In search of better NSAIDs four novel nitric oxide donating derivatives of curcumin (compounds 9aCd), and four thiophene curcuminoids (compounds 10aCc, 11) have been synthesised. 10c were non-cytotoxic at 10 M only. These results clearly indicate that the introduction of a nitroxybutyl moiety to curcumin and replacement of phenyl rings with thiophene units reduces the cytotoxic effect of the parent curcumin, whereas a methyl substituted thiophene increases the cytotoxic effects. In THP-1 Celastrol distributor cells, drugs 10a and 11 significantly decreased IL-1- production at their non-cytotoxic concentrations, whereas, they did not decrease TNF- production in CACO-2 cells. Compound 11 showed a significant decrease in CXCL-8 production. and 0.05 compared with DMSO control, * 0.05 compared with curcumin control (7). From the structure-activity relationships, it appears that the replacement of both the phenolic hydrogens of curcumin (7) with the nitroxybutyl ether moiety enhances the non-cytotoxic properties of these compounds. However, the presence of the methoxy group (-OCH3) at the positions of the phenyl rings, as is found in compounds 7 and 9d, does not seem to be crucial for the cytotoxic effects since compounds 9aCc do not possess any -OCH3 groups and these were as non-cytotoxic as 9d Celastrol distributor at 50 and 100 M (Figure 3). Furthermore, change in the position of the nitroxybutyl moiety in structures of the compounds 9aCc also did not have any effect on cell viability. Thus, it appears that all of the nitroxybutyl curcuminoids 9aCd are non-toxic to THP-1 cells and are less cytotoxic than curcumin (7) at 10, 50 and 100 M concentrations. The replacement of both of the phenyl rings of the curcumin (7) with thiophene rings resulted in lesser cytotoxic effects on THP-1 cells. Amongst all four Celastrol distributor thiophene curcuminoids, compounds 10b and 10c which are the methyl substituted derivatives of 10a at the 3 and 5 positions, respectively, show significant ( 0.05) cytotoxic effects in concentration-dependent manner, suggesting the methyl group as being responsible for the cytotoxic effects (Figure 4). On the other hand compound 11 which is a positional isomer of 10a also appeared to be less cytotoxic than 10b and 10c, which further confirms that there is a possibility of a methyl group being involved in the induction of cytotoxic effects associated with these derivatives. In comparison with the curcumin (7) the thiophene curcuminoids 10a and 11 at 10 M, have similar Mouse monoclonal to CD45RA.TB100 reacts with the 220 kDa isoform A of CD45. This is clustered as CD45RA, and is expressed on naive/resting T cells and on medullart thymocytes. In comparison, CD45RO is expressed on memory/activated T cells and cortical thymocytes. CD45RA and CD45RO are useful for discriminating between naive and memory T cells in the study of the immune system cytotoxicity to curcumin 7 whereas the methyl substituted curcuminoids 10b and 10c appeared to be more cytotoxic than curcumin (7). Since 10b and 10c at their lowest concentration (10 M) are more toxic than curcumin (7), these could serve as potential anti-cancer drugs (Figure 4). In CACO-2 cells all the compounds 10aCc, 11 had a similar toxicity profile as curcumin (7) but at 50 M concentration only the 5-methyl derivative 10c showed increased cytotoxicity that was similar to that of curcumin (7). The toxicity profile of the 5-methylthiophene derivative 10c appears to be very similar in both THP-1 and CACO-2 cells (Figure 5). Open in a separate window Figure 4 The effects of curcumin (7) and thiophene curcuminoids 10aCc, 11 on the viability of THP-1 cells as determined by the MTS assay. Results are presented as mean SD. * 0.05 compared with DMSO control, * 0.05 compared with curcumin control (7). Open in a separate window Figure 5 The effects of curcumin (7) and thiophene curcuminoids 10aCc, 11 on the viability of CACO-2 cells as determined by the MTS assay. Results are presented as mean SD. * 0.05 compared with DMSO control, * 0.05 compared with curcumin control (7). 2.2.2. Nitric Oxide Production In THP-1 cells all NO-derivatives of curcumin enhanced the production of NO in a concentration-dependent manner, except for 9c (Figure 6 and Figure 7). From the Celastrol distributor structure activity relationships it appears that the replacement of the phenolic hydrogen of curcumin (7) with the nitroxybutyl ether moiety significantly enhances nitric oxide production. Compared to the DMSO control a concentration dependent increase in the production of nitrite was observed.