Ring transformation of isoxazoles into furan and pyran derivatives

Ciller, J. A.; Martı́n, Nazario; Seoane, Carlos; Soto, J. L.

doi:10.1039/p19850002581

Cited by 45 publications

(29 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All incubations were conducted in triplicate. dmd.aspetjournals.org ␣-cyanoenol-like intermediates via ring scission, has been established over a century ago (for a review on isoxazole chemistry, see Wakefield and Wright, 1979), and this property has been conveniently exploited as a building block in synthetic methodology (McGregor et al, 1969;Wakefield and Wright, 1979;Cillar et al, 1985;Perez et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

In VITRO METABOLISM STUDIES ON THE ISOXAZOLE RING SCISSION IN THE ANTI-INFLAMMATORY AGENT LEFLUNOMIDE TO ITS ACTIVE Α-Cyanoenol METABOLITE A771726: MECHANISTIC SIMILARITIES WITH THE CYTOCHROME P450-Catalyzed DEHYDRATION OF ALDOXIMES

Kalgutkar

Nguyen²,

Vaz³

et al. 2003

Drug Metab Dispos

108

View full text Add to dashboard Cite

This article is available online at http://dmd.aspetjournals.org ABSTRACT:The 3-unsubstituted isoxazole ring in the anti-inflammatory drug leflunomide undergoes a unique N-O bond cleavage to the active ␣-cyanoenol metabolite A771726, which resides in the same oxidation state as the parent. In vitro studies were conducted to characterize drug-metabolizing enzyme(s) responsible for ring opening and to gain insight into the mechanism of ring opening. Under physiological conditions, leflunomide was converted to A771726 in rat and human plasma (rat plasma, t 1/2 ‫؍‬ 36 min; human plasma, t 1/2 ‫؍‬ 12 min) and whole blood (rat blood, t 1/2 ‫؍‬ 59 min; human blood, t 1/2 ‫؍‬ 43 min). Human serum albumin also catalyzed A771726 formation, albeit at a much slower rate (t 1/2 ‫؍‬ 110 min). Rat and human liver microsomes also demonstrated NADPH-dependent A771726 formation (human liver microsomes, V max ‫؍‬ 1,797 pmol/min/mg and K m ‫؍‬ 274 M). Leflunomide metabolism in microsomes was sensitive to furafylline treatment, suggesting P4501A2 involvement. 3-Methylleflunomide, which contained a 3-methyl substituent on the isoxazole ring, was resistant to ring opening in base, plasma, blood, and liver microsomes. In microsomes, two monohydroxylated metabolites were formed, and metabolite identification studies established the 3-and the 5-methyl groups on the isoxazole ring as sites of hydroxylation. These results indicate that the C3-H in leflunomide is essential for ring opening. Although A771726 formation in human liver microsomes or recombinant P4501A2 required NADPH, its formation was greatly reduced by oxygen or carbon monoxide, suggesting that the isoxazole ring opening was catalyzed by the P450Fe(II) form of the enzyme. A mechanism for the P450-mediated ring scission is proposed in which the isoxazole ring nitrogen or oxygen coordinates to the reduced form of the heme followed by charge transfer from P450Fe(II) to the C‫؍‬N bond or deprotonation of the C3-H, which results in a cleavage of the N-O bond.

show abstract

Section: Discussionmentioning

confidence: 99%

In VITRO METABOLISM STUDIES ON THE ISOXAZOLE RING SCISSION IN THE ANTI-INFLAMMATORY AGENT LEFLUNOMIDE TO ITS ACTIVE Α-Cyanoenol METABOLITE A771726: MECHANISTIC SIMILARITIES WITH THE CYTOCHROME P450-Catalyzed DEHYDRATION OF ALDOXIMES

Kalgutkar

Nguyen²,

Vaz³

et al. 2003

Drug Metab Dispos

108

View full text Add to dashboard Cite

show abstract

“…NMR spectra were obtained in DMSO-d 6 Preparation of PF-MCM-41 A solution of 4-methyl-pyridine (8.0 mmol) in THF (40 ml) was added to a THF solution of lithium diisopropylamine (8.0 mmol). After 2 h the brown solution was cooled to Ϫ20°C and then MCM-41 grafted with chloropropylsilyl groups was added (2.0 g).…”

Section: Methodsmentioning

confidence: 99%

“…5) 4H-Pyrans also constitute the structural unit of a series of natural products. 6,7) Tetracyanoethylene (TCNE) is the simplest of the percyanoalkenes (cyanocarbons). Due to four powerful electronwithdrawing cyano groups, the C-C double bond is highly electron-deficient and it is strongly electrophilic reagent.…”

mentioning

confidence: 99%

Pyridine-Functionalized MCM-41 as an Efficient and Recoverable Catalyst for the Synthesis of Pyran Annulated Heterocyclic Systems

Shaabani

Amini

Ghasemi

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Pyridine-functionalized MCM-41 catalyzed reactions between tetracyanoethylene and various activated CH-acid compounds are described. These reactions afford the corresponding pyran annulated heterocyclic ring systems in high yields at room temperature within a few minutes. The work-up procedure is very simple and the products do not require further purification. The catalyst can be recycled and reused for several times without observable loss of performance.

