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J Med Chem. 2015 Sep 10;58(17):6803-18. doi: 10.1021/acs.jmedchem.5b00545. Epub 2015 Aug 27.

Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding Unit.

Author information

1
Department of Chemistry, University College London , Christopher Ingold Laboratories, 20 Gordon Street, London WC1H OAJ, U.K.
2
Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
3
Department of Haematological Medicine, Leukaemia Sciences Laboratories, Rayne Institute, King's College London , 123 Coldharbour Lane, London SE5 9NU, U.K.

Abstract

A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines.

PMID:
26287310
DOI:
10.1021/acs.jmedchem.5b00545
[Indexed for MEDLINE]
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