Biological Studies of alpha-Hydroxytropolones

α-羟基托酚酮的生物学研究

基本信息

批准号：
8854644
负责人：
Ryan Murelli
金额：
$ 38.11万
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 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8854644
关键词：
Adverse effects Animal Model Antimalarials Antiviral Agents Bacterial Infections Binding Biological Biological Assay Biological Factors Bipolar Disorder Chemicals Chemistry Clinical Collaborations Data Development Disease Evaluation Funding Goals Grant HIV Heart Diseases Hepatitis B Hepatitis B Virus Herpesvirus 1 International Knowledge Lead Malaria Medical Medicine Methodology Methods Mutagenesis Oxygen Positioning Attribute Proteomics Public Health Publications RNA-Directed DNA Polymerase Research Resources Ribonuclease H Route Saints Science Series Simplexvirus Structure Testing Therapeutic Therapeutic Agents Universities anticancer activity base career college computational chemistry cycloaddition cytotoxic cytotoxicity design drug development forging human disease inhibitor/antagonist insight medical schools meetings melanoma metalloenzyme novel pharmacophore programs public health relevance research study symposium therapeutic development

项目摘要

DESCRIPTION (provided by applicant): -Hydroxytropolones are promising pharmacophores for therapeutic development. However, structure-function studies on the molecules have been hampered due to a scarcity of synthetic methods available to access them. The following research will leverage a newly established oxidopyrylium cycloaddition/ring-opening strategy in a series of biological studies on a-hydroxytropolones, and expand the methodology to include a promising subclass of the molecules. Specifically, a computational chemistry-assisted structure-function study will be carried out toward a potent and selective a-hydroxytropolone-based HIV RT RNase H inhibitor. These compounds will also be tested for their antiviral activity for Hepatitis B and Herpes Simplex Virus 1 and 2. New chemical probes will also be synthesized for use in proteomic studies for studying a-hydroxytropolone cytotoxicity. Finally, the chemistry will be expanded to include 3, 7-dihydroxytropolones, which have shown promising cellular antiviral activity for HIV, and have demonstrated activity in animal model studies for malaria and melanoma comparable to current therapeutic agents. The molecules will be tested for their antiviral activity in preliminary structure-function studies against HIV, Hepatitis B and Herpes Simplex Virus. The research proposed is thus a critical step in what is anticipated to be a long-term research program aimed at thoroughly evaluating the therapeutic potential of -hydroxytropolones, with a major goal being the establishment of a new platform for drug development.

描述（由申请人提供）：α-羟基托酚酮是用于治疗开发的有前途的药效团，但是，由于缺乏可用的合成方法，该分子的结构功能研究受到阻碍。以下研究将利用新建立的氧化吡咯鎓。环加成/开环策略在一系列关于α-羟基托酚酮的生物学研究中，并将该方法扩展到包括一个有前途的分子子类，具体来说，是一种计算方法。化学辅助结构功能研究将针对一种有效的、选择性的基于α-羟基托酚酮的HIV RT RNase H抑制剂进行，这些化合物还将测试其对乙型肝炎和单纯疱疹病毒1和2的抗病毒活性。还将合成探针用于蛋白质组学研究，以研究α-羟基托酚酮细胞毒性。最后，化学物质将扩展到包括3, 7-二羟基托酚酮，其已显示出有前景的细胞毒性。该研究在针对艾滋病毒、乙型肝炎和单纯疱疹病毒的初步结构功能研究中测试了这些分子的抗病毒活性。因此，这项提议是一项长期研究计划的关键一步，该计划旨在彻底评估α-羟基托酚酮的治疗潜力，主要目标是建立一个新的药物开发平台。