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

Autor: Winfield HJ; School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Western Road, Cork, Ireland., Cahill MM; School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Western Road, Cork, Ireland., O'Shea KD; School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Western Road, Cork, Ireland., Pierce LT; School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Western Road, Cork, Ireland., Robert T; Sorbonne Universités, UPMC Univ Paris 06, CNRS USR3151, Kinase Inhibitor Specialized Screening facility, KISSf, Station Biologique, Place Georges Teissier, Roscoff, France., Ruchaud S; Sorbonne Universités, UPMC Univ Paris 06, CNRS USR3151, Kinase Inhibitor Specialized Screening facility, KISSf, Station Biologique, Place Georges Teissier, Roscoff, France., Bach S; Sorbonne Universités, UPMC Univ Paris 06, CNRS USR3151, Kinase Inhibitor Specialized Screening facility, KISSf, Station Biologique, Place Georges Teissier, Roscoff, France., Marchand P; Département de Chimie Thérapeutique, EA1155 - IICiMed, Université de Nantes, Institut de Recherche en Santé 2, Nantes, France., McCarthy FO; School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Western Road, Cork, Ireland. Electronic address: f.mccarthy@ucc.ie.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Aug 07; Vol. 26 (14), pp. 4209-4224. Date of Electronic Publication: 2018 Jul 09.
DOI: 10.1016/j.bmc.2018.07.012
Abstrakt: 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.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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