Triflic Acid-Mediated Rearrangements of 3-Methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones: Synthesis of Methoxytropolones and Furans

Williams, Yvonne D.; Meck, Christine; Mohd, Noushad; Murelli, Ryan P.

doi:10.1021/jo401617r

Cited by 36 publications

(30 citation statements)

References 58 publications

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“…Compounds 95 to 104 were synthesized from manicol as previously described (39) and exceeded 95% purity, as determined by liquid chromatography-mass spectrometry (LCMS). Compounds 106 to 117, 119, 120, 143 to 147, and 173 were synthesized in 5 to 7 steps from kojic acid as previously described (49)(50)(51). Synthetic ␣-hydroxytropolones were pure as determined by 1 H nuclear magnetic resonance (NMR) analysis, as reported previously, and a spectrum of compound 118 is provided in Fig.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…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.…”

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confidence: 99%

“…Scheme 1). Previously described synthetic α-hydroxytropolones ( 3a–3h ) 11 and natural product β-thujaplicinol were tested for their inhibitory activity through an in vitro screen with duplicate serial dilutions, and these data are represented by IC 50 values (Table 1). K i experiments were obtained on active compounds (IC 50 < 200 μM) through more rigorous dose curves with carefully maintained concentrations of substrates ATP and kanamycin B.…”

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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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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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“…172. Most of the synthetic ␣HTs made through the Murelli laboratory's synthetic strategy (23,25,26) had a methyl substitution at C-5 and varied at C-4 with the tropolone directly linked to an aromatic (no. 112 to 114 and 144 to 147) or a carbonyl functional (no.…”

Section: Resultsmentioning

confidence: 99%

Troponoids Can Inhibit Growth of the Human Fungal Pathogen Cryptococcus neoformans

Donlin

Zunica

Lipnicky

et al. 2017

Antimicrob Agents Chemother

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Cryptococcus neoformans is a pathogen that is common in immunosuppressed patients. It can be treated with amphotericin B and fluconazole, but the mortality rate remains 15 to 30%. Thus, novel and more effective anticryptococcal therapies are needed. The troponoids are based on natural products isolated from western red cedar, and have a broad range of antimicrobial activities. Extracts of western red cedar inhibit the growth of several fungal species, but neither western red cedar extracts nor troponoid derivatives have been tested against C. neoformans. We screened 56 troponoids for their ability to inhibit C. neoformans growth and to assess whether they may be attractive candidates for development into anticryptococcal drugs. We determined MICs at which the compounds inhibited 80% of cryptococcal growth relative to vehicle-treated controls and identified 12 compounds with MICs ranging from 0.2 to 15 M. We screened compounds with MICs of Յ20 M for cytotoxicity in liver hepatoma cells. Fifty percent cytotoxicity values (CC 50 s) ranged from 4 to Ͼ100 M. The therapeutic indexes (TI, CC 50 /MIC) for most of the troponoids were fairly low, with most being Ͻ8. However, two compounds had TI values that were Ͼ8, including a tropone with a TI of Ͼ300. These tropones are fungicidal and are not antagonistic when used in combination with fluconazole or amphotericin B. Inhibition by these two tropones remains unchanged under conditions favoring cryptococcal capsule formation. These data support the hypothesis that troponoids may be a productive scaffold for the development of novel anticryptococcal therapies.

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Triflic Acid-Mediated Rearrangements of 3-Methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones: Synthesis of Methoxytropolones and Furans

Cited by 36 publications

References 58 publications

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

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

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

Troponoids Can Inhibit Growth of the Human Fungal Pathogen Cryptococcus neoformans

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