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

Abstract

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.

A Novel Curcumin-Mycophenolic Acid Conjugate Inhibited Hyperproliferation of Tumor Necrosis Factor-Alpha-Induced Human Keratinocyte Cells

“…It may be attributed to the purification step even though the purification step has been optimized in terms of the mobile and stationary phases. Besides, the TLC result showed that the reaction was not completed after 24 h, similar to the work reported by Laali and colleagues [ 40 ]. The MPA-CUR conjugate product was found as yellow solid after purification using C18-bonded silica as the stationary phase and methanol: water (8:2) as the mobile phase.…”

“…EDC was selected because the unreacted EDC can be easily removed from the reaction by partitioning with water due to its good water solubility [ 39 ]. Several organic solvents, including DCM and DMF ( N , N -dimethylformamide), are commonly used in the Steglich esterification method [ 37 , 38 , 40 , 41 ]. Due to the low solubility of curcumin in DCM, a large volume of DCM used to dissolve CUR resulted in a very diluting reaction mixture.…”

“…In addition, curcumin can be easily dissolved in acetone and a small volume of acetone is needed. Steglich esterification has been applied to synthesize other MPA or CUR ester prodrugs [ 30 , 40 , 42 ]. CUR was coupled to several non-steroid anti-inflammatory drugs, namely flufenamic acid, flurbiprofen, naproxen, and ibuprofen with a percentage yield between 17 and 30% [ 42 ].…”

Promising iron(II) complexes of curcumins: designing, density functional theory, and molecular docking

“…Curcumin is a documented antiproliferative and antiangeonic as well as a cure for Alzheimer's disease, cardiac, diabetes, and so forth. [ 1–9 ] Curcumin exists in two tautomeric structures i.e., keto and enol form. The enol form of the curcumin is more stable in solid as well as in the solution phase and is able to penetrate the blood–brain barrier.…”

“…Based on the literature, it is explained that the more negative energy for the formation of the complex between small molecule and receptor, the more will be the stability or interaction. [ 4,5,9,11,14,19,22–24 ]…”