Phenolic Benzo Research Articles

Application of coupling reaction between lithiated toluamide and benzonitrile for the synthesis of phenolic benzo[c]phenanthridine alkaloid, oxyterihanine

The total synthesis of the natural phenolic benzo[c]phenanthridine alkaloid, oxyterihanine, was accomplished via substituted 3-arylisoquinoline intermediate. The key reaction was a coupling between the o-toluamide 4 and the benzonitrile 5.

Total Synthesis of Oxyfagaronine, Phenolic Benzo[c]phenanthridine and General Synthetic Way of 2,3,7,8‐ and 2,3,8,9‐Tetrasubstituted Benzo[c]phenanthridine Alkaloids.

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Total Synthesis of Oxyfagaronine, Phenolic Benzo[c]phenanthridine and General Synthetic Way of 2,3,7,8- and 2,3,8,9-Tetrasubstituted Benzo[c]phenanthridine Alkaloids

Benzo[c]phenanthridine alkaloids such as oxynitidine, oxysanguinarine, oxyavicine and phenolic oxyfagaronine were synthesized from easily available starting benzonitriles 5 and toluamides 6 using a lithiated toluamide-benzonitrile cycloaddition reaction. The coupling reaction provided 3-arylisoquinolinones that were transformed to the benzo[c]phenanthridones. This method is highly efficient and could be useful for preparing diverse substituted aromatic benzo[c]phenanthridine compounds on a multi gram scale.

Concise Synthesis of Fagaridine (I) and Decarine (II) Phenolic Benzo[c]phenanthridine Alkaloids, Using the Palladium‐Assisted Biaryl Coupling Reaction.

Concise Synthesis of Fagaridine (I) and Decarine (II) Phenolic Benzo[c]phenanthridine Alkaloids, Using the Palladium‐Assisted Biaryl Coupling Reaction.

Concise Synthesis of Fagaridine and Decarine, Phenolic Benzo[c]-phenanthridine Alkaloids, Using the Palladium-assisted Biaryl Coupling Reaction

Total synthesis of fagaridine (5) and decarine (6), phenolic benzo[c]phenanthridine alkaloids, was accomplished via the aryl-aryl coupling reaction of bromo amides protected by an isopropyl group with palladium, followed by reduction with LiAlH 4 and treatment with conc. HCl.

Synthesis of benzo[c]phenanthridine derivatives and theirin vitro antitumor activities

Aiming at the development of anticancer agents by modification of phenolic benzo[c]phenanthridine alkaloid, additional hydroxyl group was put on C10 position of fagaridine (1) by a biomimetic synthetic procedure to afford 10-hydroxyfagaridine (12). All of the synthetic intermediates were also screenedin vitro antitumor activities against five different cell lines as well as12. Among them the representative cytotoxic results are shown as follows;p-quinone (11) [ED50 (A549=0.22 μg/ml), (HCT15=0.21 μg/ml), fagaridine (1) (HCT 15=0.41 μg/ml), olefin (6) (HCT 15=0.06 μg/ml), acetal (7) (SKMEL-2=0.07 μg/ml), dihydrofagaridne (10) (A549=0. 38 μg/ml), 10-hydroxyfagaridine (12) (A 549=0.45 μg/ml). From these observation three main remarks can be drawn; (i) the iminium part of benzo[c]phenanthridine is not essential for showing acitvities, (ii) the additional hydroxyl group did not contribute to enhance the cytotoxicity, (iii) the 3-arylisoquinolin-1(2H)-one derivatives were found to display significantin vitro antitumor activity.

