Synthesis and Preliminary Pharmacological Evaluation of Aryl Dithiolethiones with Cyclooxygenase-2-Selective Inhibitory Activity and Hydrogen Sulfide-Releasing Properties

Shannon D. Zanatta; Bevyn Jarrott; Spencer J. Williams

doi:10.1071/CH09517

RESEARCH ARTICLE

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Synthesis and Preliminary Pharmacological Evaluation of Aryl Dithiolethiones with Cyclooxygenase-2-Selective Inhibitory Activity and Hydrogen Sulfide-Releasing Properties

Shannon D. Zanatta ^A ^B , Bevyn Jarrott ^A ^C and Spencer J. Williams ^B ^D

+ Author Affiliations

- Author Affiliations

^A School of Chemistry and Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Vic. 3010, Australia.

^B Howard Florey Institute, Parkville, Vic. 3010, Australia.

^C Department of Pharmacology, University of Melbourne, Parkville, Vic. 3010, Australia.

^D Corresponding author. Email: sjwill@unimelb.edu.au

Australian Journal of Chemistry 63(6) 946-957 https://doi.org/10.1071/CH09517
Submitted: 25 September 2009 Accepted: 30 November 2009 Published: 11 June 2010

Abstract

A series of 5-aryl-1,2-dithiolethiones and 5-aryl-1,2-dithiole-3-ones were investigated as hydrogen sulfide-releasing anti-inflammatory drugs. Generally, phenolic acetophenones were best protected by methoxymethyl groups and the dithiolethione group installed by treatment with carbon disulfide, hexamethyldisilathiane, and hexachloroethane. However, ether-protected acetophenones could be elaborated to β-keto esters and converted to dithiolethiones by treatment with phosphorus pentasulfide and elemental sulfur. Dethionation of dithiolethiones to 1,2-dithiole-3-ones was accomplished by mercury(ii)-promoted hydrolysis. A preliminary investigation of the dithiolethiones and dithiole-3-ones as inhibitors of cyclooxygenases COX-1 and COX-2 is discussed. Dithiolethiones bearing a 5-(2,6-di-tert-butyl-4-hydroxyphenyl) or 5-(2,6-di-tert-butyl-4-methoxyphenyl) substituent were the most effective inhibitors of COX-2 and displayed excellent selectivity against COX-1, comparable with rofecoxib, a representative coxib. It is shown that uncatalyzed hydrolysis of the thiocarbonyl group to release hydrogen sulfide leads to the corresponding carbonyl compound, and these carbonyl compounds are moderate COX-2 selective inhibitors.

Acknowledgements

We acknowledge the Australian Research Council, the National Health and Medical Research Council of Australia and Neurotherapeutics Ltd for financial support. John Karas is thanked for his assistance with the HPLC analysis.

References

Synthesis and Preliminary Pharmacological Evaluation of Aryl Dithiolethiones with Cyclooxygenase-2-Selective Inhibitory Activity and Hydrogen Sulfide-Releasing Properties

Abstract

Acknowledgements

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