Development of novel dithiolethione compounds as cyclooxygenase inhibitors and anti-inflammatory agents

Bevyn Jarrott1, Shannon Zanatta1, Spencer Williams2
1Howard Florey Institute, Australia, 2University of Melbourne, Australia.

Hydrogen sulfide has been proposed as an endogenous molecule that inhibits the early stages of inflammation by both reducing the expression of several pro-inflammatory cytokines and suppressing the adherence of neutrophils to the vascular mesenteric endothelium and their migration into tissue (Wallace, 2007). It has been shown that compounds that release or are metabolised to hydrogen sulphide can reduce gastric damage caused by conventional nonsteroidal anti-inflammatory drugs (NSAIDs), and that coupling such a donor compound (a five membered dithiolethione moiety) onto the NSAID diclofenac via esterification produced a compound that was an anti-inflammatory/analgesic agent without the gastrointestinal toxicity of diclofenac (Wallace et al., 2007). Previous research has shown that compounds containing an antioxidant moiety, 3,5-di-tert-butyl-4-hydroxy-phenyl were cyclooxygenase and 5-lipoxygenase inhibitors (Ruiz et al, 2003) so we hypothesised that attachment of a dithiolethione ring onto this antioxidant may give a compound that inhibited cyclooxygenase and also released hydrogen sulphide. We therefore synthesised and characterised 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-3H-1,2-dithiole-3-thione and this inhibited purified cyclooxygenase-1 with an IC50 of 2 μM and cyclooxygenase-2 with an IC50 of 0.25 μM. When 5-(3,5-di-tert-butyl-4-methoxyphenyl)-3H-1,2-dithiole-3-thione was synthesised and tested, it was found to be a potent and selective cyclooxygenase-2 inhibitor with an IC50 of 0.12 μM, which was similar to rofecoxib (0.19 μM) when assayed in the same experiment. It was not possible to determine an IC50 against cyclooxygenase-1 because of insolubility of the compound above 50 μM. Both compounds were anti-inflammatory in a peripheral model of inflammation and pain (rat complete Freund's adjuvant hind paw model) after oral administration, and had reduced gastrointestinal toxicity in rats when compared to diclofenac. Also, in view of their lipid solubility, these compounds are likely to be centrally acting and neuroprotective.

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