Quantitation of Benzo(a)pyrene-glucuronic Acid Conjugates Formed in Benzo(a)pyrene Treated Cell Cultures by Continuous-flow Fast Atom Bombardment Mass Spectrometry

Abstract Glucuronic acid conjugates of phenolic benzo(a)pyrene metabolites (BP-glucuronides) were determined by continuous-flow fast atom bombardment mass spectrometry (continuous-flow FABMS). BP-glucuronides were isolated from the medium of BP-treated cell cultures by solvent/solvent extraction and microbore HPLC. A continuous-flow FABMS method was used for determining the amount of BP-glucuronides. Very high selectivity was achieved by using a mass resolving power of M/ΔM of 10000. Five picograms of BP-glucuronide gave a response with a signal-to-noise ratio of 10:1. Early passage hamster embryo cell cultures metabolized 18% of the BP to BP-glucuronides, while the mouse hepatoma cell line Hepa-lclc7 metabolized 25% of the BP to BP-glucuronides. In contrast, the amount of BP-glucuronides present in medium samples from BP-treated cultures of the human hepatoma cell line HepG2 was below the detection limits of the method (less than 0.5 ng per mL of medium).

ChemInform Abstract: Chemical Constituents of Rutaceous Plants. Part 62. Efficient Synthesis of Fagaronine, a Phenolic Benzo(c)phenanthridine Alkaloid with Antileukaemic Activity.

AbstractFagaronine chloride (XIII) is synthesized starting from isovanillin (I).

Studies on the chemical constituents of rutaceous plants. LXIV. Structural establishment of oxyterihanine, a phenolic benzo[c]phenanthridone alkaloid. Syntheses of phenolic benzo[c]phenanthridine alkaloids, terihanine and isoterihanine, and related compounds.

The structure of oxyterihanine (2c), a new phenolic benzo [c] phenanthridone alkaloid which was isolated from Formosan Xanthoxylum nitidum (ROXB.) D. C. (Fagara nitida ROXB.), was established as 8-hydroxy-9-methoxy-5-methyl-2, 3-methylenedioxybenzo [c] phenanthridin-6 (5H) one by direct comparison with a synthetic specimen, which was derived from 2- (4-isopropoxy-3-methoxyphenyl) -6, 7-methylenedioxy-3, 4-dihydronaphthalen-1 (2H) -one (8a) through the synthetic sequence shown in Charts 3 and 4.9-Hydroxy-8-methoxy-5-methyl-2, 3-methylenedioxybenzo [c] phenanthridin-6 (5H) -one [oxyisoterihanine (2d)] and two phenolic quaternary benzo [c] phenanthridine alkaloids, terihanine (1c) and isoterihanine (1d), were also synthesized.

Studies on the chemical constituents of rutaceous plants. Part 62. Efficient synthesis of fagaronine, a phenolic benzo[c]phenanthridine alkaloid with antileukaemic activity

Fagaronine (2), an antileukaemic hydroxybenzo[c]phenanthridine alkaloid, has been synthesized from the chalcone (4a) according to the synthetic sequence (Schemes 1–4). During the synthesis, the hydroxy group was protected in the form of its isopropoxy derivative.

Basic intramolecular acylation. Synthesis of 2-aryl-1-tetralones bearing isopropoxy or benzyloxy groups, synthetic key intermediates for phenolic antileukaemic benzo[c]phenanthridine alkaloids, from 2,4-diarylbutyric acid derivatives

Generally applicable intramolecular cyclisation of 2,4-diarylbutyric acids having isopropoxy (4) or benzyloxy (12) groups used to protect phenolic functions was required for the purpose of synthesis of phenolic benzo[c]phenanthridine alkaloids. Treatment of the butyric acids (4b), (4d), (4f), and (12) with POCl3 in acetonitrile in the presence of potassium carbonate furnished the corresponding tetralones (5b), (5d), (5f), and (13) in excellent yield, respectively, without the cleavage of its isopropoxy or benzyloxy groups. A plausible mechanism for basic intramolecular acylation using POCl3, is proposed.

Synthesis of fagaridine, a phenolic benzo (c) phenanthridine alkaloid.

Regioselective demethylation of oxychelerythrine (5), derived from berberine (4), with p-toluenesulfonic acid in refluxing toluene gave oxyfagaridine (6), which was converted into fagaridine (1) in good yields by successive reduction and oxidation.

