89464-63-1 Usage
Description
DMOG, also known as Dimethyloxalylglycine, is a cell permeable prolyl-4-hydroxylase inhibitor that regulates hypoxia-inducible factor (HIF). It acts as a competitive inhibitor of HIF-PH, stabilizing HIF-1α expression at normal oxygen tensions in cultured cells. DMOG is a pro-angiogenic compound that works through the HIF-1α system and is characterized by its off-white to pale pink solid appearance.
Uses
Used in Angiogenesis Research:
DMOG is used as a pro-angiogenic compound for stimulating angiogenesis in various models due to its ability to activate HIF, which in turn promotes the formation of new blood vessels.
Used in Hypoxia Signaling Pathway Studies:
In the field of cellular and molecular biology, DMOG is utilized as a research tool to investigate the hypoxia signaling pathway by inhibiting HIF-PH and stabilizing HIF-1α.
Used in Cardiovascular Research:
DMOG is used as a therapeutic agent for attenuating myocardial injury in ischemia reperfusion models, demonstrating its potential in treating cardiovascular conditions.
Used in Drug Development:
In the pharmaceutical industry, DMOG serves as a lead compound for the development of new drugs targeting the HIF pathway, which has implications for treating various diseases, including anemia, cancer, and ischemic disorders.
Biochem/physiol Actions
DMOG is a cell permeable prolyl-4-hydroxylase inhibitor, which upregulates HIF (hypoxia-inducible factor). The protein level of HIF-1α subunit is post-transcriptionally regulated by prolyl and asparaginyl hydroxylase (PAH). Suppression of PAH activity increases endogenous HIF-1α levels. DMOG is a cell permeable, competitive inhibitor of prolyl hydroxylase domain-containing proteins (PHDs and HIF-PHs). It has been discovered that the DMOG posseses neuroprotective effect on NFG deprived cell cultures through preservation of glucose metabolism. DMOG also attenuates myocardial injury in a rabbit ischemia reperfusion model. DMOG is more potent than the older inhibitor 4-Phenyl-pyridine-2,5-dicarboxylic acid (R395889; Sigma-Aldrich rare chemicals library). The IC50 is 5.18 μM.
in vitro
dmog acts to stabilize hif-1a expression under normal oxygen tension in cultured cells at concentrations from 0.1 to 1 mmol/l [2].
Enzyme inhibitor
This iron-binding a-ketoglutarate (2-oxoglutarate) analogue (FW = 147.09
g/mol; also named N-oxaloglycine) competitively inhibits prolyl-4-
hydroxylase (Reaction: Procollagen (L-proline) + a-ketoglutarate + O2 →
Procollagen ( (2S,4R) -4-hydroxyproline) + succinate + CO2). During
catalysis, prolyl-4-hydroxylase forms Fe (III), and the latter most likely
makes an extremely stable metal ion complex with N-oxaloglycine.
Substitution on the glycine moiety alters inhibitor activity stereoselectively
and that, if the w-carboxylate is homologated or replaced, either by
acylsulfonamides or anilide, activity is likewise sharply reduced. Prolyl-
4-Hydroxylase Catalysis: Each catalytic round of this posttranslational
modifying enzyme reaction occurs in two stages. O2 is bound end-on in an
axial position, producing a dioxygen unit. Nucleophilic attack at C-2
generates a tetrahedral intermediate, with loss of the double bond in
dioxygen and bonds to iron and the a-carbon of a-ketoglutarate.
Elimination of CO2 coincides with formation of the Fe (IV) =O species. The
second stage involves the abstraction of the pro-R hydrogen atom from C-4
of proline, followed by radical combination, yielding hydroxyproline. In
the presence of a-ketoglutarate, enzyme-bound Fe2+ is rapidly converted to
Fe3+, resulting in inactivation of the enzyme Ascorbate is utilized as a
cofactor to reduce Fe (III) back to Fe (II). Cell-Permeable Analogue:
Dimethyloxalylglycine (FW = 175.14 g/mol; CAS 89464-63-1; Symbol:
DMOG, also named N- (methoxyoxoacetyl) -glycine methyl ester) is
metabolicaly demethylated to form N-oxaloglycine upon entry to many
cells.
in vivo
pre-treatment with dmog attenuates systemic lps-induced activation of the nf-κb pathway. furthermore, mice treated with dmog had significantly increased survival in lps-induced shock. in addition, in vivo dmog treatment upregulates the expression of il-10, specifically in the peritoneal b-1 cell population [3].
