title: Reactivity of isothiazolones and isothiazolone-1-oxides in the inhibition of the PCAF histone acetyltransferase.
abstract: Development of small molecule inhibitors of the histone acetyltransferase p300/CBP associated factor (PCAF) is relevant for oncology. The inhibition of the enzyme PCAF and proliferation of the cancer cell line HEP G2 by a series of 5-chloroisothiazolones was compared to a series of 5-chloroisothiazolone-1-oxides. The PCAF inhibitory potency of 5-chloroisothiazolones and 5-chloroisothiazolone-1-oxides is influenced by substitution in the 4-position. A study on the reactivity of the HAT inhibitors towards thiols and thiolates indicates that 5-chloroisothiazolones reacted quickly with propane-1-thiolate to provide many products, whereas 5-chloroisothiazolone-1-oxides provide only one defined product. Growth inhibition studies indicate that 5-chloroisothiazolones inhibit proliferation of HEP G2 cells at concentrations between 8.6 and 24 microM, whereas 5-chloroisothiazolone-1-oxides required higher concentrations or showed no inhibition.
authors.affiliation: Department of Pharmaceutical Gene Modulation, Faculty of Mathematics and Natural Sciences, University of Groningen, Anthonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ghizzoni
authors.forename: Hidde J
authors.initials: HJ
authors.lastname: Haisma
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Dekker
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010087:Oxides / Q000138:chemical synthesis / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors*; D000099224:p300-CBP-Associated Factor
chemical_list: D004791:Enzyme Inhibitors; D010087:Oxides; D013844:Thiazoles; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C001490:3-isothiazolone