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J Med Chem. 2017 Jul 13;60(13):5334-5348. doi: 10.1021/acs.jmedchem.6b01538. Epub 2017 Jun 19.

Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines.

Author information

1
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf , Universitätsstraße 1, 40225 Düsseldorf, Germany.
2
Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Leipzig University , Brüderstraße 34, 04103 Leipzig, Germany.
3
Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg , Albertstraße 25, 79104 Freiburg, Germany.
4
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University , Moorenstraße 5, 40225 Düsseldorf, Germany.
5
Department of Neuropathology, Medical Faculty, Heinrich-Heine-University , Moorenstraße 5, 40225 Düsseldorf, Germany.
6
Division of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Moorenstraße 5, 40225 Düsseldorf, Germany.
7
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.

Abstract

The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1g-i showed IC50 values in the low μM and sub-μM range. 1g-i revealed low nM IC50 values for HDAC6 with up to 15-fold preference over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of 1g-i significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1g-i interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR.

PMID:
28581289
DOI:
10.1021/acs.jmedchem.6b01538
[Indexed for MEDLINE]

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