Issue 27, 2014

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 pKa 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.

Graphical abstract: Antitumour indolequinones: synthesis and activity against human pancreatic cancer cells

Supplementary files

Article information

Article type
Paper
Submitted
03 Apr 2014
Accepted
13 May 2014
First published
13 May 2014

Org. Biomol. Chem., 2014,12, 4848-4861

Antitumour indolequinones: synthesis and activity against human pancreatic cancer cells

M. Inman, A. Visconti, C. Yan, D. Siegel, D. Ross and C. J. Moody, Org. Biomol. Chem., 2014, 12, 4848 DOI: 10.1039/C4OB00711E

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