Antitumour indolequinones: synthesis and activity against human pancreatic cancer cells

Abstract

An important determinant of the growth inhibitory activity of indolequinones against pancreatic cancer cells is substitution on the 2-position with 2-unsubstituted derivatives being markedly more potent. A series of indolequinones bearing a range of substituents on nitrogen and at the indolylcarbinyl position was prepared by copper(II)-mediated reaction of bromoquinones and enamines, followed by functional group interconversions. The compounds were then assayed for their ability to inhibit the growth of pancreatic cancer cells. The pK_a of the leaving group at the 3-position was shown to influence growth inhibitory activity that is consistent with the proposed mechanism of action of reduction, loss of leaving group and formation of a reactive iminium species. Substitutions on the indole nitrogen were well tolerated with little influence on growth inhibitory activity while substitutions at the 5- and 6-positions larger than methoxy led to decreased activity. The studies presented define the range of substitutions of 2-unsubstituted indolequinones required for optimal growth inhibitory activity.