INFIQC 05475
INSTITUTO DE INVESTIGACIONES EN FISICO- QUIMICA DE CORDOBA
Unidad Ejecutora - UE
artículos
Título:
Curcumin Conjugates of Non‐steroidal Anti‐Inflammatory Drugs: Synthesis, Structures, Anti‐proliferative Assays, Computational Docking, and Inflammatory Response
Autor/es:
LAALI, KENNETH K.; BOROSKY, GABRIELA L.; BECK, NICHOLAS; KENNEDY, GREGORY D.; ZWARYCZ, ANGELA T.; NUKAYA, MANABU
Revista:
ChemistryOpen
Editorial:
Wiley
Referencias:
Lugar: Weinheim; Año: 2020 vol. 9 p. 822 - 834
ISSN:
2191-1363
Resumen:
In an effort to combine the anti-proliferative effect of CUR-BF2 and CUR compounds with anti-inflammatory benefits of nonsteroidal anti-inflammatory drugs (NSAIDs), a library of the bisandmono-NSAID/CUR-BF2 and NSAID/CUR conjugates were synthesized by coupling flufenamic acid, flurbiprofen, naproxen, indomethacin, and ibuprofen to diversely substituted hydroxybenzaldehydesvia 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 cellviability 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 monoflurbiprofen CUR-BF2 adducts exhibited remarkable anti-proliferative and apoptopic activity in NCI-60 assay most notablyagainst 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 aswell 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 hydrogenbonds were also observed. A sub-set of six compounds that had exhibited little or no cytotoxicity were tested for their antiinflammatory response with THP-1 human macrophages in comparison to parent NSAIDs or parent curcumin.
