Synthesis of curcuminoids as non-steroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed therapeutic agents used worldwide, to treat various inflammatory diseases. However, these drugs do not solve the underlying problem of inflammation and their long-term administration is associated with serious gastrointestinal complications, such as gastric ulcers and bleeding. Curcumin 1, (figure A) the diferuloylmethane, a yellow pigment found in the rhizomes of turmeric (Curcuma longa) possesses a well established role as an anti-inflammatory agent since ancient times to treat various inflammatory diseases. Thiophene features in many natural products and possesses anti-inflammatory properties. Similarly, nitric oxide donating NSAIDs are emerging as a novel class of NSAIDs which offers better efficacy and possesses lesser side-effects associated with the conventional NSAIDs. In search of better NSAIDs, we have successfully synthesised and spectroscopically characterised four thiophene curcuminoids 47a-d and novel nitric oxide donating derivatives of curcumin 51a-d, (figure A) using Pabon's method. The cytotoxic effects of these drugs along with the lead compound curcumin 1 and their effect on the production of reactive oxygen species i.e. nitric oxide and pro-inflammatory cytokines IL-1beta, TNF-alpha and CXCL-8 were evaluated using THP-1 and CACO-2 cancer cells.The thiophene curcuminoids 47a at 10,50 and 100 muM and 47d at 10 and 50 muM, appeared to be non-cytotoxic to THP-1 cells, whereas, 47b and 47c were non-cytotoxic at 10 muM only. When compared with curcumin 1, at 10 muM, 47a and 47d were as non-cytotoxic as curcumin 1, however, 47b and 47c were more toxic than curcumin 1. In CACO-2 cells, 47b and 47d appeared to be non-toxic at 10 to 100 uM, whereas, 47a was non-toxic at 10 and 100 muM and 47c was non-cytotoxic at 10 muM only. In THP-1 cells, drugs 47a-d significantly decreased the IL-1beta production at their non-cytotoxic concentrations, whereas, did not decrease the TNF-? production. For the effects on CXCL-8 in CACO-2 cells, 47a at 100 muM and 47b and 47d at 50 and 100 muM showed significant decrease in CXCL-8 production. In comparison to curcumin 1 at 10 muM only drug 47c significantly reduced CXCL-8 production. All of the nitric oxide donating curcuminoids 51a-d are non-cytotoxic to THP-1 cells at a concentration range of 10-100 muM and in comparison with curcumin 1, all drugs at 10 muM were as non-toxic as curcumin 1, whereas at 50 and 100 muM were significantly more nontoxic to the cells. All of them except 51c enhanced the production of nitric oxide in unstimulated THP-1 cells, whereas in LPS stimulated cells drugs 51a and 51d showed similar effects to unstimulated cells, however drug 51b equally produced NO at 10, 50 and 100 muM and 51c was effective at 100 muM only. In comparison with crucumin 1 drug 51b at 10 muM enhanced the NO production both in LPS stimulated and unstimulated cells. These results clearly indicate that the replacement of both of the phenyl rings of the curcumin 1 with unsubstituted thiophenes and the introduction of a nitroxybutyl moiety to curcumin 1 reduce the cytotoxic effect of the parent curcumin 1, whereas, methyl substituted thiophenes increase its cytotoxic effects in THP-1 cells.The synthesis of fused-ring aromatic heterocyclic curcuminoids 57b and 61 (figure A) was carried out via two different routes however both methods resulted in poor yields. On the other hand in case of nitrogen derived curcuminoids 63, 65 and 69 (figure A) no product was obtained at all. New method for the synthesis of curcuminoids using Claisen condensation reaction was tried but complete evidence of curcumin formation was not achieved.