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. 2019;9(59):34227-34234.
doi: 10.1039/c9ra06383h. Epub 2019 Oct 23.

Divergent synthesis of a thiolate-based α-hydroxytropolone library with a dynamic bioactivity profile

Nana B Agyemang  1   2 , Cassandra R Kukla  3 , Tiffany C Edwards  3 , Qilan Li  3 , Madison K Langen  4 , Alexandra Schaal  4 , Abaigeal D Franson  3 , Andreu Gazquez Casals  3 , Katherine A Donald  3 , Alice J Yu  3 , Maureen J Donlin  4 , Lynda A Morrison  3   5 , John E Tavis  3 , Ryan P Murelli  1   2
Affiliations

Divergent synthesis of a thiolate-based α-hydroxytropolone library with a dynamic bioactivity profile

Nana B Agyemang et al. RSC Adv. 2019.

Abstract

Here we describe a rapid and divergent synthetic route toward structurally novel αHTs functionalized with either one or two thioether or sulfonyl appendages. Evaluation of this library against hepatitis B and herpes simplex virus, as well as the pathogenic fungus Cryptococcus neoformans, and a human hepatoblastoma (HepDES19) revealed complementary biological profiles and new lead compounds with sub-micromolar activity against each pathogen.

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Conflict of interest statement

Conflict of Interest MJD, LAM, JET, and RPM are co-inventors on a patent describing αHTs as drug leads for the three diseases described herein.

Figures

Fig. 1
Fig. 1. α-Hydroxytropolone (αHT) overview. (A) αHT and potential mode of inhibition of dinuclear metalloenzymes. (B) αHT natural product β-thujaplicinol, and previously published data against HBV, HSV-1, and C. neoformans.
Scheme 1
Scheme 1. Oxidopyrylium cycloaddition/ring-opening strategy for αHT synthesis. Inset is a structure representative of a high percentage of current library made through this approach.
Scheme 2
Scheme 2. Halogenation/functionalization approaches to substituted tropolones. (A) Halogenation/cross-coupling strategy to functionalize 3,7-dihydroxytropolones. (B) Halogenation/thiolate addition/oxidation strategy described herein.
Scheme 3
Scheme 3. Synthesis of thioether and sulfonyl αHTs. aIsolated yields following C18-capped silica gel chromatography. bThiolates made and used in situ from sodium hydride and the corresponding thiol. See ESI for detail.
Fig. 2
Fig. 2. Overview of biological activity of thiolate-base αHT library against a panel of pathogenic microbes. aFor HBV antiviral activity and HepDES19 cytotoxicity, potency is judged based on 50% effective inhibitory concentrations (EC50) for HBV antiviral activity, and 50% cytotoxicity concentrations (CC50) for HepDES19 cytotoxicity: most potent <1.0 μM; moderate potency = 1.0–10 μM; least potency >49 μM. For HSV potency is judged by whether the molecules showed 10-fold or greater replication inhibition at different concentrations: most potent = effective at 0.33 μM; moderate potency = effective at 1.0 μM; low potency = effective at 5.0 μM; least potent are inactive at 5.0 μM. For C. neoformans, potency is judged based on 80% minimum growth inhibition (MIC80): most potent <1.0 μM; moderate potency = 1.0–10 μM; low potency = 10–49 μM; least potent >49 μM. bI = selectivity index, defined as CC50/MIC80 for 13h, or CC50/EC50 for 14a and 15c. cCytotoxicity value shown for HepDES19. 15c is not cytotoxic against host Vero cell line at up to 100 μM for 48 hours.
Fig. 3
Fig. 3. Representative examples of potent anti-HSV-1 αHTs previously tested..
Fig. 4
Fig. 4. Previously described αHTs with C. neoformans antifungal activity.
Fig. 5
Fig. 5. Representative examples of previously described anti-HBV αHTs. (EC50) along with cytotoxicity against HepDES19 cells (CC50).
See this image and copyright information in PMC

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