Inhibition of glutathione S-transferases by calix[4]arene-based phosphinic acids

Abstract

Calix[4]arene-, thiacalix[4]arene- and sulfonylcalix[4]arene-based derivatives with upper rim phosphinic acid groups were studied as inhibitors of glutathione S-transferases. It was found that the macrocyclic compounds can exhibit good to potent activity against GST from equine liver and human recombinant GSTA1-1, while being selective over the enzyme from human placenta and GSTP1-1. The thiacalix[4]arene phosphinic acid was the most active inhibitor of equine liver GST and GSTA1-1 with IC50 values of 85 nM and 50 nM, respectively. Kinetic studies revealed that the inhibition was of non-competitive type concerning both enzyme substrates, glutathione, and 1-chloro-2,4-dinitrobenzene. Molecular docking was carried out to predict possible binding sites for thiacalix[4]arene-based phosphinic acid on the surface of homodimeric GSTA1-1