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.

• Authors: Martyn Inman, Andrea Visconti, Chao Yan, David Siegel, David Ross, Christopher J Moody
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 12 Issue 27 Pg. 4848-61 (Jul 21 2014) ISSN: 1477-0539 [Electronic] England
• PMID: 24848343 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indolequinones

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Humans
• Indolequinones (chemical synthesis, pharmacology)
• Pancreatic Neoplasms (drug therapy)