Biological Studies of alpha-Hydroxytropolones

 描述(申请人提供)：-羟基孕酮是很有前途的药物载体，可用于治疗开发。然而，由于缺乏可用的合成方法来获取它们，对这些分子的结构-功能研究一直受到阻碍。下面的研究将利用新建立的氧化吡喃环加成/开环策略，在一系列关于α-羟基孕酮的生物学研究中，并将方法学扩展到包括一个有希望的分子亚类。具体地说，将开展一项计算化学辅助的结构-功能研究，以开发一种有效和选择性的基于α-羟基托洛酮的HIV RT RNaseH抑制剂。这些化合物还将测试它们对乙肝和单纯疱疹病毒1和2的抗病毒活性。还将合成新的化学探针，用于蛋白质组研究，以研究α-羟色胺的细胞毒性。最后，化学成分将扩大到包括3，7-二羟基紫罗兰酮，它们已经显示出对艾滋病毒有良好的细胞抗病毒活性，并在疟疾和黑色素瘤的动物模型研究中显示出与目前治疗药物相当的活性。这些分子将在针对艾滋病毒、乙肝和单纯疱疹病毒的初步结构-功能研究中测试它们的抗病毒活性。因此，拟议的研究是旨在彻底评估-羟色胺治疗潜力的长期研究计划的关键一步，主要目标是建立一个新的药物开发平台。

 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.