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.
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.
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