Development and Exploitation of New Synthetic Strategies for Tropolones

托酚酮新合成策略的开发和利用

基本信息

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
项目类别：
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

项目摘要

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 Troponoids 是天然存在的芳香族 7 元环，尽管众所周知， ist，在药物化学研究中，以及更广泛的功能开发中，都没有得到充分利用。这在很大程度上与其合成相关的挑战以及限制有关。人们对如何在分子设计中利用它们的独特性质表示赞赏。当前提案的目标是开发与类肌钙蛋白相关的新工具和知识，重点是目标 1 将利用其广泛的疱疹病毒抗病毒活性。 α-羟基托酚酮对卡波西肉瘤相关疱疹病毒 (KSHV) 的“踢杀”策略。具体来说，我们将优化 α-羟基托酚酮作为 KSHV ORF29 C 末端结构域的抑制剂。作为这一目标的一部分，我们还将对新鉴定的 KSHV 裂解激活剂进行优化研究，该激活剂与 KSHV PAN ENE 结合，目标 2 将探索氧化吡咯鎓环加成/开环方法。 4-羟基托酚酮类药物将增进与 3-羟基-4-吡喃酮基氧化吡咯鎓有关的知识。环加成化学，还为吡喃稠合托酚酮提供了一条新的有效途径，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最后，目标 3 将探索托酚酮的布氏扩环/空气氧化方法，它将用于抗疟天然产物等分子的靶向合成这一目标的核心是重新审视一种极其有效的托酚酮生成方法。我们将通过利用高效的空气氧化来改进该程序。我们实验室最近发现了化过程，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的完成预计将凸显其生物医学潜力。肌钙蛋白作为药物片段，完善我们实验室之前开发的合成策略，建立新的托酚酮合成方法，以及与相关化学反应相关的先进知识，例如氧化吡咯鎓环加成和环丙烷化化学。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses.

合成α-羟基托酚酮抑制野生型和阿昔洛韦抗性单纯疱疹病毒的复制。

DOI：
发表时间：
2016-04
期刊：
影响因子：
4.9
作者：
Ireland, Peter J;Tavis, John E;D'Erasmo, Michael P;Hirsch, Danielle R;Murelli, Ryan P;Cadiz, Mark M;Patel, Bindi S;Gupta, Ankit K;Edwards, Tiffany C;Korom, Maria;Moran, Eileen A;Morrison, Lynda A
通讯作者：
Morrison, Lynda A

Sensitivity of the C-Terminal Nuclease Domain of Kaposi's Sarcoma-Associated Herpesvirus ORF29 to Two Classes of Active-Site Ligands.

卡波西肉瘤相关疱疹病毒 ORF29 C 末端核酸酶结构域对两类活性位点配体的敏感性。

DOI：
发表时间：
2018-10
期刊：
影响因子：
4.9
作者：
Miller, Jennifer T;Zhao, Haiyan;Masaoka, Takashi;Varnado, Brittany;Cornejo Castro, Elena M;Marshall, Vickie A;Kouhestani, Kaivon;Lynn, Anna Y;Aron, Keith E;Xia, Anqi;Beutler, John A;Hirsch, Danielle R;Tang, Liang;Whitby, Denise;Murelli, Ryan
通讯作者：
Murelli, Ryan

Amidation Strategy for Final-Step α-Hydroxytropolone Diversification.

最后一步α-Hydroxytropolone 多样化的酰胺化策略。