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The biology and synthesis of ?-hydroxytropolones.

ABSTRACT: ?-Hydroxytropolones are a subclass of the troponoid family of natural products that are of high interest due to their broad biological activity and potential as treatment options for several diseases. Despite this promise, there have been scarce synthetic chemistry-driven optimization studies on the molecules. The following review highlights key developments in the biological studies conducted on ?-hydroxytropolones to date, including the few synthetic chemistry-driven optimization studies. In addition, we provide an overview of the methods currently available to access these molecules. This review is intended to serve as a resource for those interested in biological activity of ?-hydroxytropolones, and inspire the development of new synthetic methods and strategies that could aid in this pursuit.

SUBMITTER: Meck C

PROVIDER: S-EPMC4114738 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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The biology and synthesis of α-hydroxytropolones.

Meck Christine C D'Erasmo Michael P MP Hirsch Danielle R DR Murelli Ryan P RP

MedChemComm 20140701 7

α-Hydroxytropolones are a subclass of the troponoid family of natural products that are of high interest due to their broad biological activity and potential as treatment options for several diseases. Despite this promise, there have been scarce synthetic chemistry-driven optimization studies on the molecules. The following review highlights key developments in the biological studies conducted on α-hydroxytropolones to date, including the few synthetic chemistry-driven optimization studies. In a ...[more]

PMID: 25089179

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Amide-containing α-hydroxytropolones as inhibitors of hepatitis B virus replication.

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Importance of lipophilicity for potent anti-herpes simplex virus-1 activity of α-hydroxytropolones.

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Antiviral activity of amide-appended α-hydroxytropolones against herpes simplex virus-1 and -2.

Project description:α-Hydroxytropolones (αHTs) have potent antiviral activity against herpes simplex virus-1 and -2 (HSV-1 and HSV-2) in cell culture, including against acyclovir-resistant mutants, and as a result have the potential to be developed as antiviral drugs targeting these viruses. We recently described a convenient final-step amidation strategy to their synthesis, and this was used to generate 57 amide-substituted αHTs that were tested against hepatitis B virus. The following manuscript describes the evaluation of this library against HSV-1, as well as a subset against HSV-2. The structure-function analysis obtained from these studies demonstrates the importance of lipophilicity and rigidity to αHT-based anti-HSV potency, consistent with our prior work on smaller libraries. We used this information to synthesize and test a targeted library of 4 additional amide-appended αHTs. The most potent of this new series had a 50% effective concentration (EC50) for viral inhibition of 72 nM, on par with the most potent αHT antivirals we have found to date. Given the ease of synthesis of amide-appended αHTs, this new class of antiviral compounds and the chemistry to make them should be highly valuable in future anti-HSV drug development.

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