Synthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 kinase inhibition

Hannah J Winfield; Michael M Cahill; Kevin D O'Shea; Larry T Pierce; Thomas Robert; Sandrine Ruchaud; Stéphane Bach; Pascal Marchand; Florence O McCarthy

doi:10.1016/j.bmc.2018.07.012

Synthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 kinase inhibition

Bioorg Med Chem. 2018 Aug 7;26(14):4209-4224. doi: 10.1016/j.bmc.2018.07.012. Epub 2018 Jul 9.

Authors

Hannah J Winfield¹, Michael M Cahill¹, Kevin D O'Shea¹, Larry T Pierce¹, Thomas Robert², Sandrine Ruchaud², Stéphane Bach², Pascal Marchand³, Florence O McCarthy⁴

Affiliations

¹ School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Western Road, Cork, Ireland.
² Sorbonne Universités, UPMC Univ Paris 06, CNRS USR3151, Kinase Inhibitor Specialized Screening facility, KISSf, Station Biologique, Place Georges Teissier, Roscoff, France.
³ Département de Chimie Thérapeutique, EA1155 - IICiMed, Université de Nantes, Institut de Recherche en Santé 2, Nantes, France.
⁴ School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Western Road, Cork, Ireland. Electronic address: f.mccarthy@ucc.ie.

PMID: 30026041
DOI: 10.1016/j.bmc.2018.07.012

Abstract

Synthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases. Subsequently, the anticancer activity of bisindolylmaleimides were assessed using the NCI-60 cell screen, disclosing the discovery of growth inhibitory profiles towards a number of cell lines, such as SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. The potential for selective kinase inhibition by modulation of this template is evident and will inform future selective clinical candidates.

Keywords: Bisindolylmaleimide; Drug discovery; Kinase screening; Maleimide substitution; NCI anticancer screen.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
Humans
Maleimides / chemical synthesis
Maleimides / chemistry
Maleimides / pharmacology*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Maleimides
Protein Kinase Inhibitors
maleimide
Glycogen Synthase Kinase 3