IMD-0354 Chemical Properties

Boiling point:

323.1±42.0 °C(Predicted)

Density 

1.561

storage temp. 

-20°C

solubility 

DMSO (5 mg/ml) or Ethanol (1 mg/ml).

pka

7.61±0.43(Predicted)

form 

White solid

color 

White to off-white

Sensitive 

Light Sensitive

CAS DataBase Reference

978-62-1

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38

Safety Statements 

26-36

WGK Germany 

3

HS Code 

29242990

IMD-0354 Usage And Synthesis

Uses

IMD 0354 is an IKKβ (IKK2) inhibitor that blocks NF-κB phosphorylation (IC50 = ~250 nM) and subsequent NF-κB p65 nuclear translocation. It exhibits cardioprotective properties by decreasing expression of P-selectin and ICAM-1 in the vasculature and blocking cardiomyocyte IL-1β and MCP-1 production, resulting in suppressed neutrophil accumulation in a rat model of ischemia/reperfusion injury. IMD 0354, suppresses the growth of human breast cancer cells by inducing cell cycle arrest and apoptosis. It induces apoptosis of chronic lymphocytic leukemia cells at 1-10 μM by directly targeting the NF-κB pathway, decreasing expression of anti-apoptotic genes and increasing expression of proapoptotic genes.

Uses

IMD-0354 has been used to study the effect of NF-κB (nuclear factor) inhibition on differentially expressed in chondrocytes 2. It has also been used to study the role of NF-κB signaling in tumor necrosis factor-induced certain transcription factors expression using human primary fibroblasts.

Definition

ChEBI: N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide is a member of benzamides.

Biological Activity

Inhibitor of I κ B kinase-2 (IKK-2, IKK- β ) that blocks NF- κ B nuclear translocation. Attenuates myocardial ischemia/reperfusion injury by decreasing expression of adhesion molecules ICAM-1 and P-selectin and inhibiting cytokine and chemokine production in cardiomyocytes. Induces G 0 /G 1 cell cycle arrest and apoptosis in HMC-1? and breast cancer cells.

Biochem/physiol Actions

IMD-0354 acts as an inhibitor by inhibiting the phosphorylation of the NF-κB (nuclear factor) and its translocation into the nucleus. It blocks IκBα phosphorylation (IC50 ~ 250 nM). Cardioprotectant, that reduces IL-1β and MCP-1 production (IC50 < 1 μM) in cardiomyocytes. IMD-0354 affects angiogenesis, which has been observed in human umbilical vein endothelial cells. It prevents tube formation and migration of the cells. In vivo studies also prove that IMD-0354 inhibits retinal vessel growth. IMD-0354 also acts as an inhibitor of Aquaporin 4 (AQP4) inhibitor (IC50 0.2μM) with no inhibitory potency to IKK-β. [4]

Synthesis

Using 5-chlorosalicylic acid (6.90 g, 40 mmol) and m-bis(trifluoromethyl)aniline (9.16 g, 40 mmol) as raw materials, phosphorus trichloride (1.74 mL, 20 mmol) and toluene (80 mL) were added and the reaction was carried out at reflux for 3 hours under argon protection. After completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate (240 mL). The organic layer was washed sequentially with water and saturated saline, and then dried with anhydrous magnesium sulfate. The solvent was removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4:1, v/v) to afford N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (13.12 g, 85.5% yield) as a light yellow solid.1H-NMR (DMSO-d6) δ: 7.05 (1H, d, J= 8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.85 (1H, s), 7.87 (1H, d, J=2.7 Hz), 8.45 (2H, s), 10.85 (1H, s), 11.39 (1H, s).

in vitro

imd-0354, at the concentration of less than 5 m, down-regulated the expression of nf-κb and blocked the translocation of nf-κb to the nucleus in hmc-1 cells. study from hmc-1 cells also showed that imd-0354 inhibited cell proliferation in a time and dose dependent manner. in addition, imd-0354 at the concentration of 0.5 μm inhibited the proliferation of ic-2g559 cells and ic-2v814 cells. this agent was also reported to arrest the cell cycle at the g0/g1 phase and decreased the ratio of cells in s and g2/m phases in hmc-1 cells. 1 μm imd-0354 was reported to decrease cyclin d3 expression and reduce prb phosphorylation level in a time-dependent manner in hmc-1 cells. [1]

in vivo

a study from lungs of ova-sensitized mice showed that 5 mg/kg imd-0354 significantly inhibited nf-κb, although the magnitude of inhibition is lower than that caused by 20 mg/kg imd-0354. 20 mg/kg imd-0354 ameliorated airway hyper-responsiveness and decreased the numbers of bronchial eosinophils and mucus-producing cells in ova-sensitized mice. in addition, the total numbers of cells and eosinophils was also reduced by imd-0354 in ova-sensitized mice. moreover, imd-0354 suppressed the production of th2 cytokines inclusing il-5, il-13 and eotaxin in the airways and/or lungs of ova-sensitized mice, whereas it did not alter the restoration of th1 cytokines under the same experimental conditions. [2]

IC 50

imd-0354 showed anti-tumor effect on seven hematologic malignancy cells with ic50 ranged from 0.1m to 0.6 m.

storage

Store at +4°C

References

[1]tanaka a, konno m, muto s, kambe n, morii e, nakahata t, itai a and matsuda h. a novel nf-kappab inhibitor, imd-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors. blood. 2005 mar; 105(6): 2324-31.
[2]sugita a, ogawa h, azuma m, muto s, honjo a, yanagawa h, nishioka y, tani k, itai a and sone s. antiallergic and anti-inflammatory effects of a novel i kappab kinase beta inhibitor, imd-0354, in a mouse model of allergic inflammation. int arch allergy immunol. 2009; 148(3): 186-98.
[3]verstrepen l and beyaert r. receptor proximal kinases in nf-κb signaling as potential therapeutic targets in cancer and inflammation. biochem pharm. 2014; 92: 519-29.

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