Methylcarbazoles

Therapeutic Function Antiinflammatory Chamical Name 6-Chloro-a-methylcarbazole-2-acetic acid Structural Formula ci... 

A stirred mixture of 11 g of 6-chloro-a-methylcarbazole-2-acetic acid ethyl ester, 100 ml ethanol and 100 ml of 3N sodium hydroxide was heated (N2 atmosphere). After 2 hours at reflux, the reaction mixture was concentrated to dryness under reduced pressure. Water (300 ml) and ice (200 g) were added to the residue and concentrated hydrochloric acid was added until the mixture was strongly acid. The acidic mixture was extracted with ether (3 X 200 ml). The ether extracts were combined, washed by extraction with water (3 x 100 ml) and dried over anhydrous magnesium sulfate. Following filtration of the desiccant and evaporation of the solvent, a yield of 9.8 g (98.2%) was obtained. Crystallization from CHCI3 yielded 6.2 g (62.0%) of 6-chloro-0 -methylcarbazole-2-acetic acid, MP 197°-198°C. A second crop of 1.6g,MP 195°-199°C was obtained from the mother liquors. 

Yang, W. and Davis, P.J. (1992) Microbial models of mammalian metabolism biotransformation of N-methylcarbazole using the fungus Cunninghamella echinulata. Drug Metabolism and Disposition The Biological Fate of Chemicals, 20, 58 46. 

Carbazole, A-methylcarbazole, IV-ethylcarbazole, dibenzofuran, dibenzothiophene, fluorene, dibenzo-p-dioxin, phenoxathiin, phenoxazine, phenothiazine, xanthene, biphenyl, naphthalene, phenanthrene, anthracene, and fluoranthene could be transformed by E. coli, [314] which was transformed using a plasmid bearing the carAa, Ac, and Ad genes, and expressing only the carA-encoded proteins. Further work is needed to develop a final biocatalyst and to prove the advantages that this degradative pathway would incorporate in a refining bioprocess. 

Shen T, Hollenberg PF. The mechanism of stimulation of NADPH oxidation during the mechanism-based inactivation of cytochrome P450 2B1 by N-methylcarbazole redox cycling and DNA scission. Chem Res Toxicol 1994 7(2) 231-238. 

In contrast to the 1- and 2-oxygenated tricyclic carbazole alkaloids, most of the 3-oxygenated and the 3,4-dioxygenated tricyclic carbazole alkaloids were isolated from Streptomyces (Scheme 2). Their common structural feature is a 2-methylcarbazole, although biosynthetic studies on carbazomycin B have shown that tryptophan is the precursor of the carbazole nucleus [26]. 4-De-... 

The dimeric carbazole alkaloids often occur along with the corresponding monomeric carbazoles in terrestrial plants [7,62] (Scheme 7). Clausenamine-A was obtained by Wu from the stem bark of Clausena excavata [63]. Clausen-amine-A and its synthetic analogs, like bis(O-demethylmurrayafoline-A), show cytotoxic activities against diverse human cancer cell lines [64] and exhibit moderate antimalarial activity [65,66]. Furukawa isolated l,r-bis(2-hy-droxy-3-methylcarbazole) and bismurrayaquinone-A, the first dimeric car-bazolequinone alkaloid found in nature, from Murraya koenigii [67]. 

The iron-mediated synthesis of 2-oxygenated carbazole alkaloids is limited and provides only a moderate yield (11%) for the oxidative cyclization to 2-methoxy-3-methylcarbazole using iodine in pyridine as the reagent [90]. Ferricenium hexafluorophosphate is the superior reagent for the iron-mediated arylamine cyclization leading to 3-oxygenated carbazoles (Scheme 12). Electrophilic substitution of the arylamines 16 with the complex salt 6a leads to the iron complexes 17. Oxidative cyclization of the complexes 17 with an excess of ferricenium hexafluorophosphate in the presence of sodium carbonate affords... 

Scheme 25 Synthesis of the 2-oxygenated tricyclic carbazole alkaloids 66-69 and l,r-bis(2-hydroxy-3-methylcarbazole) 70...

The formation of a small amount of naphthalene as a by-product of the reaction of benzyne with iV -methylpyrrole was noted by Wittig and Behnisch. Some related examples have recently been described. The tetrachloronaphthalen-l,4-imine (108) with benz5me gave N-methylcarbazole, which it is tempting to see as arising from the reaction of an intermediate zwitterion (compare 166) with another molecule of benzyne or, more likely, a benzyne precursor. The complementary product, 1,2,3,4-tetrachloronaphthalene, was not identified in this case. 

Determination of various analgesic and antipyretic pharmaceuticals on reversed phase has included not only the analysis of serum levels of aspirin, salicylic acid and salicyluric acid using acidified acetonitrile (557), or methanol (338), but also suUinpyrazone under isocratic conditions (339), and 6-chloro-a-methylcarbazole-2-acetic acid (340). The polar thiol metabolites of acetaminophen were analyzed by RPC and the method was found to be superior to other chromatographic techniques used in this analysis (341). 

Several hypotheses have been proposed for the biogenesis of carbazole alkaloids (see Chapter 3 of this review). However, there is no deep experimental knowledge of the biosynthesis of this class of alkaloids. A comparison of the structural features of carbazole alkaloids isolated from higher plants suggests that 3-methylcarbazole (2) may represent the key intermediate in their biosynthesis (Scheme 1.1). 

The isolation of carbazole (1), 3-methylcarbazole (2), and several oxidized derivatives of 3-methylcarbazole from taxonomically related higher plants of the genera Glycosmis, Glausena, and Murraya (family Rutaceae) indicates that the aromatic methyl group of the biogenetic key intermediate 3-methylcarbazole can be eliminated oxidatively (5,6). Most of the carbazole alkaloids isolated from the... 

In 1997, Chakrabarty et al. reported the isolation of 9-carbethoxy-3-methylcarba-zole (5) and 9-formyl-3-methylcarbazole (6) from the roots of M. koenigii (17). These metabolites are the first 9-formyl and 9-carbethoxy carbazole derivatives obtained from plant sources. 9-Formyl-3-methylcarbazole (6) showed weak cytotoxicity against both mouse melanoma B16 and adriamycin-resistant P388 mouse leukemia cell lines. The structural assignment of these two alkaloids was based on the IR- and H-NMR spectra which were lacking any signal of an NH group. Additional structural support for 9-carbethoxy-3-methylcarbazole (5) was provided by the similarity of the UV absorption spectrum with that of a synthetic sample, obtained by reaction of 3-methylcarbazole with ethyl chloroformate in the presence of base. Further structural support for 9-formyl-3-methylcarbazole (6) was derived from a comparison of the UV spectrum and the IR carbonyl absorption (1696 cm ) with those of an authentic sample of 9-formyl-3-methylcarbazole (1700 cm ), prepared by the treatment of 3-methylcarbazole (2) with 98% formic acid (17) (Scheme 2.3). 

Among the large number of carbazole alkaloids that have been isolated from M. koenigii are also many 2-oxygenated derivatives. In 1985, Bhattacharyya et al. isolated 2-methoxy-3-methylcarbazole (37) from the petroleum ether extract of the seeds of M. koenigii (55). The UV spectrum (Tmax 235,255,300, and 328 nm) and the IR... 

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