The Hantzsch Reaction. I. Oxidative Dealkylation of Certain Dihydropyridines

Loev, Bernard; Snader, Kenneth M.

doi:10.1021/jo01017a048

Cited by 278 publications

(102 citation statements)

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“…Nifedipine had a retention time of 5.0 min and its metabolite of 3.6 min. Authentic metabolite was prepared from nifedipine by means of NaNOz oxidation (Loev and Snader, 1965).…”

Section: Nijedipine Oxidationmentioning

confidence: 99%

Expression of human liver cytochrome P450 IIIA4 in yeast

Renaud

Cullin

Pompon

et al. 1990

European Journal of Biochemistry

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Cytochrome P-450 (P450) NF, a member of the P450 IIIA subfamily, is the major contributor to the oxidation of the calcium-channel blocker nifedipine in human liver microsomes. A cDNA clone designated NF25 encoding for human P450 NF was isolated from a bacteriophage (pVNF25) showed a ferrous -CO spectrum typical of cytochrome P-450. Microsomal preparations contained a protein with an apparent molecular mass identical to that of P450-5 (a form isolated from human liver indistinguishable from P450 NF) that was not present in microsomes from control yeast (transformed with pYeDP1/8-2 alone), as revealed by immunoblotting with anti-P450-5 antibodies. On the other hand, antibodies raised in rabbits against human liver P450 IIC8-10 and rat liver P450 IA1 and P450 IIEl did not recognize yeastexpressed P450 NF25. The P450 NF25 content in microsomes was about 90 pmol/mg protein. Microsomal, yeast-expressed P450 NF25 exhibited a high affinity for different substrates including macrolide antibiotics, dihydroergotamine and miconazole as shown by difference visible spectroscopy. Microsomal suspensions containing P450 NF25 were also able to catalyze several oxidation reactions that were expected from the activities of the protein isolated from human liver, including nifedipine 1 ,Coxidation, quinidine 3-hydroxylation and Noxygenation, and N-demethylation of the macrolide antibiotics erythromycin and troleandomycin. The yeast endogenous NADPH -cytochrome P-450 reductase thus couples efficiently with the heterologous P450 NF25 though its level is far lower than that of its ortholog in human liver. Indeed addition of rabbit liver NADPHcytochrome P-450 reductase increased the oxidation rates. Rabbit liver cytochrome b5 also caused a marked enhancement of catalytic activities, as had been noted previously for this particular P450 enzyme in a reconstituted system involving the protein purified from human liver. Furthermore, the level of the yeast endogenous cytochrome P-450 (lanosterol 14-demethylase) has been found to be negligible compared to the heterologously expressed cytochrome P-450 (30 times less). Thus, yeast microsomes containing P450 NF25 constitute by themselves a good functional model for studying the binding capacities and catalytic activities of this individual form of human hepatic cytochrome P-450.Cytochromes P-450 (P450s) are members of a superfamily of heme proteins that catalyze the oxidation of a wide variety of endogenous and exogenous compounds including most drugs and carcinogens, the existence of multiple enzymes being the origin of the broad substrate specificity (Gonzalez, 1989). This enzyme multiplicity is now well established on the basis of purification, amino acid composition, electrophoretic and

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“…Nifedipine had a retention time of 5.0 min and its metabolite of 3.6 min. Authentic metabolite was prepared from nifedipine by means of NaNOz oxidation (Loev and Snader, 1965).…”

Section: Nijedipine Oxidationmentioning

confidence: 99%

Expression of human liver cytochrome P450 IIIA4 in yeast

Renaud

Cullin

Pompon

et al. 1990

European Journal of Biochemistry

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“…which is specific for nitroso compounds. The hplc separations were performed on a Partisil-10 PAC-column.J The silica gel (mesh 40-140)' was used for flash chromatography instead of 230-400 mesh used in the original method (19). In the work-up procedures for various syntheses, unless otherwise noted, the solvents were removed with a rotary evaporator under reduced pressure (0.3 Torr; I Torr = 133.3 Pa) at a bath temperature of 80°C.…”

Section: Because Of the Longer Half-life Of Fluorine-18 (Trlr = 110mentioning

confidence: 99%

Synthesis of ¹⁸F-labelled 2-fluoroethyl-nitrosoureas

Farrokhzad¹,

Dikšić²,

Yamamoto³

et al. 1984

Can. J. Chem.

