49843-98-3 Usage
Description
6-CHLORO-2,3,4,9-TETRAHYDRO-1H-CARBAZOLE-1-CARBOXAMIDE, also known as EX-527, is a cell-permeable indole compound that acts as a potent and highly selective inhibitor of SIRT1 (sirtuin 1) with an IC50 of 98 nM. It is more selective for SIRT1 than for SIRT2 or SIRT3 (200-500 fold) and has been shown to be a potent SIRT6 inhibitor as well. EX-527 does not inhibit class I/II HDAC activity at concentrations up to 100 μM and has been demonstrated to be orally bioavailable with a serum half-life of 136 minutes in mice in vivo.
Uses
Used in Pharmaceutical Research:
6-CHLORO-2,3,4,9-TETRAHYDRO-1H-CARBAZOLE-1-CARBOXAMIDE is used as a selective SIRT1 inhibitor for studying the role of sirtuins in various cellular processes and diseases. Its high selectivity and potency make it a valuable tool in understanding the molecular mechanisms underlying sirtuin function.
Used in Cancer Research:
In the field of oncology, 6-CHLORO-2,3,4,9-TETRAHYDRO-1H-CARBAZOLE-1-CARBOXAMIDE is used as an inhibitor of sirtuin 1 to study its effects on mitochondrial ATP production in human cancer cell lines such as MCF-7 (Michigan Cancer Foundation-7) and HCT116 (colon cancer cell line). It has been shown to enhance p53 acetylation in response to DNA damaging agents, which may have implications for cancer treatment.
Used in Neurological Research:
In the field of neurology, 6-CHLORO-2,3,4,9-TETRAHYDRO-1H-CARBAZOLE-1-CARBOXAMIDE is used as a tool to study the role of sirtuin 1 in epileptogenesis. It has been administered intracerebroventricularly in rat models to assess kainic acid-induced status epilepticus and its effect on sirtuin 1 activity.
Used in Preclinical Studies:
6-CHLORO-2,3,4,9-TETRAHYDRO-1H-CARBAZOLE-1-CARBOXAMIDE is used in preclinical studies to evaluate its potential therapeutic effects on various conditions, such as intestinal morphological changes and crypt cell apoptosis in C57BL/6 N mice treated with 1% dimethyl sulfoxide, 30% polyethylene glycol-400, and 1% Tween 80.
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.