Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding Unit.
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.
Department of Chemistry, University College London , Christopher Ingold Laboratories, 20 Gordon Street, London WC1H OAJ, U.K.
Charles M
CM
Marson
Department of Chemistry, University College London , Christopher Ingold Laboratories, 20 Gordon Street, London WC1H OAJ, U.K.
Christopher J
CJ
Matthews
Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
Stephen J
SJ
Atkinson
Department of Haematological Medicine, Leukaemia Sciences Laboratories, Rayne Institute, King's College London , 123 Coldharbour Lane, London SE5 9NU, U.K.
Nermina
N
Lamadema
Department of Haematological Medicine, Leukaemia Sciences Laboratories, Rayne Institute, King's College London , 123 Coldharbour Lane, London SE5 9NU, U.K.
N Shaun B
NS
Thomas
D000107:Acetylation; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D048288:Imidazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010539:Permeability; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D012709:Serum Albumin / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099186:Histone Deacetylase 3
D000813:Anilides; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D048288:Imidazolines; D007527:Isoenzymes; D010080:Oxazoles; D011743:Pyrimidines; D012709:Serum Albumin; D000099186:Histone Deacetylase 3; C000603346:N-(2-aminophenyl)-4-(((4,5-diphenyl-4,5-dihydrooxazol-2-yl)amino)methyl)benzamide; C523184:mocetinostat