The instability of polyhydroxylated aromatic protein tyrosine kinase inhibitors in the presence of manganese.

Abstract

Inhibition of the tyrosine kinase activity of Src by forty-three different compounds from five chemical families (cinnamic acid, salicylic acid, phenol, coumarin and flavonoid derivatives) representing plant and microbial secondary metabolites were studied in the presence of MgCl2 versus MnCl2. Within each chemical family, compounds containing multiple hydroxyl substituents demonstrated the greatest inhibitor potency. The ortho-substituted dihydroxy compounds were the most inhibitory. Except for the flavonoids, inhibition was higher in the presence of manganese compared to that observed with magnesium. UV-Vis spectra, HPLC, and mass spectrometric analyses demonstrate that manganese catalyzed the oxidation of these compounds. The general instability of such compounds, especially in the presence of manganese, and the associated problems it causes in the use of such compounds for developing selective protein tyrosine kinase inhibitors, is discussed.