Curcumin conjugates of non‐steroidal anti‐inflammatory drugs: Synthesis, structures, anti‐proliferative assays, computational docking, and inflammatory response

• Autores: Laali, Kenneth K.; Zwarycz, Angela T.; Beck, Nicholas; Borosky, Gabriela Leonor; Nukaya, Manabu; Kennedy, Gregory D.
• Año de publicación: 2020
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: ANTI-INFLAMMATORY ASSAYS; ANTI-PROLIFERATIVE ACTIVITY; ANTIPROLIFERATIVE ASSAYS; COMPUTATIONAL DOCKING; CONJUGATES; CURCUMIN; DOCKING STUDIES; INFLAMMATION RESPONSE; NSAID/CUR-BF2 AND NSAID/CUR CONJUGATES; SYNTHESIS
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Laali, Kenneth K.. University Of North Florida; Estados Unidos
Fil: Zwarycz, Angela T.. University Of North Florida; Estados Unidos
Fil: Beck, Nicholas. University Of North Florida; Estados Unidos
Fil: Borosky, Gabriela Leonor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina
Fil: Nukaya, Manabu. University of Alabama at Birmingahm; Estados Unidos
Fil: Kennedy, Gregory D.. University of Alabama at Birmingahm; Estados Unidos