49843-98-3 Usage
Description
EX-527 (49843-98-3) is a selective SIRT1 inhibitor (IC50=98 nM). Does not inhibit other HDACs or SIRT family members. Increases p53 acetylation following DNA damage. Cell permeable.
Uses
Different sources of media describe the Uses of 49843-98-3 differently. You can refer to the following data:
1. EX-527 has been used:in 1% dimethyl sulfoxide, 30%, polyethylene glycol-400 and 1% Tween 80 for treating C57BL/6 N mice to study its effect on intestinal morphological changes and crypt cell apoptosisas a an inhibitor of sirtuin 1, in treating human cancer lines MCF-7 (Michigan cancer foundation-7) and HCT116 (colon cancer cell line) incubated in Dulbecco′s modified Eagle′s medium, to study its effect on mitochondrial ATP (adenosine triphosphate) productionIntracerebroventricularly infused in rat model of epileptogenesis, to access kainic acid–induced status epilepticus stimulated sirtuin 1 activity
2. A selective inhibitor of SIRT1 over SIRT2 and SIRT3
3. EX-527 is a potent and selective sirtuin 1 (SIRT1) inhibitor (IC50 38 nM) identified from a high throughput screen. EX-527 is more selective (200-500-fold) for SIRT1 than for SIRT2 or SIRT3 and has been shown to be a potent SIRT6 inhibitor using H3K56 deacetylation site based substrate. EX-527 does not inhibit class I/II HDAC activity at concentrations up to 100uM. Enhances p53 acetylation in response to DNA damaging agents. EX-527 is racemic; the active isomer (EX-243) gives similar results and potency whereas the other isomer (designated EX-242) is inactive.
General Description
A cell-permeable indole compound that acts as a potent and highly selective inhibitor of SIRT1 (IC50 = 98 nM). It inhibits other sirtuin family deacetylases only at much higher concentrations (IC50 = 19.6 and 48.7 μM for SIRT2 and SIRT3, respectively) and shows no inhibitory effect against class I and II HDACs or NAD glycohydrolase even at concentrations as high as 100 μM. Shown to be orally bioavailable with a serum half-life of 136 minutes in mice in vivo.
Biological Activity
Selective inhibitor of SIRT1 that does not inhibit histone deacetylase (HDAC) or other sirtuin deacetylase family members (IC 50 values are 98, 19600, 48700, > 100000 and > 100000 nM for SIRT1, SIRT2, SIRT3, HDAC and NADase respectively). Enhances p53 acetylation in response to DNA damaging agents.
Biochem/physiol Actions
Primary TargetSIRT1
References
1) Napper et al. (2005), Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1; J. Med. Chem., 48 8045
2) Solomon et al. (2006) Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage; Mol. Cell, 26 28
3) Gertz et al. (2013) EX-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism; Proc. Natl. Acad. Sci. USA, 110 e2772
Check Digit Verification of cas no
The CAS Registry Mumber 49843-98-3 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 4,9,8,4 and 3 respectively; the second part has 2 digits, 9 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 49843-98:
(7*4)+(6*9)+(5*8)+(4*4)+(3*3)+(2*9)+(1*8)=173
173 % 10 = 3
So 49843-98-3 is a valid CAS Registry Number.
49843-98-3Relevant articles and documents
Tetrahydrocarbazole Inhibitors Of SIRT1 Receptors
-
, (2017/08/01)
Described are deuterium-substituted tetrahydrocarbazole compounds of Formulae I, II, or III which are inhibitors of sirtuin 1 (SIRT1). Also described are pharmaceutical compositions comprising the deuterium-substituted tetrahydrocarbazole compounds, and methods of use thereof.
Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1
Napper, Andrew D.,Hixon, Jeffrey,McDonagh, Thomas,Keavey, Kenneth,Pons, Jean-Francois,Barker, Jonathan,Yau, Wei Tsung,Amouzegh, Patricia,Flegg, Adam,Hamelin, Estelle,Thomas, Russell J.,Kates, Michael,Jones, Stephen,Navia, Manuel A.,Saunders, Jeffrey O.,DiStefano, Peter S.,Curtis, Rory
, p. 8045 - 8054 (2007/10/03)
High-throughput screening against the human sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.
