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: 10192742
• 负责人: Ryan Murelli
• 金额: $ 37.09万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192742
• 关键词: Acids; Air; Alder plant; Anti-Inflammatory Agents; Antimalarials; Antiviral Agents; Architecture; Binding; Biology; C-terminal; Chemicals; Chemistry; Colchicine; Development; Eligibility Determination; Environment; FDA approved; Funding; Funding Mechanisms; Funding Opportunities; Future; Generations; Goals; Grant; Health; Herpesviridae; Human; Human Herpesvirus 8; Knowledge; Learning; Legal patent; Literature; Lytic; Malaria; 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; Structure; Synthesis Chemistry; Techniques; Testing; Textbooks; Therapeutic; Tropolone; anti-cancer; base; bioactive natural products; career; catalyst; chemical reaction; cycloaddition; design; improved; inhibitor/antagonist; innovation; interest; 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.

项目摘要和摘要 类胡萝卜素是天然存在的芳香族7元环，尽管对化学来说是众所周知的- 在药物化学研究方面，更广泛地说，在功能开发方面是严重不足的。 传统性小分子。这在很大程度上与它们的合成相关的挑战有关，而LIM- 他们的独特性质如何在分子设计中得到了利用，这一点得到了赞赏。更广泛的目标是- 目前建议的目标是开发与肌钙蛋白相关的新工具和知识，重点是- SIS关于它们在生物医学上的用途。目标1将开发广泛的疱疹病毒抗病毒活性 α-羟色胺对卡波西肉瘤相关疱疹病毒(KSHV)采取“踢杀”策略。 具体地说，我们将优化α-羟色胺作为KSHVORF29 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。目标2将探索一种氧化吡喃的环加成/开环方法 4-羟基托洛酮。这一目标将促进与3-羟基-4-吡喃氧化吡喃相关的知识 环加成化学，也提供了一条合成吡喃聚环酮的新的有效途径，这是一种 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 吡虫二酮。最后，目标3将探索一种Büchner环膨胀/空气氧化方法来处理透波罗酮， 它将用于抗疟疾天然产物等分子的靶向合成 杨梅酸。这一针对其核心的目标将重新审视一种非常有效的产生透音波的方法 这是半个多世纪前研究过的。我们将通过利用高效的空气氧化剂来改进程序- 并研究了底物和催化剂对区域选择性的控制。 芳烃环丙烷化反应。这些目标的完成有望突显生物医学的潜力 将肌钙蛋白作为药物片段，完善我们实验室先前开发的合成策略，建立新的 特罗隆的合成方法，以及与相关化学反应相关的高级知识， 这样的氧化吡喃环加成和环丙烷化化学。