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‐BF(2) and CUR compounds with anti‐inflammatory benefits of non‐steroidal anti‐inflammatory drugs (NSAIDs), a library of the bis‐ and mono‐NSAID/CUR‐BF(2) 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‐BF(2) to form the bis‐ and the mono‐NSAID/CUR‐BF(2) 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‐BF(2) 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‐BF(2) 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.