Design, synthesis and biological evaluation of novel hydrogen sulfide releasing capsaicin derivatives

Abstract

Capsaicin (CAP), the prototypical TRPV1 agonist, is the major active component in chili peppers with health-promoting benefits. However, its use is limited by the low bioavailability and irritating quality. In this study, for improving the activity of CAP and alleviating its irritating effects, a series of H₂S-releasing CAPs were designed and synthesized by combining capsaicin and dihydro capsaicin with various hydrogen sulfide donors. The resulting compounds were evaluated their TRPV1 agonist activity, analgesic activity, anticancer activities, H₂S-releasing ability, and gastric mucosa irritation. Biological evaluation indicated that the most active compound B₉, containing 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione moiety as H₂S donor, had better analgesic activity and displayed more potent cytotoxic effects on the test cell lines than the lead compound CAP. Furthermore, the preferred compound, B₉ reduced rat gastric mucosa irritation caused by CAP. Notably, the improved properties of this derivative are associated with its H₂S-releasing capability.

Keywords: Analgesic; Anticancer; Capsaicin; Gastric mucosa irritation; Hydrogen sulfide; TRPV1 agonist.