Cycloisomerization of acetylenic oximes and hydrazones under gold catalysis: Synthesis and cytotoxic evaluation of isoxazoles and pyrazoles

Abstract

The synthesis of substituted isoxazoles and pyrazoles through a general cycloisomerization methodology has been reported. The capability of gold(III) chloride to promote cycloisomerization of both α, β-acetylenic oximes and α, β-acetylenic hydrazones is the centrepiece of the strategy. A range of acetylenic precursors were investigated to afford 28 examples of the products with good to excellent chemical yields. Selected compounds were screened for their cytotoxic potential towards COLO320 cancer cell lines. The IC50 values of the tested compounds were in the micromolar range, with the best compound, 5-(6-Methoxy-naphthalen-2-yl)-3-phenyl-isoxazole (3h) displaying an IC50 of 38.9 μM. For this compound, the crystal structure in complex with Aurora-A kinase was obtained which revealed details of its binding mode within the active site with a free energy of binding -9.54 kcal/mol. An integration process for the synthesis of isoxazoles and pyrazoles was achieved by taking advantage of the gold catalyzed cycloisomerization strategy. These compounds show cytotoxic effect against COLO320 cancer cells with IC50 values ranging between 38.9 and 55.9 μM.