Synthesis and Structure-Activity Relationships of 1-Benzyl-4,5,6-trimethoxyindoles as a Novel Class of Potent Antimitotic Agents

A series of 1-benzyl-4,5,6-trimethoxyindoles was designed and prepared as a novel class of potent antimitotic agents acting through the colchicine binding site of tubulin. Compounds 10 and 11 showed excellent antiproliferative activity with mean IC50 values of 26 and 27 nM, respectively, in a diverse set of human cancer lines from different organs, including a MDR+ line. They also displayed substantial antitubulin efficacy with IC50 values of 3.5 and 2.6 mu M, respectively, representing an improvement over colchicine (IC50=4.3 mu M).