Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors

Hiren Patel; Irina Chuckowree; Peter Coxhead; Matthew Guille; Minghua Wang; Alexandra Zuckermann; Robin S. B. Williams; Mariangela Librizzi; Ronald M. Paranal; James E. Bradner; John Spencer

doi:10.1039/C4MD00211C

Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors†

Hiren Patel,^a Irina Chuckowree,^ab Peter Coxhead,^c Matthew Guille,^c Minghua Wang,^d Alexandra Zuckermann,^e Robin S. B. Williams,^e Mariangela Librizzi,^f Ronald M. Paranal,^g James E. Bradner^g and John Spencer*^ab

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* Corresponding authors

^a School of Science at Medway, University of Greenwich, Chatham, UK

^b Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, UK
E-mail: j.spencer@sussex.ac.uk

^c School of Biological Sciences, University of Portsmouth, King Henry Building, Portsmouth, UK

^d Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada

^e Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, UK

^f Dipartimento STEBICEF, Università di Palermo, Edificio 16, Viale delle Scienze, 90128 Palermo, Italy

^g Dana-Farber Cancer Institute, 44 Binney Street, Dana Building, Boston, MA 02115, USA

Abstract

Fragments based on the VEGFR2i Semaxanib (SU5416, (vascular endothelial growth factor receptor-2 inhibitor) and the HDACi (histone deacetylase inhibitor) SAHA (suberanilohydroxamic acid) have been merged to form a range of low molecular weight dual action hybrids. Vindication of this approach is provided by SAR, docking studies, in vitro cancer cell line and biochemical enzyme inhibition data as well as in vivo Xenopus data for the lead molecule (Z)-N1-(3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-5-yl)-N8-hydroxyoctanediamide 6.

MedChemComm

Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors†

Abstract

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Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors

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