Oxidation of 4-aryl- and 4-alkyl-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihydropyridines by human liver microsomes and immunochemical evidence for the involvement of a form of cytochrome P-450

Abstract

4-Substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihydropyridines are important because of their roles as calcium channel blockers. The mixed-function oxidation of 14 4-aryl- and four 4-alkyl-substituted derivatives by human liver microsomes was examined. The major product of enzymatic oxidation of all the 4-aryl compounds was the pyridine derivative containing the 4-aryl group. The 4-alkyl compounds, in contrast, formed a pyridine derivative in which a hydrogen atom was present at the 4-position and the alkyl group was lost; these compounds also inactivated cytochrome P-450 and caused the loss of nifedipine oxidase activity after enzymatic oxidation. All of these reactions were extensively inhibited by an antibody raised to purified human liver nifedipine oxidase cytochrome P-450 (P-450NF), indicating a major role for this enzyme in the oxidation of these compounds. Oxidation of the 4-alkyl compounds led not only to the loss of P-450NF but also to decreases in catalytic activities of cytochrome P-450 isozymes catalyzing other reactions (phenacetin O-deethylation and hexobarbital 3'-hydroxylation). The results indicate that P-450NF (or closely related enzyme forms) is responsible for the oxidation of these nifedipine-related compounds in human liver microsomes and that metabolism is highly dependent upon 4-substitution; with alkyl substituents, radicals are postulated to leave P-450NF to attack other proteins.

Inhibitory Effects of Silibinin on Cytochrome P‐450 Enzymes in Human Liver Microsomes

“…In the case of CYP3A4, two model substrates were used, i.e. denitronifedipine (Böcker et al 1986) and erythromycin (Riley & Howbrook 1997;Wang et al 1997), because for this enzyme multiple conformers with distinct substrate specificity may exist (Koley et al 1996(Koley et al & 1997.…”

A simple and efficient approach for synthesis of 1,4-dihydro-pyridines using nano-crystalline solid acid catalyst

“…The DHP heterocyclic rings are a common feature of various bioactive compounds such as anticonvulsant, antidiabatic, antianxiety, antidepressive, antitumor, analgesic, seditative, vasodilator, bronchodilator, hypnotic, and anti-inflammatory agents [2]. DHPs exhibit significant biological activities in the treatment of cardiovascular disease as calcium channel blockers [3]. They also present vasodilating activity [4], and are NADH mimics [5].…”

“…However, the yield of 1,4-DHP obtained by Hantzsch method is generally low [13][14][15]. Various methods for the synthesis of dihydropyridine derivatives are described in the literature including condensation of aromatic aldehydes, β-dicarbonyl compounds and ammonium acetate using of microwave [16], ionic liquids [17], tetrabutylammonium hydrogen sulfate [18], silica gel/NaHSO 4 [19], AlCl 3 .6H 2 O [20], TMSI [21], triphenylphosphine [22], InCl 3 [23], I 2 [24], cellulose sulfuric acid [25], alumina sulfuric acid [26], SiO 2 /HClO 4 [27], metal triflate [28], Fe(CF 3 CO 2 ) 3 [29], nano CuO [30], nano MgO [31], ultrasound irradiation [32], solvent free [33], and aqueous media [34].…”

Aromatization of Hantzsch 1,4-Dihydropyridines with Urea-Hydrogen Peroxide/Maleic Anhydride

“…These compounds are oxidized to pyridine derivatives by the action of cytochrome P-450 in the liver [2]. Furthermore, the oxidation of Hantzsch 1,4-DHPs provides an easy access to pyridine derivatives.…”