Efficient and Scalable Synthesis of Bardoxolone Methyl (CDDO-methyl Ester)

Fu, Liangfeng; Gribble, Gordon W.

doi:10.1021/ol400399x

Cited by 34 publications

(31 citation statements)

References 13 publications

(11 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Under name bardoxolone methyl (XX) it started, under auspices of Reata Pharmaceuticals (Dallas, TX, USA) parallel clinical trials, first to assess its anticancer properties and later towards advanced chronic kidney disease in patients with type 2 diabetis (Pergola et al, 2011). In parallel with Phase 1 clinical trials XX synthesis was elaborated into five-step scalable process, proceeding in about 50% overall yield from 105 (Fu & Gribble, 2013). Evident antioxidant and anti-inflammatory action, believed to operate via induction of transcription factor Nrf2, which reduces activity of the IKKβ/NFκB pathway suggested possibility of various other therapeutic indications.…”

Section: Semisynthetic Derivatives Of Oleanenementioning

confidence: 99%

“…C-28 imidazolide and analogs) of the active substance, which offers promise of new generation API. Process chemistry for semi-synthesis for CDDO analogs is clearly in sight (Fu & Gribble, 2013), which may be taken as an encouragement to start SAR supported exploratory chemistry with numerous polyhydroxyl analogs of 105.…”

Section: Semisynthetic Derivatives Of Oleanenementioning

confidence: 99%

See 1 more Smart Citation

Triterpene sapogenins with oleanene skeleton: chemotypes and biological activities.

Jatczak

Grynkiewicz

2014

Acta Biochim Pol

View full text Add to dashboard Cite

Critical survey of a selected class of pentacyclic triterpenes -the oleanane family, is presented based on current literature in order to underline their value for medicinal chemistry and drug development potential. Oleanenes may be considered as a renewable resource of valuable research materials which are structurally diverse, inherently biocompatible and have built-in affinity for many categories of functional proteins. Although availability of particular compounds from natural sources may be very low, synthetic methods elaborated by generations of chemists, secure a way to obtaining desirable structures from commercial starting materials.

show abstract

Section: Semisynthetic Derivatives Of Oleanenementioning

confidence: 99%

Section: Semisynthetic Derivatives Of Oleanenementioning

confidence: 99%

Triterpene sapogenins with oleanene skeleton: chemotypes and biological activities.

Jatczak

Grynkiewicz

2014

Acta Biochim Pol

View full text Add to dashboard Cite

show abstract

“…One of the directions of their modification is the oxyfunctionalization of cycles А, C, and E, leading to new bioactive compounds [3][4][5][6][7][8][9][10][11][12][13][14].…”

mentioning

confidence: 99%

“…Methyl ester CDDO (methyl bardoxolone) passed the first phase of clinical trials as a drug for cancer treatment and second phase as a drug for treatment of chronical kidney diseases for patients suffering from sugar diabetes of the second type [5]. 12-Hydroxy-11-oxoolean-12-enes [3] exhibited a high cytotoxicity.…”

mentioning

confidence: 99%

Oxidative lactonization of oleanane and ursane acids by treating with ozone

et al. 2015

View full text Add to dashboard Cite

Features of process of oxidative lactonization of 3-oxooleanolic and 3-oxoursolic acids under treatment with ozone were established. The similarity of the processes consists in generation of 3-oxooleanolic or 3-oxoursolic 13β,28-lactones with 12-oxo or 12-hydroxy group. In the case of ursane derivative the generation exclusively of compounds with β-oriented 12-hydroxy group was observed, in the case of oleanane lactones prevailingly compounds with α-oriented 12-hydroxy group were obtained. The processes differ by the generation of the product of allylic oxidation, 3,11-dioxoursolic acid, or the isolation of the product of the lactone cycle opening with participation of the solvent, 3,12-dioxoolean-28-olic acid.Oleanolic and ursolic acids, belonging to triterpenoids of the series of β-and α-amirine, are widely spread in plants and exhibit various pharmacological properties [1, 2]. One of the directions of their modification is the oxyfunctionalization of cycles А, C, and E, leading to new bioactive compounds [3][4][5][6][7][8][9][10][11][12][13][14].One of the successful examples of oxidative functionalization of oleanolic acid that should be mentioned is the synthesis of 2-cyano-3,12-dioxo-olean-1 (2),9(11)-dien-28-olic acid (CDDO), possessing antiphlogistic, antitumor, antidiabetic, and antiangiogenic activity [15][16][17][18][19]. Methyl ester CDDO (methyl bardoxolone) passed the first phase of clinical trials as a drug for cancer treatment and second phase as a drug for treatment of chronical kidney diseases for patients suffering from sugar diabetes of the second type [5]. 12-Hydroxy-11-oxoolean-12-enes[3] exhibited a high cytotoxicity. 3β,12α-Dihydrooxyoleanolic 13β,28-olide is the key intermediate in the synthesis of endoteline of A receptors and a promising antidiabetic agent [8]. 2-Cyano-3-oxo-12α-fluorours-1-ene-13β,28-olide is effective against the cancer cells of pancreatic gland [20]. One of the products of oxidative transformation of ursolic acid in the presence of ruthenium porphyrins, 12β-hydroxyurs-11-ene-13β,28-olide, proved to be active against the cancer cells of human skin А431 [9, 10].Despite the fact that triterpenoids of the series of α-and β-amirine have very close structure and differ only by the position of a single methyl group in the E cycle, there is a significant difference in their oxidation processes. For example, the oxidation of methyl ursolate with ozone proceeds with generation of 12-oxo-11S,13R-oxetane fragment in the cycle С [21], whereas the oxidation of methyl oleanate leads to methyl 12-oxooleane [22]. Different courses of oxidation processes of triterpenoids belonging to the α-and β-amirine series with reagents like m-chloroperoxybenzoic acid and HCOOH-H 2 O 2 underlie their separation in the form of oxyderivatives, because in plants these metabolites often accompany each other [3,23,24].In continuation of our research on the oxidative transformations of vegetable terpenoids [25][26][27][28][29][30][31] we investigated in the present study the oxidation of С 12 =С 13 bond...

