Stereoisomerization of human constitutive androstane receptor agonist CITCO

Abstract CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime) is a widely used agonist of the human constitutive androstane receptor (hCAR), a key hepatic xenobiotic sensor protein with emerging therapeutic indications. To address the insufficient stability of CITCO, which limits its therapeutic potential, the E- and Z-isomers of CITCO were synthesized and characterized by X-ray crystallography, one- and two-dimensional NMR spectroscopy. The two isomers were found to undergo E/Z isomerizations in solution likely via a protonation-rotation mechanism, time- and concentration-dependently. Our molecular modeling studies suggests both stereoisomers can bind to hCAR.