tenovin-1 and tenovin-6

Introduction of hydrophilic groups can improve the solubility of leading drugs but inevitably affect their interaction with proteins. This study selected sirtuin inhibitors Tenovin-1 (T1) and Tenovin-6 (T6) as drug models to determine differences in binding mode to human serum albumin (HSA). T1 and T6 quenched the endogenous fluorescence of HSA via static quenching mechanism. Introduction of hydrophilic groups greatly reduced the binding constant, i.e., from 1.302 × 10

Topics: Acetanilides; Benzamides; Binding Sites; Circular Dichroism; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Docking Simulation; Pharmaceutical Preparations; Protein Binding; Serum Albumin, Human; Sirtuins; Spectrometry, Fluorescence; Thermodynamics; Thiourea

The tenovins are small molecule inhibitors of the NAD(+)-dependent family of protein deacetylases known as the sirtuins. There remains considerable interest in inhibitors of this enzyme family due to possible applications in both cancer and neurodegenerative disease therapy. Through the synthesis of novel tenovin analogues, further insights into the structural requirements for activity against the sirtuins in vitro are provided. In addition, the activity of one of the analogues in cells led to an improved understanding of the function of SirT1 in cells.

Topics: Antineoplastic Agents; Benzamides; Histone Deacetylase Inhibitors; Humans; Hydrogen Bonding; MCF-7 Cells; Molecular Conformation; Sirtuins; Structure-Activity Relationship