show abstract

“…Oxygenation of ring C is an important technique for modifying their structures in order to prepare new biologically active compounds. Examples include the synthesis from oleanolic acid of bardoxolone methyl (2-cyano-3,12-dioxooleane-1(2),9(11)-dien-28-oic acid methyl ester), which passed phase I clinical trials for treating cancer and phase II for treating chronic kidney disease in type 2 diabetes patients [4]. 3E,12D-Dihydroxyoleane-13E,28-lactone is a key intermediate in the synthesis of endothelin A receptor antagonists and a promising antidiabetic agent [5].…”

mentioning

confidence: 99%

Oxidation of Methyl 2-Cyano-3,4-seco-4(23)-Ene-Ursolate by Ozone

et al. 2014

View full text Add to dashboard Cite

oxetane. The last was formed by oxidation of intermediate 12-oxoursolate. Ozonolysis of the ursolic acid derivative with two unsaturated bonds in the C-4(23) and C-12(13) positions was non-selective, in contrast with that reported previously for an analogous oleanolic-acid derivative.The triterpenoids oleanolic and ursolic acids are widespread in the plant world and exhibit various biological activities including antidiabetic, anticancer, antiviral, etc. [1][2][3]. Oxygenation of ring C is an important technique for modifying their structures in order to prepare new biologically active compounds. Examples include the synthesis from oleanolic acid of bardoxolone methyl (2-cyano-3,12-dioxooleane-1(2),9(11)-dien-28-oic acid methyl ester), which passed phase I clinical trials for treating cancer and phase II for treating chronic kidney disease in type 2 diabetes patients [4]. 3E,12D-Dihydroxyoleane-13E,28-lactone is a key intermediate in the synthesis of endothelin A receptor antagonists and a promising antidiabetic agent [5]. 12E-Hydroxyurs-11-ene-13E,28-lactone was produced by oxidative transformation of ursolic acid by ruthenium porphyrins and was active against A431 human skin cancer cells [5,6].The structures of the starting substrates are known to affect considerably the oxidation of triterpenoids [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. For example, the reactivities of oleanolic and ursolic acid derivatives were found to differ during oxidation by dimethyldioxirane although these triterpenoids differ only by the location of the methyl in ring E [21]. Proposed schemes for separating mixtures of ursolic and oleanolic acids, which occur together in natural sources, were based on the inertness of the C-12(13) unsaturated bond of the former to the action of m-CPBA and HCOOH/H 2 O 2 [21,22]. We found earlier that oleanolic acid methyl ester was oxidized by ozone to methyl 12-oxoolean-28-oate [23] whereas oxidation of the analogous ursolic acid derivative gave 12-oxo-11S,13R-oxetane on ring C [24]. Limitations of methods for synthesizing such chiral non-racemic oxetanes were noted [25].Considering the aforementioned examples and continuing research on oxidative transformations of plant terpenoids [11,12,14,17,18,[26][27][28], we decided to determine the direction of the oxidation by ozone of 2-cyano-3,4-seco-4(23)-ene ursolic acid methyl ester (1) and to compare the results with those published for oxidation of the analogous oleanolic acid derivative [23].Oxidation of 1 with two unsaturated bonds in the C-4(23) (ring A) and C-12(13) (ring C) positions by ozone in CH 2 Cl 2 formed the three 2-cyano-3,4-seco-4-oxo derivatives 12-oxours-11S,13R-oxetane (2, 68%), 11-oxours-12-ene (3, 12%), and 12-hydroxy-4,11-dioxours-12-ene (4, 8%) (Scheme 1). Thus, oxidation of methyl 2-cyano-3,4-seco-4(23)-ene ursolate by ozone was non-selective, in contrast with the oxidation of the analogous oleanolic acid derivative, which enabled selective transformations of rings A and C to be carried out [23].

show abstract

Efficient and Scalable Synthesis of Bardoxolone Methyl (CDDO-methyl Ester)

Cited by 34 publications

References 13 publications

Triterpene sapogenins with oleanene skeleton: chemotypes and biological activities.

Triterpene sapogenins with oleanene skeleton: chemotypes and biological activities.

Oxidative lactonization of oleanane and ursane acids by treating with ozone

Oxidation of Methyl 2-Cyano-3,4-seco-4(23)-Ene-Ursolate by Ozone

Contact Info

Product

Resources

About