Curcumin Conjugates of Non-steroidal Anti-Inflammatory Drugs: Synthesis, Structures, Anti-proliferative Assays, Computational Docking, and Inflammatory Response

In an effort to combine the anti-proliferative effect of CUR-BF₂ and CUR compounds with anti-inflammatory benefits of non-steroidal anti-inflammatory drugs (NSAIDs), a library of the bis- and mono-NSAID/CUR-BF₂ and NSAID/CUR conjugates were synthesized by coupling flufenamic acid, flurbiprofen, naproxen, indomethacin, and ibuprofen to diversely substituted hydroxy-benzaldehydes via an ester linkage, and by subsequent reaction with acetylacetone-BF₂ to form the bis- and the mono-NSAID/CUR-BF₂ adducts. Since conversion to NSAID/CUR by the previously developed decomplexation protocol showed limited success, a set of NSAID/CUR conjugates were independently prepared by directly coupling the NSAIDs with parent curcumin. The bis-NSAID/CUR-BF₂ and bis-NSAID-CUR hybrids exhibited low cytotoxicity in NCI-60 assay, and in independent cell viability assay on colorectal cancer (CRC) cells (HCT116, HT29, DLD-1, RKO, SW837, CaCo2) and in normal CR cells (CCD841CoN). By contrast, the mono-naproxin and mono-flurbiprofen CUR-BF₂ adducts exhibited remarkable anti-proliferative and apoptopic activity in NCI-60 assay most notably against HCT-116 (colon), OVCAR-3 (ovarian), and ACHN (renal) cells. Computational molecular docking calculations showed favorable binding energies to HER2, VEGFR2, BRAF, and Bcl-2 as well as to COX-1 and COX-2, which in several cases exceeded known inhibitors. The main interactions between the ligands and the proteins were hydrophobic, although several hydrogen bonds were also observed. A sub-set of six compounds that had exhibited little or no cytotoxicity were tested for their anti-inflammatory response with THP-1 human macrophages in comparison to parent NSAIDs or parent curcumin.

Keywords: NSAID/CUR-BF2 and NSAID/CUR conjugates; anti-inflammatory assays; anti-proliferative activity; antiproliferative assays; computational docking; conjugates; curcumin; docking studies; inflammation response; synthesis.