?-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.
?-Hydroxytropolones have broad therapeutic potential for various diseases that are significant to public health, including HIV, malaria, heart disease, bipolar disorder, bacterial infections, and many more. However, very few structure function studies have been performed on them to date in part due to a scarcity of synthetic methods available to access and study them. The following grant will leverage a recent synthetic strategy developed in our lab to carry out in-depth structure function studies toward a clinically viable anti-HIV ?-hydroxytropolone, assess these molecules for their antiviral activity for hepatitis B and herpes simplex virus 1 and 2, perform experiments aimed at understanding the cytotoxicity of ?-hydroxytropolones, and expand our chemistry to include 3,7-dihydroxytropolones, which have shown promising antiviral, antimalarial, and anticancer activity.
|Bejcek, Lauren P; Murelli, Ryan P (2018) Oxidopyrylium [5+2] Cycloaddition Chemistry: Historical Perspective and Recent Advances (2008-2018). Tetrahedron 74:2501-2521|
|D'Erasmo, Michael P; Murelli, Ryan P (2018) Fluorous-Phase Approach to ?-Hydroxytropolone Synthesis. J Org Chem 83:1478-1485|
|Miller, Jennifer T; Zhao, Haiyan; Masaoka, Takashi et al. (2018) Sensitivity of the C-Terminal Nuclease Domain of Kaposi's Sarcoma-Associated Herpesvirus ORF29 to Two Classes of Active-Site Ligands. Antimicrob Agents Chemother 62:|
|Grady, Lorry M; Szczepaniak, Renata; Murelli, Ryan P et al. (2017) The exonuclease activity of HSV-1 UL12 is required for the production of viral DNA that can be packaged to produce infectious virus. J Virol :|
|Hirsch, D R; Schiavone, D V; Berkowitz, A J et al. (2017) Synthesis and biological assessment of 3,7-dihydroxytropolones. Org Biomol Chem 16:62-69|
|Fuhr, Katherine N; Hirsch, Danielle R; Murelli, Ryan P et al. (2017) Catalytic Enantioselective Intermolecular [5 + 2] Dipolar Cycloadditions of a 3-Hydroxy-4-pyrone-Derived Oxidopyrylium Ylide. Org Lett 19:6356-6359|
|Lomonosova, Elena; Daw, Jil; Garimallaprabhakaran, Aswin K et al. (2017) Efficacy and cytotoxicity in cell culture of novel ?-hydroxytropolone inhibitors of hepatitis B virus ribonuclease H. Antiviral Res 144:164-172|
|Donlin, Maureen J; Zunica, Anthony; Lipnicky, Ashlyn et al. (2017) Troponoids Can Inhibit Growth of the Human Fungal Pathogen Cryptococcus neoformans. Antimicrob Agents Chemother 61:|
|Murelli, Ryan P; D'Erasmo, Michael P; Hirsch, Danielle R et al. (2016) Synthetic ?-Hydroxytropolones as Inhibitors of HIV Reverse Transcriptase Ribonuclease H Activity. Medchemcomm 7:1783-1788|
|Ireland, Peter J; Tavis, John E; D'Erasmo, Michael P et al. (2016) Synthetic ?-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses. Antimicrob Agents Chemother 60:2140-9|
Showing the most recent 10 out of 15 publications