Studies on the chemical constituents of rutaceous plants. LIX. The chemical constituents of Xanthoxylum nitidum (Roxb.) D.C. (Fagara nitida Roxb.) (1) Examination of the alkaloidal fraction of the bark

Chemical constituents in the alkaloidal fraction of the bark of Formosan X. nitidum (ROXB.) D.C. (F. nitida ROXB.) (Japanese name : Teriha-Zansho), Rutaceae, which was collected in the area of Ping-Tung Hsien, were examined. Twelve alkaloids [nitidine (1), oxynitidine (2), 6-methoxy-5, 7-dihydrochelerythrine (4), oxychelerythrine (6), des-N-methyl-chelerythrine (7), chelerythrine (14), arnottianamide (24), liriodenine (25), bocconoline (26), decarine (27), integriamide (28), and isoarnottianamide (13)] and three lignans [l-asarinin (20), l-sesamin (21), and l-syringaresinol (29)], a coumarin, aesculetin dimethyl ether (22), together with β-sitosterol (23) were isolated. Other than the above seventeen known compounds a new phenolic benzo [c] phenanthridone alkaloid designated as oxyterihanine (30a) was also isolated as a minor component. While the past three groups reported that nitidine (1) was a sole quaternary benzo-[c] phenanthridine alkaloid in the same plants collected in the areas of Hong-Kong and of China mainland (Gauanx and Gauantung), in our case, chelerythrine (14) was isolated as a major component. Nitidine (1) was isolated from the plant collected at March as a second component, but chelecythrine (14) was essentially a sole benzo [c] phenanthridine alkaloid in the case of the plant collected at July and at September. The seasonal variation of the contents of the quaternary benzo [c] phenanthridine alkaloids is discussed.

Effective total synthesis of fagaronine: Antileukemic phenolic benzo(c)phenanthridine alkaloid.

Synthese a partir d'isopropoxy-3' trimethoxy-3,4,4' chalcone via la reaction de Bischler Napieralski du dimethoxy-3',4' benzyl-6 methoxy-3 N-methylformamido-5 naphtol-2

Determination of phenolic benzo( a)pyrene metabolites formed by human hair follicles

A modified fluoreometric procedure for the determination of basal arly hydrocarbon hydroxylase activity in human hair follicles is described. The method is also applicable for measurement of induction of the enzyme in primary cultures of keratinocytes originating from hair follicles. For good sensitivity of the assay the use of small incubation and extraction volumes, ultrapure chemicals, and adaptations in the measurement of the fluorescent signal are required. Moreover a sensitive micromethod for measuring DNA as a reference variable has to be employed. The sensitivity of the assay permits the measurement of aryl hydrocarbon hydroxylase in 20 hair follicles or in the outgrowth of 6 cultured hair follicles with good reproducibility. The method gives the opportunity to identify individuals with genetically controlled differences in the metabolism of polycyclic aromatic hydrocarbons, using an easily obtainable biopsy tissue of epithelial origin.

Aryl hydrocarbon (benzo[a]pyrene) mono-oxygenase activity in human primary amnion cell cultures

Amnion cells were isolated from placenta at term of healthy women and grown in monolayer cultures. The amnion cells formed dense sheets of cells of epithelial appearance after several days of growth. To evaluate these cells as targets for xenobiotics which have to be metabolically activated we have investigated their level and inducibility of the primary drug-metabolizing enzyme, aryl hydrocarbon (benzo[a]pyrene) mono-oxygenase (AHM). Amnion cells were found to contain very low levels of AHM which were highly inducible by addition of benz[a]anthracence to the growth medium. The inducibility of the enzyme was greatest during the first days of culture and declined by about two-thirds during the 5th and 8th day. After addition of the inducer, AHM activity increased several fold within 3 hr and reached a maximum at 16–24 hr. The culture age had no significant effect on the time course of induction. Constitutive and benz[a]anthracene-induced AHM were strongly inhibited by 7,8-benzoflavone suggesting that amnion cells in culture contain predominantly a cytochrome P-448-dependent mono-oxygenase form. Induced AHM activities in cultured amnion cells from 13 healthy donors ranged from 0.6 to 8.0 pmole of phenolic benzo[a]pyrene products/ min/ mg protein. The results indicate that primary amnion monolayer cultures offer a valuable model to study in human epithelial cells the activation and inactivation of cytotoxic and mutagenic substances which are metabolized by cytochrome P-448-dependent mono-oxygenase(s).