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18F-labelled 1,3-bis-(2-fluoroethyl) nitrosourea (18F-BFNU) (9) and 1-(2-chloroethyl)-3-(2-fluoroethyl) nitrosourea (18F-CFNU) (isomeric mixture, 11,12) were synthesized by nucleophilic attack of 18F-labelled tetra-n-butylammonium fluoride on the aziridine ring of 1,3-substituted ureas. Diethyleneurea (DEU) (5), 1-(2-fluoroethyl)-3-ethyleneurea (FEU) (7), and 1-(2-chloroethyl)-3-ethyleneurea (CEU) (14) were used as starting materials in the synthesis. Nitrosation of 18F-labelled 1,3-bis-(2-fluoroethyl) urea (18F-BFU) (6) produced 18F-BFNU with a radiochemical yield of 5–10%. Nitrosation of 18F-labelled 1-(2-chloroethyl)-3-(2-fluoroethyl) urea (18F-CFU) (15) gave 18F-CFNU as a mixture of two isomers. Geometrical isomers of CFNU were separated by hplc, and the radiochemical yield of the two isomers ranged from 8% to 15%, with a radiochemical purity exceeding 96%. Syntheses, which took about 60 min, yielded products with specific activity of 680 mCi/mmol when n-Bu4N+F− was used, or 300 mCi/mmol when HF was used to complete the opening of the aziridine ring.

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“…Particularly, 4-aryl-1,4-dihydropyridines are well known as calcium channel blockers and have emerged as one of the most important class of drugs for the treatment of cardiovascular diseases 7 . Cardiovascular agents such as nifedipine, nicardipine, amlodipine, and other related derivatives are dihydropyridyl compounds, which are effective for the treatment of hypertension [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

“…However, despite their importance from a pharmacological, and synthetic point of view, comparatively very few methods for their preparation have been reported. Generally, 1,4-dihydropyridines are synthesized by the Hantszch condensation method, which involves cyclocondensation of aldehyde, β-ketoester and ammonia either in acetic acid at room temperature or refluxing in alcohol for a long time 7,11 . However, these methods suffer from several drawbacks such as long reaction time, an excess of organic solvent, lower product yields, and harsh refluxing conditions.…”

Section: Introductionmentioning

confidence: 99%

Carbon-Based Solid Acid Catalyzed Synthesis of Polyhydroquinoline Derivatives via Hantzsch Reaction Under Solvent-Free Conditions

Davoodnia

Khojastehnezhad

2012

J. Chil. Chem. Soc.

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An easy method for the synthesis of polyhydroquinoline derivatives via one-pot four-component Hantzsch condensation of dimedone, aryl aldehydes, ethyl acetoacetate and ammonium acetate in the presence of a catalytic amount of carbon-based solid acid (CBSA) in solvent-free conditions is described. The main advantages of the present approach are relatively short reaction times, high product yields, clean reaction profiles, simple experimental and work-up procedure.

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The Hantzsch Reaction. I. Oxidative Dealkylation of Certain Dihydropyridines

Cited by 278 publications

References 1 publication

Expression of human liver cytochrome P450 IIIA4 in yeast

Expression of human liver cytochrome P450 IIIA4 in yeast

Synthesis of ¹⁸F-labelled 2-fluoroethyl-nitrosoureas

Carbon-Based Solid Acid Catalyzed Synthesis of Polyhydroquinoline Derivatives via Hantzsch Reaction Under Solvent-Free Conditions

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The Hantzsch Reaction. I. Oxidative Dealkylation of Certain Dihydropyridines

Cited by 278 publications

References 1 publication

Expression of human liver cytochrome P450 IIIA4 in yeast

Expression of human liver cytochrome P450 IIIA4 in yeast

Synthesis of 18F-labelled 2-fluoroethyl-nitrosoureas

Carbon-Based Solid Acid Catalyzed Synthesis of Polyhydroquinoline Derivatives via Hantzsch Reaction Under Solvent-Free Conditions

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Synthesis of ¹⁸F-labelled 2-fluoroethyl-nitrosoureas