Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives

Abstract An efficient and versatile synthesis of 5- N -acetylardeemin ( 1a ) and sixteen 2-, 3- and 13-substituted derivatives 1b – q was achieved through Ugi three-component reaction of 3,3a,8,8a-tetrahydropyrrolo[2,3- b ]indole and cyclization/epimerization. Their inhibitory activity on the drug efflux of breast cancer resistance protein (ABCG2) was evaluated by flow cytometric analysis of accumulation of Hoechst 33342 stain in Flp-In-293/ABCG2 cells. Most of the derivatives exhibited a stronger ABCG2 inhibitory effect compared with natural product 1a . The derivative 1m with a 4-tolyl substituent at the C-13 position exhibited the most potent ABCG2 inhibition. This preliminary structure–activity relationship study indicates that an electron-rich aryl moiety as the 13-substituent is key to increasing the inhibitory activity.