Biological Studies of alpha-Hydroxytropolones

 性状（由申请方提供）：β-羟基环庚三烯酚酮是用于治疗开发的有前景的药效团。然而，由于缺乏合成方法，对分子的结构-功能研究受到阻碍。下面的研究将利用一个新建立的oxidopyrylium环加成/开环策略在一系列的生物学研究的α-羟基tropolones，并扩大方法，包括一个有前途的子类的分子。具体而言，将进行计算化学辅助的结构-功能研究，以获得有效的和选择性的基于α-羟基托酚酮的HIV RT RNA酶H抑制剂。还将测试这些化合物对乙型肝炎B和单纯疱疹病毒1型和2型的抗病毒活性。还将合成新的化学探针用于蛋白质组学研究，以研究α-羟基托酚酮的细胞毒性。最后，化学将扩大到包括3，7-二羟基环庚三烯酚酮，它已显示出有前途的细胞抗病毒活性的艾滋病毒，并已证明在动物模型研究的疟疾和黑色素瘤的活性与目前的治疗剂。这些分子将在针对HIV、B型肝炎和单纯疱疹病毒的初步结构-功能研究中测试其抗病毒活性。因此，拟议的研究是一项长期研究计划的关键一步，该计划旨在彻底评估β-羟基托酚酮的治疗潜力，其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.