Bardoxolone

Bardoxolone is a novel nuclear regulator factor (Nrf-2) activator.

Bardoxolone is a member of cyclohexenones.|Bardoxolone has been used in trials studying the treatment of LYMPHOMA and Solid Tumors. It is a synthetic triterpenoid and a highly potent activator of redox-sensitive signaling pathways that induce programmed cell death (apoptosis) in cancer cells that are under high levels of intrinsic oxidative stress. In contrast, Bardoxolone in normal cells induces protective antioxidant/anti-inflammatory responses.|Bardoxolone is a synthetic triterpenoid compound with potential antineoplastic and anti-inflammatory activities. Bardoxolone blocks the synthesis of inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2), two enzymes involved in inflammation and carcinogenesis. This agent also inhibits the interleukin-1 (IL-1)-induced expression of the pro-inflammatory proteins matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-13 (MMP-13) and the expression of Bcl-3; Bcl-3 is an IL-1-responsive gene that preferentially contributes to MMP-1 gene expression.

Dinitrile 1 was synthesized from CDDO by the method as shown in Scheme 1. Oxalyl chloride gave acyl chloride 19 in quantitative yield. Amide 3 was prepared in 91% yield from 19 with ammonia gas in benzene. Dehydration of 3 with thionyl chloride gave 1 in 89% yield (Drefahl and Huneck, 1958). Ester 5 was synthesized in 83% yield from CDDO by a nucleophilic substitution method using an alkyl halide and DBU in toluene (reflux) (Ono et al., 1978) (Method A) Amides including imidazolides were synthesized in good yield by condensation reactions (Method B, scheme 1) between acyl chloride 19 and the corresponding amines and imidazoles. Tetra-O-acetyl-beta-D-glucopyranoside 2 was prepared in 75% yield from tetra-O-acetyl-alpha-D-glucopyranoside bromide (Lemieux, 1963) and CDDO using a phase-transfer catalyst (Bliard et al., 1994) (Scheme 2) (Method C). Because in the 1H-NMR spectrum (300 MHz, CDCl3) of 2 the anomeric proton was observed at delta5.70 ppm (1H, d, J=7.8 Hz) the proton was assigned the beta-configuration.Dinitrile 1 was synthesized from CDDO by the method as shown in Scheme 1. Oxalyl chloride gave acyl chloride 19 in quantitative yield. Amide 3 was prepared in 91% yield from 19 with ammonia gas in benzene. Dehydration of 3 with thionyl chloride gave 1 in 89% yield (Drefahl and Huneck, 1958). Ester 5 was synthesized in 83% yield from CDDO by a nucleophilic substitution method using an alkyl halide and DBU in toluene (reflux) (Ono et al., 1978) (Method A) Amides including imidazolides were synthesized in good yield by condensation reactions (Method B, scheme 1) between acyl chloride 19 and the corresponding amines and imidazoles. Tetra-O-acetyl-beta-D-glucopyranoside 2 was prepared in 75% yield from tetra-O-acetyl-alpha-D-glucopyranoside bromide (Lemieux, 1963) and CDDO using a phase-transfer catalyst (Bliard et al., 1994) (Scheme 2) (Method C). Because in the 1H-NMR spectrum (300 MHz, CDCl3) of 2 the anomeric proton was observed at delta5.70 ppm (1H, d, J=7.8 Hz) the proton was assigned the beta-configuration.A mixture of CDDO(6.1 mmol) and oxalyl chloride (5 mL) in anhydrous CH2Cl2 (50 mL)was stirred at room temperature overnight. The solvent wasremoved in vacuo, and the residue was coevaporated with anhydrousCH2Cl2 three times, and then used for the next reactionwithout further purification.To a magnetically-stirred solution of compound 6 (Honda et ah, 2000b) (2.00 g, 4.07 mmol) in CH2Cl2 (15 mL) under a nitrogen atmosphere was added dropwise over 30 min a solution of oxalyl chloride (1.04 g, 8.19 mmol) in CH2Cl2 (4 mL). Gas evolution was observed after each drop, but no exotherm was noted. After stirring the yellow reaction solution for 16 h at -18-22 C, a sample (~3 drops) of the solution was quenched in a CH2C12/CH3OH (95/5) solution (-1-2 mL) and warmed just to reflux. TLC Compound 10 was prepared by formylation of OA (Compound 9) (Simonsen and Ross, 1957) with ethyl formate in the presence of sodium methoxide in THE (Clinton et al., 1961). Compound 7 was obtained by introduction of a double bond at C-1 of Compound 10 with phenylselenenyl chloride in ethyl acetate and sequential addition of 30% hydrogen peroxide (Sharpless et al., 1973). Compound II was synthesized from Compound 10 by addition of hydroxylamine in aqueous ethanol; cleavage of Compound 11 with sodium methoxide gave Compound 12 (Johnson and Shelberg, 1945). Compound 14 was prepared from Compound 13 (Picard et al., 1939) by alkali hydrolysis followed by Jones oxidation. Compound 15 was prepared by formylation of Compound 14 with ethyl formate in the presence of sodium methoxide in benzene. Compound 16 was synthesized from Compound 15 by addition of hydroxylamine. Nitrile 17 was obtained by cleavage of isoxazole 16 with sodium methoxide (yield, 100%), followed by introduction of a double bond at C-1 with PhSeCl-H2O2 (yield, 40%). CDDO (6) was prepared in 71% yield by halogenolysis of 17 with lithium iodide in DMF (Dean, P. D. G., 1965).Dissolve 2 g of CDDO-Me in 80 ml of anhydrous DMF, add 12 g of anhydrous lithium iodide, protect with nitrogen and heat to reflux (153 C) for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was diluted with 200 ml of ethyl acetate, 200 ml of 5%Dilute hydrochloric acid, partition, aqueous layer was washed with ethyl acetate (120ml × 2), the organic layers were combined and washed with saturated sodium chloride(200ml), dried over anhydrous sodium sulfate, suction filtered and dried. residue was purified by column chromatography (PE / EA = 3: 1) to give 1.37g of white powder. Yield 70.3%.

Bardoxolone is a synthetic oleanane triterpenoid that exerts multifunctional activities in the control of cellular growth and differentiation. Bardoxolone is capable of activating the transcription factor peroxisome proliferator activator receptor-γ (PPARγ), its apoptotic effects in malignant cells have been shown to occur independently of PPARγ. Bardoxolone was developed as an potential drug for the improvement of hyperglycemia, proteinuria, glomerulus structure, serum creatine, which may in turn be beneficial to treat diabetic kidney diseases, cancer and thromboembolic events.

Molecular Weight:491.7
XLogP3:6.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:491.30355879
Monoisotopic Mass:491.30355879
Topological Polar Surface Area:95.2
Heavy Atom Count:36
Complexity:1200
Defined Atom Stereocenter Count:7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes