 will explore a Büchner ring-expansion/ air oxidation approach to tropolones, which will be used in target-oriented synthesis towards molecules such as the antimalarial natural product puberulonic acid. This aim at its core will revisit an exceptionally efficient method to generate tropolones that was studied over half a century ago. We will improve the procedure by leveraging an efficient air oxida- tion process recently discovered in our lab, and study substrate and catalyst control on the regioselectivity of arene cyclopropanation. The completion of these aims are expected to highlight the biomedical potential of troponoid as a drug fragment, refine synthetic strategies previously developed in our lab, establish new methods for tropolone synthesis, and advance knowledge related to the associated chemical reactions, such oxidopyrylium cycloaddition and cyclopropanation chemistry.

项目概要和摘要 肌钙蛋白是天然存在的芳香族7元环，尽管其在化学上是众所周知的， 在药物化学研究中，以及更广泛地在功能性药物的开发中， 常规小分子。这在很大程度上与其合成相关的挑战有关，并且限制了 他们的独特性质如何在分子设计中发挥作用，这一点值得赞赏。更广泛的Ob- 当前提案的目标是开发与肌钙蛋白相关的新工具和知识，重点是 在生物医学上的应用目的1将开发广泛的疱疹病毒抗病毒活性的 α-羟基酚酮在卡波西肉瘤相关疱疹病毒（KSHV）的“踢杀”策略中。 具体而言，我们将优化α-羟基环庚三烯酚酮作为KSHV ORF 29的C-末端结构域的抑制剂。 作为这一目标的一部分，我们还将对一种新发现的KSHV裂解激活剂进行优化研究， 与KSHV PAN ENE结合。目的2将探索氧化吡喃鎓环加成/开环方法， 4-羟基托酚酮。这一目标将推进与3-羟基-4-吡喃酮基氧化吡喃鎓相关的知识 环加成反应，也提供了一个新的和有效的途径，吡喃稠环酚酮，这是一个 存在于各种生物活性天然产物中的结构特征，包括有效的抗癌分子 碧萝芷。最后，aim 3将探索环膨胀/空气氧化方法， 其将用于靶向合成诸如抗疟疾天然产物的分子 毛孢糖酸这一目标的核心将重新审视一个非常有效的方法来产生tropolones 半个世纪前的研究。我们将通过利用高效的空气氧化来改进程序- 研究了底物和催化剂对区域选择性的影响 芳烃环丙烷化。这些目标的完成将突出生物医学的潜力 作为药物片段，完善我们实验室以前开发的合成策略，建立新的 环庚三烯酚酮的合成方法，以及与相关化学反应相关的先进知识， 例如氧化吡喃鎓环加成和环丙烷化化学。