کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1360787 | 981448 | 2009 | 8 صفحه PDF | دانلود رایگان |
High-throughput screening led to the identification of isothiazolones 1 and 2 as inhibitors of histone acetyltransferase (HAT) with IC50s of 3 μM and 5 μM, respectively. Analogues of these hit compounds with variations of the N-phenyl group, and with variety of substituents at C-4, C-5 of the thiazolone ring, were prepared and assayed for inhibition of the HAT enzyme PCAF. Potency is modestly favoured when the N-aryl group is electron deficient (4-pyridyl derivative 10 has IC50 = 1.5 μM); alkyl substitution at C-4 has little effect, whilst similar substitution at C-5 causes a significant drop in potency. The ring–fused compound 38 has activity (IC50 = 6.1 μM) to encourage further exploration of this bicyclic structure. The foregoing SAR is consistent with an inhibitory mechanism involving cleavage of the S–N bond of the isothiazolone ring by a catalytically important thiol residue.
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Journal: Bioorganic & Medicinal Chemistry - Volume 17, Issue 2, 15 January 2009, Pages 467–474