Green synthesis and two-step chromatographic separation of thiocanthal and thiocanthol: Two novel biologically active sulfur derivatives of oleocanthal and oleacein from extra virgin olive oil.

Oleocanthal and oleacein are the two major secoiridoids exclusively present in extra virgin olive oil (EVOO). Both compounds exert important pharmacological activities, including anti-inflammatory, anti-tumoral, neuro- and cardiovascular protective effects. Due to their enormous potential as possible drugs the extraction of these two bioactive natural products from EVOO has been extensively investigated in the last years and is generally supported by the use of organic chemistry. It is quite difficult to produce large quantities of these two compounds, either by organic solvent extraction and purification or by chemical synthesis, and furthermore organic processes such as cleaning, defatting, and extraction of EVOO pose a threat to the environment and are potentially harmful to workers. In this work we set up a novel aqueous extraction and isolation method from EVOO by transforming oleocanthal and oleacein into two water-soluble sulfonated products. The two derived compounds, here named thiocanthal and thiocanthol, were isolated by a two-step organic free chromatographic strategy, chemically characterized, and evaluated for their inhibitory activity on cyclooxygenase (COX). The results demonstrate that thiocanthal and thiocanthol possess anti-inflammatory effect, which is comparable to their precursors and higher than the well-known non-steroidal anti-inflammatory drug ibuprofen. Computational docking studies were performed to obtain and analyse putative models of the interaction of thiocanthal and thiocanthol with COX-1 and COX-2 binding sites. Predicted binding energy values suggested that both compounds might preferentially bind COX-2, which may have a significant pharmacological impact. Therefore, thiocanthal and thiocanthol, obtained by this novel green process, are extremely interesting both as new bioactive compounds per se and as lead compounds for the development of novel non-steroidal anti-inflammatory drugs (NSAIDs).