Amidation Strategy for Final-Step α-Hydroxytropolone Diversification

Overview

Journal Tetrahedron Lett

Publisher Elsevier

Specialty Chemistry

Date 2019 Mar 16

PMID 30872871

Citations 12

Authors

Alex J Berkowitz

Rudolf G Abdelmessih

Ryan P Murelli

Affiliations

Soon will be listed here.

Abstract

α-Hydroxytropolones (αHTs) are excellent metalloenzyme-inhibiting fragments that have been the basis for the development of potent inhibitors of various therapeutically important enzymes. The following manuscript describes a final-step amidation approach for αHT diversification. The method takes advantage of a scalable, chromatography-free synthesis of a carboxylic acid-appended αHT, and in the present manuscript we describe the synthesis of eight amide-containing αHTs, three of which we envision using as chemical probes. We expect that the general strategy will find widespread usage in both chemical biology and medicinal chemistry studies on αHTs.

Citing Articles

Targeting Metalloenzymes: The "Achilles' Heel" of Viruses and Parasites.

Moianos D, Prifti G, Makri M, Zoidis G Pharmaceuticals (Basel). 2023; 16(6).

PMID: 37375848 PMC: 10304105. DOI: 10.3390/ph16060901.

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

Gazquez Casals A, Berkowitz A, Yu A, Waters H, Schiavone D, Kapkayeva D RSC Adv. 2023; 13(13):8743-8752.

PMID: 36936842 PMC: 10016935. DOI: 10.1039/d2ra06749h.

Carbocycloaddition Strategies for Troponoid Synthesis.

Murelli R, Berkowitz A, Zuschlag D Tetrahedron. 2023; 130.

PMID: 36777111 PMC: 9910567. DOI: 10.1016/j.tet.2022.133175.

Metal coordinating inhibitors of Rift Valley fever virus replication.

Geerling E, Murphy V, Mai M, Stone E, Gazquez Casals A, Hassert M PLoS One. 2022; 17(9):e0274266.

PMID: 36112605 PMC: 9481026. DOI: 10.1371/journal.pone.0274266.

Synthesis of α-Tropolones through Autoxidation of Dioxole-Fused Cycloheptatrienes.

Berkowitz A, Murelli R J Org Chem. 2022; 87(7):4499-4507.

PMID: 35007070 PMC: 9002940. DOI: 10.1021/acs.joc.1c02713.

References

DErasmo M, Murelli R . Fluorous-Phase Approach to α-Hydroxytropolone Synthesis. J Org Chem. 2018; 83(3):1478-1485. PMC: 5859309. DOI: 10.1021/acs.joc.7b03032. View

Sennari G, Saito R, Hirose T, Iwatsuki M, Ishiyama A, Hokari R . Antimalarial troponoids, puberulic acid and viticolins; divergent synthesis and structure-activity relationship studies. Sci Rep. 2017; 7(1):7259. PMC: 5543150. DOI: 10.1038/s41598-017-07718-3. View

Anees M, Benbow E . Dansyl fluoride, a fluorescent inhibitor for the location of tumour cells in human tissues. J Enzyme Inhib. 1996; 10(3):195-201. DOI: 10.3109/14756369609030313. View

Niemann A, Baltes J, Elsasser H . Fluorescence properties and staining behavior of monodansylpentane, a structural homologue of the lysosomotropic agent monodansylcadaverine. J Histochem Cytochem. 2001; 49(2):177-85. DOI: 10.1177/002215540104900205. View

Meck C, Mohd N, Murelli R . An oxidopyrylium cyclization/ring-opening route to polysubstituted α-hydroxytropolones. Org Lett. 2012; 14(23):5988-91. PMC: 3518617. DOI: 10.1021/ol302892g. View

Williams Y, Meck C, Mohd N, Murelli R . Triflic acid-mediated rearrangements of 3-methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones: synthesis of methoxytropolones and furans. J Org Chem. 2013; 78(23):11707-13. PMC: 3909939. DOI: 10.1021/jo401617r. View

