Description
The peroxisome proliferator-
activated receptor-
γ (PPARγ) is the nuclear receptor responsible for transducing the therapeutic activity of the thiazolidinediones (TZDs). TZDs are a group of structurally related synthetic PPARγ receptor agonists with antidiabetic actions
in vivo. There are many PPARγ agonists, including 15-
deoxy-
Δ
12,14-
prostaglandin J
2 and azelaoyl PAF, which are naturally derived. However, only a few antagonists have been reported. T0070907 is a potent and selective antagonist of the human PPARγ with an apparent IC
50 of 1 nM for the binding inhibition of rosiglitazone, a reference TZD. T0070907 covalently binds to Cys
313 of PPARγ, inducing conformational changes that block the recruitment of transcriptional cofactors to the PPARγ/RXR heterodimer.
Chemical Properties
Off-White Solid
Uses
A cell-permeable chloro-nitro-benzamido compound that acts as a potent, specific, irreversible, and high-affinity antagonist of PPAR with a Ki of 1 nM. Displays >800-fold greater selectivity for PPAR over PPARa and PPARd (Ki = 0.85 and 1.8 ,
Uses
T0070907 has been used to reduce peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in lipopolysaccharide (LPS)-induced leukemia RAW264.7 cell line. It also has been used to evaluate the involvement of wogonin in alleviating EtOH (ethanol)-induced inflammation in RAW264.7 cell line.
Definition
ChEBI: 2-chloro-5-nitro-N-pyridin-4-ylbenzamide is a carbonyl compound and an organohalogen compound.
General Description
T0070907 has antimicrotubule, antitumor and radiosensitizing properties. It decreases tubulin protein levels, which is associated with cell cycle arrest, apoptosis and also reduces metastasis of colorectal carcinoma cells. T0070907 is used as a therapeutic target in breast cancer. It stimulates proteasome-dependent degradation of tubulin.
Biological Activity
Potent and selective PPAR γ antagonist (IC 50 = 1 nM). Displays > 800-fold selectivity for PPAR γ over PPAR α and PPAR δ . In vitro, blocks transcriptional activity of PPAR γ and inhibits rosiglitazone-induced adipogenesis.
Biochem/physiol Actions
T0070907 is very similar in structure and activity to the PPAR-γ antagonist GW9662. T0070907 is more potent and has higher selectivity for PPAR-γ over all other subtypes (about 800-fold) whereas GW9662 has been reported to have some PPAR-α agonist activity.
Synthesis
GENERAL STEPS: To a solution of 2-chloro-5-nitrobenzoic acid (0.500 g, 2.48 mmol) in dichloromethane (8.3 mL) was slowly added oxalyl chloride (0.239 mL, 2.73 mmol), followed by the addition of N,N-dimethylformamide (1 drop) as a catalyst. The reaction mixture was stirred at room temperature for 2 hours to complete the generation of the acyl chloride. Subsequently, triethylamine (0.691 mL, 4.96 mmol) was added to the reaction system as a base, followed by the slow addition of a dichloromethane (1 mL) solution of pyridin-4-amine (0.467 g, 4.96 mmol). The reaction mixture was continued to be stirred at room temperature for 16 h to ensure complete amidation reaction. Upon completion of the reaction, purification was carried out by fast column chromatography using 0-100% ethyl acetate/hexane gradient elution to afford the target compound 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide as a brown solid (0.401 g, 58% yield). The structure of the product was analyzed by 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.64-8.45 (m, 3H), 8.37 (dd, J = 8.9, 2.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.73-7.61 (m, 2H); 13C NMR (101 MHz, DMSO-d6) δ 163.67, 150.56, 146.14, 145.04, 136.95, 131.40, 126.06, 124.00, 113.68; ESI-MS m/z 278 ([M + H]+) confirmed.
References
[1] lee g, elwood f, mcnally j, weiszmann j, lindstrom m, amaral k, nakamura m, miao s, cao p, learned rm, chen jl, li y. t0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities. j biol chem. 2002 may 31;277(22):19649-57.