Phenolic benzo(a)pyrene metabolites are mutagens

Phenolic benzo(a)pyrene metabolites are mutagens

Aryl hydrocarbon hydroxylase induction in retinal pigmented epithelium: Possible association of genetic differences in a drug-metabolizing enzyme system with retinal degeneration

The aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity induced in the eye of the C57BL 6 N (responsive) inbred mouse strain by β-naphthoflavone is two- to more than 10-fold higher than that in the eye of the DBA 2 N (non-responsive) inbred mouse strain. Genetic expression of the hydroxylase induction in the eye appears to be under the same genetic regulation as that in the liver. The hydroxylase activity can be induced in cultured cells of chick embryonic retinal pigmented epithelium by 1,2-benz[a]anthracene. It is proposed that genetically regulated induction of the hydroxylase activity in the retinal pigmented epithelium plays an important role in metabolic potentiation, as well as detoxification, of drugs and other xenobiotic compounds. All known mouse strains which develop retinal degeneration are aromatic hydrocarbon responsive strains. Some of the major products of the aryl hydrocarbon hydroxylase reaction, phenolic benzo[a]pyrene derivatives, have a marked labilizing effect on lysosomal membranes. On the basis of these two observations, a possible involvement of the hydroxylase activity in initiating retinal degeneration is suggested.

Mutagenesis of certain activated carcinogens in vitro associated with genetically mediated increases in monooxygenase activity and cytochrome P 1-450.

A bacterial mutagenesis assay and genetic differences in microsomal CO-binding cytochromes were combined in vitro to evaluate the metabolic activation of several known carcinogens to frameshift mutagens. With the use of liver fractions from C57BL/6N and DBA/2N control mice and mice treated in vivo with 3-methylcholanthrene, beta-naphthoglavone, phenobarbital, or 2,3,7,,-tetrachlorodibenzo-p-dioxin, the in vitro mutagenicity of 3-methylcholanthrene, 6-aminochrysene, and 2-acetylaminofluorene --but not benzo[a]pyrene==is closely associated with the genetically mediated difference in both aromatic hydrocarbon-inducible aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity and new cytochrome P1-450 formation; such an association between 7,12-dimethylbenz[a]anthracene or benz[a]anthracene activation to mutagens in vitro and these genetic differences between C57BL/6N and DBA/2N mouse strains in uncertain. The Salmonella typhimurium histidine mutant TA1538 is more effective than tester strains TA1537 and TA1535 in the determination of 3-methylcholanthrene mutagenesis in vitro. The relationships between the histidine revertant rate as a function of both liver protein concentration per plate and mutagen concentration per plate are illustrated for 3-methylcholanthrene, benzo[a]pyrene, 6-aminochrysene, and 2-acetylaminofluorene. With the use of offspring from the appropriate genetic crosses, the aromatic hydrocarbon-inducible hydroxylase activity appears to be expressed as an autosomal dominant trait, whereas the mutagenesis of 3-methylcholanthrene in vitro appears to be expressed additively; this apparent discrepancy probably reflects different proportional amounts of phenolic benzo[a]pyrene, compared with mutagenic 3-methylcholanthrene metabolites, formed by the monooxygenase(s). 3-Methylcholanthrene, 6-aminochrysene, and 2-acetylaminofluorene--but not benzo[a]pyrene--are each more mutagenic in vitro per molecule of cytochrome P1-450 than per molecule of CO-binding cytochrome other than P1450. Diethylmaleate, a compound which depletes flutathione content in liver, and 1,1,1-trichloropropene-2,3-epoxide, an inhibitor of epoxide hydrase (EC 4.2.1.63), were also studied in vitro. Diethylmaleate, and especially 1,1,1-trichloropropene-2,3-epoxide, increases the mutagenicity of benzo[a]pyrene, whereas no increases occur with 3-methylcholanthrene, 6-aminochrysene, or 2-acetylaminofluorene activation to mutagens in vitro. Both diethylmaleate and 1,1,1-trichloropropene-2,3-epoxide cause decreases in 2-acetylaminofluorene mutagenesis in vitro when liver fractions from phenobarbital-treated mice are used.