show abstract

“…Studies on the ring transformation of 3,4-unsubstituted isoxazoles under chemical conditions (Scheme 3,I) revealed that the formed cyanoenols (II) or 3-oxopropanenitriles (III) can react in situ with aldehydes, leading to the corresponding condensed products (IV). The un-isolated intermediate IV reacts with propanedinitrile, affording 3,5-dicyano-4H-pyran-2-amine (V) after a Michael addition and spontaneous cyclization (Eugster et al, 1963;Ciller et al, 1984Ciller et al, , 1985. These reactions suggest that the 3,4-unsubstituted isoxazole ring-opened product, ␣-cyanoenol, is reactive.…”

Section: Introductionmentioning

confidence: 99%

“…When 5-methylisoxazole and benzaldehyde were allowed to react with sodium ethoxide in dry ethanol at room temperature followed by acid treatments, Eugster et al (1963) have successfully isolated the aldol condensation product, benzylidenecyanoacetone. The condensation reaction between the isoxazole ring-opened products and aldehydes has been used to bring about the transformation of 5-substituted isoxazoles into different kinds of heterocycles, such as furan and pyran derivatives (Ciller et al, 1984(Ciller et al, , 1985. When the isoxazole ring cleavage occurs during biotransformation, it is not surprising that the formed ␣-cyanoenol can further condense with an aldehyde if present in the in vitro system.…”

Section: Bioactivation Of 34-unsubstituted Isoxazole Ringmentioning

confidence: 99%

Elucidation of a Novel Bioactivation Pathway of a 3,4-Unsubstituted Isoxazole in Human Liver Microsomes: Formation of a Glutathione Adduct of a Cyanoacrolein Derivative after Isoxazole Ring Opening

Yu¹,

Folmer²,

Hoesch³

et al. 2010

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Studies on the biotransformation of isoxazole rings have shown that molecules containing a C3-substituted isoxazole or a 1,2-benzisoxazole can undergo a two-electron reductive ring cleavage to form an imine. In the absence of a C3 substituent, the isoxazole ring opens via deprotonation of the C3 proton followed by N-O bond cleavage to yield an ␣-cyanoenol analog. We report the identification of a novel bioactivation pathway of a 3,4-unsubstituted isoxazole in human liver microsomes. After the enzyme-catalyzed cleavage of the 3,4-unsubstituted isoxazole ring of N-((2-isopropyl-7-methyl-1-oxoisoindolin-5-yl)methyl)isoxazole-5-carboxamide (P) in human liver microsomes, the formed ␣-cyanoenol (M1) condenses with formaldehyde to generate an ␣,␤-unsaturated Michael acceptor intermediate (a cyanoacrolein derivative, VII), which further reacts with the cysteinyl thiol of glutathione to yield a GSH adduct of a cyanoacrolein derivative (M3). The same adduct also is formed when M1, generated in 0.1 N NaOH aqueous solution, reacts with formaldehyde and GSH. 13Clabeled methanol was used to confirm that methanol from the drug stock solution was oxidized by liver microsomal enzymes to formaldehyde and the carbon atom from methanol was finally incorporated in the corresponding GSH adduct. The formation of isoxazole ringopened products (M1 and M2) in human liver microsomes is NADPHdependent. M1 and M2 were found in human liver microsomes preincubated with 1-aminobenzotriazole (1 mM) and NADPH (5 mM) at ϳ10% of the levels found in the samples in the absence of 1-aminobenzotriazole, suggesting that this biotransformation pathway is primarily catalyzed by cytochrome P450. The formation of M3 also was inhibited by 1-aminobenzotriazole at a similar level.

show abstract

Ring transformation of isoxazoles into furan and pyran derivatives

Cited by 45 publications

References 4 publications

In VITRO METABOLISM STUDIES ON THE ISOXAZOLE RING SCISSION IN THE ANTI-INFLAMMATORY AGENT LEFLUNOMIDE TO ITS ACTIVE Α-Cyanoenol METABOLITE A771726: MECHANISTIC SIMILARITIES WITH THE CYTOCHROME P450-Catalyzed DEHYDRATION OF ALDOXIMES

In VITRO METABOLISM STUDIES ON THE ISOXAZOLE RING SCISSION IN THE ANTI-INFLAMMATORY AGENT LEFLUNOMIDE TO ITS ACTIVE Α-Cyanoenol METABOLITE A771726: MECHANISTIC SIMILARITIES WITH THE CYTOCHROME P450-Catalyzed DEHYDRATION OF ALDOXIMES

Pyridine-Functionalized MCM-41 as an Efficient and Recoverable Catalyst for the Synthesis of Pyran Annulated Heterocyclic Systems

Elucidation of a Novel Bioactivation Pathway of a 3,4-Unsubstituted Isoxazole in Human Liver Microsomes: Formation of a Glutathione Adduct of a Cyanoacrolein Derivative after Isoxazole Ring Opening

Contact Info

Product

Resources

About