| Description | AK-7 is a brain-permeable SIRT2 inhibitor and to characterize its cholesterol-reducing properties in neuronal models with an IC50 of 15.5 μM. |
| In vitro | AK-7 is a selective cell- and brain-permeable SIRT2 inhibitor,this SIRT2 inhibitor stimulated cytoplasmic retention of sterol regulatory element binding protein-2 and subsequent transcriptional downregulation of cholesterol biosynthesis genes, resulting in reduced total cholesterol in primary striatal neurons. Furthermore, the identified inhibitor reduced cholesterol in cultured na?ve neuronal cells and brain slices from wild-type mice[1].AK-7 has roles in metabolic diseases, cancer, age-related disorders, and neurodegenerative diseases, potentially including Alzheimer's, Huntington's, and Parkinson's diseases[2][3]. |
| In vivo | AK-7 (15 mg/kg/dose, i.p.) is brain-permeable in wild-type and HD mice[1]. |
| Cell experiments | Neuronal nuclear antigen (NeuN)-positive neurons and some astroglia were derived from mechanically dissociated ganglionic eminences of E16 rat embryos. The HD model based on the expression of mutant huntingtin has been described previously. Treatments of cultures with AK-7 were at 10 μM for 24 h unless stated otherwise. DMSO was included at the same concentrations as a control. Lower dose, chronic treatments with AK-7 were introduced to neurons at DIV4 and continued weekly coinciding with normal medium change [1]. |
| Animal experiments | AK-7, solubilized at 1.5 mg/mL in 25% Cremophor EL (BASF)/ 10% DMSO in water, was administered by intraperitoneal injection to 11 week old mice at 15 mg/kg/dose. Blood was collected and centrifuged at 7,000 rpm for 7 min, and then serum was aspirated and immediately frozen in liquid nitrogen. Brains were immediately frozen in liquid nitrogen and stored at -80 C. Brains were weighed and then homogenized in four volumes of 10% Cremophor RH40 in water using homogenizer, and 2% v/v phosphoric acid was added to the homogenate, vortexed, and centrifuged at 10,000g at 25 C for 1 h. The supernatant was aspirated, and solid phase extraction was performed immediately. Serum samples were vortexed into 2% v/v phosphoric acid and centrifuged at 2500 rpm for 10 min[1] |
| Target activity | SIRT2:15.5 μM |
| molecular weight | 437.35 |
| Molecular formula | C19H21BrN2O3S |
| CAS | 420831-40-9 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year |
| Solubility | DMSO: 50 mg/mL (114.32 mM) |
| References | 1. Taylor DM, et al. A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase. ACS Chem Biol. 2011 Jun 17;6(6):540-6. 2. Machado D O R , Jana S , Kazantsev A G , et al. SIRT2 as a Therapeutic Target for Age-Related Disorders[J]. Frontiers in Pharmacology, 2012, 3. 3. Fridén-Saxin, Maria, Seifert T , Landergren, Marie Rydén, et al. Synthesis and Evaluation of Substituted Chroman-4-one and Chromone Derivatives as Sirtuin 2-Selective Inhibitors[J]. Journal of Medicinal Chemistry, 2012, 55(16):7104-7113. |