The biology and synthesis of α-hydroxytropolones

Meck, Christine; D’Erasmo, Michael P.; Hirsch, Danielle R.; Murelli, Ryan P.

doi:10.1039/c4md00055b

Cited by 55 publications

(42 citation statements)

References 71 publications

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“…11 Driving these studies is the large number of therapeutically relevant targets that α-hydroxytropolones have been identified as lead compounds for, 12 and the relative scarcity of accompanying synthetic chemistry-driven structure-function studies. 13 We believe that a general, reliable, and practical de novo method to access these compounds would be instrumental in fully assessing their therapeutic potential.…”

mentioning

confidence: 99%

Inhibition of the ANT(2″)-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic α-hydroxytropolones

Hirsch

Cox

D’Erasmo

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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Aminoglycoside-2″-O-nucleotidyltransferase ANT(2″)-Ia is an aminoglycoside resistance enzyme prevalent among Gram-negative bacteria, and is one of the most common determinants of enzyme-dependant aminoglycoside-resistance. The following report outlines the use of our recently described oxidopyrylium cycloaddition/ring-opening strategy in the synthesis and profiling of a library of synthetic α-hydroxytropolones against ANT(2″)-Ia. In addition, we show that two of these synthetic constructs are capable of rescuing gentamicin activity against ANT-(2″)-Ia-expressing bacteria.

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confidence: 99%

Inhibition of the ANT(2″)-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic α-hydroxytropolones

Hirsch

Cox

D’Erasmo

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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“…We previously demonstrated that numerous compounds selected for the capacity to suppress HIV or HBV RNase H activity or close chemical relatives of these compounds also inhibit HSV replication in cell cultures (33). One of these compounds, the natural product ␤-thujaplicinol (34), is the most widely studied member of a class of troponoids called ␣-hydroxytropolones that have been identified as anticancer agents (35,36) as well as lead therapeutic agents for a number of infections, including HIV (37)(38)(39)(40)(41), HBV (42), malaria (43), and many bacteria (44). This antimicrobial activity is often attributed to the capacity of the compounds to sequester divalent cations in the active sites of dinuclear metalloenzymes, a feature arising from the three contiguous oxygen atoms on the troponoid ring (45)(46)(47).…”

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confidence: 99%

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

Ireland

Tavis

D’Erasmo

et al. 2016

Antimicrob Agents Chemother

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cHerpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as ␤-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic ␣-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the ␣-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 M, and 10 compounds inhibited HSV-1 and HSV-2 at 5 M, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC 50 ) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC 50 ] of 50 to >100 M). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically ␣-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.

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“…24–27 Three recent reviews focused on special classes of compounds, such as colchicine, 28 the five tropones derived from the Cephalotaxus species, 29 and α-hydroxytropolones (dihydroxytropones). 30 …”

Section: Introductionmentioning

confidence: 99%

Synthesis of naturally occurring tropones and tropolones

et al. 2014

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Tropones and tropolones are an important class of seven-membered non-benzenoid aromatic compounds. They can be prepared directly by oxidation of seven-membered rings. They can also be derived from cyclization or cycloaddition of appropriate precursors followed by elimination or rearrangement. This review discusses the types of naturally occurring tropones and tropolones and outlines important methods developed for the synthesis of tropone and tropolone natural products.

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The biology and synthesis of α-hydroxytropolones

Cited by 55 publications

References 71 publications

Inhibition of the ANT(2″)-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic α-hydroxytropolones

Inhibition of the ANT(2″)-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic α-hydroxytropolones

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

Synthesis of naturally occurring tropones and tropolones

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