Send to

Choose Destination
J Med Chem. 2017 Jul 13;60(13):5493-5506. doi: 10.1021/acs.jmedchem.7b00197. Epub 2017 Jun 16.

Design, Multicomponent Synthesis, and Anticancer Activity of a Focused Histone Deacetylase (HDAC) Inhibitor Library with Peptoid-Based Cap Groups.

Author information

Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf , Universitätsstraße 1, 40225 Düsseldorf, Germany.
Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen , 9712 Groningen, The Netherlands.
Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM , 1 Rue Laurent Fries, 67404 Illkirch Cedex, France.
Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Leipzig University , Brüderstraße 34, 04103 Leipzig, Germany.


In this work, we report the multicomponent synthesis of a focused histone deacetylase (HDAC) inhibitor library with peptoid-based cap groups and different zinc-binding groups. All synthesized compounds were tested in a cellular HDAC inhibition assay and an MTT assay for cytotoxicity. On the basis of their noteworthy activity in the cellular HDAC assays, four compounds were further screened for their inhibitory activity against recombinant HDAC1-3, HDAC6, and HDAC8. All four compounds showed potent inhibition of HDAC1-3 as well as significant inhibition of HDAC6 with IC50 values in the submicromolar concentration range. Compound 4j, the most potent HDAC inhibitor in the cellular HDAC assay, revealed remarkable chemosensitizing properties and enhanced the cisplatin sensitivity of the cisplatin-resistant head-neck cancer cell line Cal27CisR by almost 7-fold. Furthermore, 4j almost completely reversed the cisplatin resistance in Cal27CisR. This effect is related to a synergistic induction of apoptosis as seen in the combination of 4j with cisplatin.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center