Non-pungent capsaicinoids from sweet pepper: Synthesis and evaluation of the chemopreventive and anticancer potential

Background: Capsiate, the non-pungent ester isoster of capsaicin, and its dihydroderivative are the major capsaicinoids of sweet peppers. The remarkable difference between the sensory properties of capsaicin vs capsiate is solely due to the way the vanillyl and the acyl moieties of this basic structural motif are linked, via an amide bond in capsaicin-type compounds and via an ester bond in capsiate-type compounds. Aim of the study: Since capsaicin induces apoptosis in tumoral cells by a vanilloid receptor type 1 (VR1)-independent pathway, we examined the effects of capsiates derived from sweet peppers in the ROS generation and induction of apoptosis in tumoral cells and if these are mediated independently from VR1. Methods: We have developed an expeditious synthesis of capsiates based on the esterification of vanillol with the Mitsunobu protocol. Capsiate-induction of apoptosis, generation of reactive oxygen species and disruption of the mitochondria transmembrane potential in tumoral cell lines were measured by flow cytometry. Chemopreventive activity was studied in a two-stage mouse skin carcinogenesis assay. Results: Capsiates induce apoptosis that was preceded by an increase in the production of reactive oxygen species and by a subsequent loss of mitochondria transmembrane potential (ΔΨ_m). These properties were retained in simplified synthetic analogues of natural capsiates, one of which (nor-dihydrocapsiate) showed powerful chemopreventive activity. Conclusions: These results suggest that capsiates and related synthetic analogues target a variety of pathways involved in cancer development and inflammation, and have considerable potential for dietary health benefits as well as for pharmaceutical development.