ABSTRACT
We previously reported the discovery of BRD0476 (1), a small molecule generated by diversity-oriented synthesis that suppresses cytokine-induced ß-cell apoptosis. Herein, we report the synthesis and biological evaluation of 1 and analogues with improved aqueous solubility. By replacing naphthyl with quinoline moieties, we prepared active analogues with up to a 1400-fold increase in solubility from 1. In addition, we demonstrated that 1 and analogues inhibit STAT1 signal transduction induced by IFN-γ.
Subject(s)
Cytokines/antagonists & inhibitors , Insulin-Secreting Cells/drug effects , STAT1 Transcription Factor/antagonists & inhibitors , Signal Transduction/drug effects , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Apoptosis/drug effects , Blotting, Western , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line , Chemistry, Pharmaceutical , Cytokines/physiology , Humans , Indicators and Reagents , Interferon-gamma/pharmacology , Phosphorylation , Solubility , Structure-Activity Relationship , Thermodynamics , Urea/analogs & derivatives , Urea/chemistry , Urea/pharmacologyABSTRACT
Cytokine-induced beta-cell apoptosis is important to the etiology of type-1 diabetes. Although previous reports have shown that general inhibitors of histone deacetylase (HDAC) activity, such as suberoylanilide hydroxamic acid and trichostatin A, can partially prevent beta-cell death, they do not fully restore beta-cell function. To understand HDAC isoform selectivity in beta cells, we measured the cellular effects of 11 structurally diverse HDAC inhibitors on cytokine-induced apoptosis in the rat INS-1E cell line. All 11 compounds restored ATP levels and reduced nitrite secretion. However, caspase-3 activity was reduced only by MS-275 and CI-994, both of which target HDAC1, 2, and 3. Importantly, both MS-275 and genetic knockdown of Hdac3 alone were sufficient to restore glucose-stimulated insulin secretion in the presence of cytokines. These results suggest that HDAC3-selective inhibitors may be effective in preventing cytokine-induced beta-cell apoptosis.
