Specific Inhibitors of Tyrosine-Specific Protein Kinase. I. Synthesis and Inhibitory Activities of a-Cyanocinnamamides

Abstract

A series of α-cyanocinnamamide derivatives was synthesized and evaluated for inhibitory activity against tyrosine-specific protein kinase using intact plasma membrane fractions from an epidermoid carcinoma cell line, A-431 cells. Among these compounds, several novel α-cyano-4-hydroxy-3,5-disubstituted cinnamamide derivatives, e.g., α-cyano-3-ethoxy-4-hydroxy-5-phenyl-thiomethylcinnamamide (ST 638), showed potent inhibitory activity. The studies on the structure-activity relationship revealed that the presence of the hydroxy group at the 4 position and the double bond in the oc-cyano-4-hydroxycinnamamide skeleton was important for potent inhibitory activity, and that the presence of hydrophobic groups at the 3 and 5 positions on the benzene ring also enhanced the inhibitory activity of α-cyano-4-hydroxycinnamamide derivatives. © 1988, The Pharmaceutical Society of Japan. All rights reserved.