Indole Derivatives as Src Family Kinase and Glutathione S-Transferase Inhibitors: Evaluation of Their Selectivity and Drug Resistance Properties;

Abstract

The increased activity levels of Glutathione S-transferases (GST) have been correlated with human cancers and the anticancer drug resistance. Similarly, Src family kinases (SFKs), has been reported in many cancers including breast, colon, lung, and skin with relatively high catalytic activity. Therefore, the inhibition of both GSTs and Src may enhance the therapeutic efficacy of chemotherapeutics by increasing the selectivity and resistance of compounds. The recent efforts of our laboratory to design and synthesize novel c-Src inhibitors were accomplished with four indole-3-amine derivatives substituted at N1 and C5 (8c, 8f 8g, and 8h), with IC 50s values of 4.69, 74.79, 75.06, and 84.23 μM, respectively. In this present work, the inhibitory activities against SFKs (Lyn, Hck, Fyn), GSTs and selectivity studies of these compounds were performed. Among the compounds, 8c and 8g are found the best GST inhibitors with IC 50s values of 120.1, and 67.33 μM, respectively, and are reported as the Src inhibitors with dual action. The compounds 8f and 8h are also showed reasonable inhibitory levels of GSTs with IC 50s of 161.1, and 272.2 μM, However inhibition profiles of compounds are not found suitable for further developments.