IC 50
9.3 and 3.7 μm for hydroxyproline synthesis inhibition of embryonic chicken lung extracted from tissue and culture medium [1].
References
1) Asikainen et al. (2005), Activation of hypoxia-inducible factors in hyperoxia through prolyl 4-hydroxylase blockade in cells and explants of primate lung; Proc. Natl. Acad. Sci. USA, 102 10212
2) Jaakkola et al. (2001), Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation; Science, 292 468
3) Hamada et al. (2009), Synthesis and activity of N-oxalylglycine and it’s derivatives as jumonji C-domain-containing histone lysine demethylase inhibitors; Bioorg. Med. Chem. Lett., 19 2852
4) Lomb et al. (2009), Prolyl hydroxylase inhibitors depend on extracellular glucose and hypoxia-inducible factor (HIF)-2alpha to inhibit cell death caused by nerve growth factor deprivation: evidence that HIF-2alpha has a role in NGF-promoted survival of sympathetic neurons; Mol. Pharmacol., 75 1198
5) Xie et al. (2012), PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response; J. Clin. Invest., 122 2827
Check Digit Verification of cas no
The CAS Registry Mumber 89464-63-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 8,9,4,6 and 4 respectively; the second part has 2 digits, 6 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 89464-63:
(7*8)+(6*9)+(5*4)+(4*6)+(3*4)+(2*6)+(1*3)=181
181 % 10 = 1
So 89464-63-1 is a valid CAS Registry Number.
InChI:InChI=1/C6H9NO5/c1-11-4(8)3-7-5(9)6(10)12-2/h3H2,1-2H3,(H,7,9)
89464-63-1Relevant articles and documents
Triflic anhydride-mediated synthesis of oxazoles
Thalhammer, Armin,Mecinovi?, Jasmin,Schofield, Christopher J.
supporting information; experimental part, p. 1045 - 1047 (2009/05/31)
N-Acyl amino acid esters undergo triflic anhydride-mediated cyclodehydration to form oxazoles and bisoxazoles in a simple one-pot transformation.
Selective inhibition of factor inhibiting hypoxia-inducible factor
McDonough, Michael A.,McNeill, Luke A.,Tilliet, Melanie,Papamicael, Cyril A.,Chen, Qiu-Yun,Banerji, Biswadip,Hewitson, Kirsty S.,Schofield, Christopher J.
, p. 7680 - 7681 (2007/10/03)
A set of four non-heme iron(II) and 2-oxoglutarate-dependent enzymes catalyze the post-translational modification of a transcription factor, hypoxia inducible factor (HIF), that mediates the hypoxic response in animals. Hydroxylation of HIF both causes it
A novel [2 + 3] cycloaddition reaction: Singlet oxygen mediated formation of 1,3-dipole from iminodiacetic acid dimethyl ester and its addition to maleimides
Cheng,Gan,Shi,Wei
, p. 6369 - 6374 (2007/10/03)
Sensitized photolysis of iminodiacetic acid methyl ester and maleimides follows a [2 + 3] cycloaddition pathway yielding pyrrolidine derivatives. This is similar to the photochemical reaction between C60 and amines. A series of pyrrolidine derivatives are prepared by the method including multipyrrolidines from bis- and tris-maleimide starting materials. The yields range from 13% to 85%. The reaction is highly stereoselective. All the isolated products have the 1,3-dimethoxycarbonyl groups in the cis configuration. Various sensitizers may be used with slightly different yields. A plausible mechanism is proposed that involves the singlet oxygen abstraction of two α hydrogen atoms from the iminodiacetate and formation of a 1,3-dipole with a structure similar to the classical thermally generated 1,3-dipole.