Donlin M, Zunica A, Lipnicky A, Garimallaprabhakaran A, Berkowitz A, Grigoryan A . Troponoids Can Inhibit Growth of the Human Fungal Pathogen Cryptococcus neoformans. Antimicrob Agents Chemother. 2017; 61(4). PMC: 5365692. DOI: 10.1128/AAC.02574-16. View

Gretch D, Suter M, Stinski M . The use of biotinylated monoclonal antibodies and streptavidin affinity chromatography to isolate herpesvirus hydrophobic proteins or glycoproteins. Anal Biochem. 1987; 163(1):270-7. DOI: 10.1016/0003-2697(87)90123-0. View

Lea W, Simeonov A . Fluorescence polarization assays in small molecule screening. Expert Opin Drug Discov. 2012; 6(1):17-32. PMC: 3277431. DOI: 10.1517/17460441.2011.537322. View

10.

Meck C, DErasmo M, Hirsch D, Murelli R . The biology and synthesis of α-hydroxytropolones. Medchemcomm. 2014; 5(7):842-852. PMC: 4114738. DOI: 10.1039/C4MD00055B. View

11.

Dubinsky L, Krom B, Meijler M . Diazirine based photoaffinity labeling. Bioorg Med Chem. 2011; 20(2):554-70. DOI: 10.1016/j.bmc.2011.06.066. View

12.

Chung S, Himmel D, Jiang J, Wojtak K, Bauman J, Rausch J . Synthesis, activity, and structural analysis of novel α-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H. J Med Chem. 2011; 54(13):4462-73. PMC: 3133734. DOI: 10.1021/jm2000757. View

13.

Murelli R, DErasmo M, Hirsch D, Meck C, Masaoka T, Wilson J . Synthetic α-Hydroxytropolones as Inhibitors of HIV Reverse Transcriptase Ribonuclease H Activity. Medchemcomm. 2017; 7(9):1783-1788. PMC: 5234084. DOI: 10.1039/C6MD00238B. View

14.

Piettre S, Andre C, Chanal M, Ducep J, Lesur B, Piriou F . Monoaryl- and bisaryldihydroxytropolones as potent inhibitors of inositol monophosphatase. J Med Chem. 1998; 40(26):4208-21. DOI: 10.1021/jm9701942. View

15.

Diamandis E, Christopoulos T . The biotin-(strept)avidin system: principles and applications in biotechnology. Clin Chem. 1991; 37(5):625-36. View

16.

Hirsch D, Cox G, DErasmo M, Shakya T, Meck C, Mohd N . Inhibition of the ANT(2")-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic α-hydroxytropolones. Bioorg Med Chem Lett. 2014; 24(21):4943-7. PMC: 4798002. DOI: 10.1016/j.bmcl.2014.09.037. View

17.

Alonso D, Vazquez-Villa H, Gamo A, Martinez-Esperon M, Tortosa M, Viso A . Development of Fluorescent Ligands for the Human 5-HT1A Receptor. ACS Med Chem Lett. 2014; 1(6):249-53. PMC: 4007967. DOI: 10.1021/ml100053y. View

18.

Ireland P, Tavis J, DErasmo M, Hirsch D, Murelli R, Cadiz M . Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses. Antimicrob Agents Chemother. 2016; 60(4):2140-9. PMC: 4808205. DOI: 10.1128/AAC.02675-15. View

19.

Wulff J, Siegrist R, Myers A . The natural product avrainvillamide binds to the oncoprotein nucleophosmin. J Am Chem Soc. 2007; 129(46):14444-51. PMC: 2557551. DOI: 10.1021/ja075327f. View

20.

Long K, Lomonosova E, Li Q, Ponzar N, Villa J, Touchette E . Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice. Antiviral Res. 2017; 149:41-47. PMC: 5743599. DOI: 10.1016/j.antiviral.2017.11.008. View