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 ?-hydroxytropolones in a `kick-and-kill' strategy for Kaposi's sarcoma-associated herpesvirus (KSHV). Specifically, we will optimize ?-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 Bchner 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.

Public Health Relevance

This project will provide tools and knowledge necessary to leverage troponoids in a broad range of studies relevant to human health. As examples, the current application describes the use of new troponoid chemis- try to develop antivirals for Kaposi's sarcoma-associated herpesvirus, as well as synthetic routes to novel molecular architectures that could be useful in developing anti-cancer and anti-malarial drugs.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Enhancement Award (SC1)
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Special Emphasis Panel (ZGM1)
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Fabian, Miles
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Brooklyn College
Schools of Arts and Sciences
New York
United States
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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:
D'Erasmo, Michael P; Masaoka, Takashi; Wilson, Jennifer A et al. (2016) Traceless Solid-Phase ?-Hydroxytropolone Synthesis. Medchemcomm 7:1789-1792
Zhang, Baofeng; D'Erasmo, Michael P; Murelli, Ryan P et al. (2016) Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV-1 Reverse Transcriptase. ACS Omega 1:435-447

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