Bardoxolone methyl

Bardoxolone is a synthetic triterpenoid compound with potential antineoplastic and anti-inflammatory activities, acting as an activator of the Nrf2 pathway and an inhibitor of the NF-κB pathway.

Bardoxolone methyl is a member of cyclohexenones.|Bardoxolone Methyl is the methyl ester form of bardoxolone, 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.

5.58 g of compound V (10 mmol) were dissolved in 80 ml of anhydrous DMF, 1.1648 g of cuprous cyanide (13 mmol) and0.332 g of potassium iodide (2 mmol) was added, and a balloon was added to prevent the water in the air from entering the reaction system and reacting at 120 ° C for 30 hours. reactionAfter the reaction was cooled to room temperature, the reaction solution was poured into 200ml of water to quench, add 500ml of ethyl acetate, stir, filterThe insolubles were removed and the organic layer was washed with saturated sodium bicarbonate (200 ml x 2) and saturated sodium chloride (200 ml), respectively, Drying, suction filtration, rotary drying and column chromatography (PE / EA = 5: 1) gave 4.22 g of yellow powder with a yield of 83.6percent.As shown in Scheme 4, the natural triterpenoid oleanolic acid (1) was used as the starting material in the synthesis of CDDO-Me. The improved method commences with methylation of the carboxylic acid of oleanolic acid (1) to afford methyl ester 2 in quantitative yield. With ester 2, activation of the A-ring is fulfilled by 2-iodoxybenzoic acid-mediated two-fold oxidation to give enone 3. Epoxidation with meta-chloroperoxybenzoic acid, followed by direct C-ring enolization and A-ring enone bromination with bromine and hydrobromic acid, affords key intermediate 4. With bromide 4 in hand, a cross-coupling reaction with copper cyanide provides CDDO-Me (5) in only five steps (four operations) from oleanolic acid (Scheme 4). This is an improvement over conventional methods, which require 10 steps. Moreover, intermediate 4 was prepared in high yield and few overall steps, thereby providing a base compound for development of additional analogs and derivatives.As a specific example of using this synthetic method in the synthesis of triterpenoids, CDDO-Me was synthesized from oleanolic acid. As shown in Scheme 2, the natural triterpenoid oleanolic acid (1) was used as the starting material in the synthesis of CDDO-Me. The method commences with methylation of the carboxylic acid of oleanolic acid (1) to afford methyl ester 2 in quantitative yield. With ester 2, activation of the A-ring is fulfilled by 2-iodoxybenzoic acid-mediated two-fold oxidation to give enone 3. Epoxidation with meta-chloroperoxybenzoic acid, followed by direct C-ring enolization and A-ring enone bromination with bromine and hydrobromic acid, affords key intermediate 4. With bromide 4 in hand, a cross-coupling reaction with copper cyanide provides CDDO-Me (5) (Scheme 2). Intermediate 4 was prepared in high yield and few overall steps, thereby providing a base compound for development of the analogs and derivatives described herein.

CDDO Methyl Ester is a synthetic triterpenoid that inhibits I Wei Bα kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor Wei B-regulated gene products in human leukemic cells. CDDO Methyl Ester is a novel therapeutic agent in the treatment of acute myeloid leukemia and in the treatment of pancreatic cancer as well as other forms of cancer.

Molecular Weight:505.7
XLogP3:6.7
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:505.31920885
Monoisotopic Mass:505.31920885
Topological Polar Surface Area:84.2
Heavy Atom Count:37
Complexity:1210
Defined Atom Stereocenter Count:7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes