Proteasome inhibition and cytostatic effects on human cancer cells by pyrazolone-enamines: a combined crystallographic, structural and computational study?

New Journal of Chemistry Pub Date: 2015-01-05 DOI: 10.1039/C4NJ01906G

Abstract

Nine compounds were designed and synthesized by the condensation reaction of the carbonyl in 4-benzoyl-3-methyl-1-phenyl-2-pyrazolin-5-one (HPMBP) with the amino groups in 5-aminoisophthalic acid, 4,4′-diaminodiphenylmethane, 4-aminophenylacetic acid, 4-aminobenzamide, 2-amino-4-methylphenol, 5-amino-2-methylphenol, 2-aminophenol, 3-aminophenol and 4-aminophenol. They were then characterized by IR, 1H NMR, elemental analysis, and X-ray crystallography, which suggested that all of them exist as the pyrazolone-enamine forms in the solid state and in a DMSO solution through tautomeric reactions. The nine compounds (compounds 1–9) were evaluated for their ability to inhibit the proliferation of human liver cancer HepG2 cells. Compounds 5, 6, 7 and 8 demonstrated a strong inhibitory effect on the proliferation of HepG2 cells. The nine compounds can also inhibit the activity of the human cancer cellular 20S proteasome. Further studies on compound 6 as the representative indicate that it can cause the accumulation of ubiquitinated proteins and the proteasome target proteins Bax and p27, and exhibit a cytostatic effect in HepG2 cells in a concentration-dependent and time-dependent manner. The four potential tautomers of compound 6 were optimized and their single point energies were calculated by the density functional theory (DFT) B3LYP method based on the polarized continuum model (PCM) in water to identify the most likely tautomer existing in cancer cells. Based on the optimized structure of the most stable tautomer in water, the Wiberg bond orders, molecular electrostatic potential (MEP) maps and frontier molecular orbital were calculated. As compounds 5, 6, 7 and 8 have hydroxyl in the ortho-position or meta-position, our study can provide some information to study their anticancer mechanism and the substitution effect of different functional groups.

Graphical abstract: Proteasome inhibition and cytostatic effects on human cancer cells by pyrazolone-enamines: a combined crystallographic, structural and computational study
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