Norharman derivatives

Methylthiazolidine-4-carboxylic acid, a condensation product of cysteine and acetaldehyde, occurs even in human blood as a consequence of ethanol consumption. Serine and threonine analogously produce C-2 substituted (2J S,4S)-oxazolidine-4-carboxylic acids (2-124). Heterocyclic products, C-2 substituted (2J S,4S)-pyrimidine-4-carboxylic acids, are also produced in the reaction of aldehydes with asparagine (2-125). Phenylalanine yields C-1 substituted (lJ S,3S)-tetrahydroisoquinoline-3-carboxylic acids (2-126) and analogous products arise from tyrosine. Tryptophan reacts with aldehydes under the formation of 9H-pyrido[3,4-b]indole (also known as -carboline or norharmane) derivatives, (lJ S,3S)-l,2,3,4-tetrahydro-fi-carboline-3-carboxylic acids (2-127, R = H or alkyl or residues of other aldehydes and sugars), the reaction of tryptamine yields the corresponding (lRS)-l,2,3,4-tetrahydro-P-carbolines. 

M. Nagao, T. Yahagi, M. Honda, Y. Seino, T. Kawachi, and T. Sugimura, Comutagenic actions of norharman derivatives with 4-dimethylaminoazobenzene and related compounds, Cancer Lett. 3, 339-346 (1977). 

Trp-P-2 (3-amino-l-methyl-5//-pyrido[4,3-h]indole), AaC (2-amino-9//-pyrido[2,3-bJindole), MeAaC (2-amino-3-methyl-9//-pyrido[2,3- ]indole), and PhIP (2-amino-1-methyl-6-phenyl-imidazo[4,5-h]pyridine) and two /3-carbolines comutagens harman (l-methyl-9//-pyrido[4,3-h]indole) and norharman (9//-pyrido[4,3-h]indole). The optimized SPE procedure for isolation and preconcentration comprises the use of diatomaceous earth, propylsulfonyl silica gel, and C18 cartridges to separate selectively the imidazopyridine and indolpyridine derivatives from those of... 

Suzuki J, Koyama T, Suzuki S. 1983. Mutagenicity of mono-nitrobenzene derivatives in the presence of norharman. Mutat Res 120 105-110. 

Some of these compounds have been detected upon thermal decomposition of certain foods, amino acids, and proteins. Significant amounts of compound (13), known as norharman, and its 9-methyl derivative, commonly called harman, have been found in tryptophan pyrolyzates. Similarly, cigarette smoke condensate has been found to contain significant amounts of both of these compounds <82JC331>. 

The 6-bromo and 7-bromo derivatives of norharman (13), known as eudistomin N and O, respectively, have been shown to have both antiviral and antimicrobial activity <87JA3378>. Compound (13) and some of its derivatives, including tetrahydro derivatives, were investigated for their ability to bind to benzodiazepine receptors in the brain. Trends showed that fully aromatic deriva-... 

Suzuki J, Takahashi N, Kobayashi Y, et al. 1987. Dependence on Salmonella typhimurium enzymes for mutagenicities of nitrobenzene and its derivatives in the presence of rat-liver S9 and norharman. Mutat Res 178 187-193. 

Although not originally classified at the time as cooked food mutagens, several amino acid-derived iV-heterocyclic compounds were identified in cigarette smoke condensate (CSC) in the early 1960s 5//,10//-Dipyrrolo[l,2-a r,2 -(i] pyrazine-5,10-dione (pyrocoll) 1 by Mold et al. (2592) and 9H-pyrido[3,4-fc]indole (norharman) 11 and l-methyl-9-H-pyrido[3,4-fc ]indole (harman) 111 by Poindexter and Carpenter (2972) (Figure XVll.F-1). 

In its 1985 review, published in 1986, of the various problems from exposure to numerous components in tobacco smoke, the lARC (1870) did not designate the A-heterocyclic amines as a problem. lARC did list several tryptophan-derived tobacco smoke isolates including 9A-pyrido[3,4-f>]indole (norharman) and l-methyl-9A-pyrido[3,4-f>]indole (harman). The per cigarette MSS yields of these two components were listed as 9.5 to 14.1 and 2.5 to 5.8 xg/cig, respectively. No mention was made of the A-heterocyclic amines in CSC or the degree of evidence for their carcinogenicity in animals and humans. 

Umezawa, K. Shirai, A. Matsushima, T. Sugimura, T. 1978. Comutagenic effect of norharman and barman with 2-acetyl-aminofluorene derivatives. Proceedings of the National Academy of Sciences Vol. 75 928-930. 

Uezono T, Maruyama W, Matsubara K, Naoi M, Shimizu K, Saito O, Ogawa K, Mizukami H, Hayase N, Shiono H (2001) Norharman, an indoleamine-derived betacarboline, but not Trp-P-2, a gamma-carboline, induces apoptotic cell death in human neuroblastoma SH-SY5Y cells. J Neural Transm 108 943-953... 

Decarboxylation and oxidation products of 1,2,3,4-tetrahydro-P-carbohne-3-carboxylic acids derived from formaldehyde, 9H-pyrido(3,4-fo]indole (norharmane, 2-127), and acetaldehyde, 1-methyl-9//-pyrido[3,4-fo]indole (harmane, 2-127), were identified in a number of foods at levels up to 700 mg/kg, although more typically their concentrations in smoked, cooked and fermented foods range from a few mg/kg to 1-2 orders of magnitude less. Typical norharmane and harmane findings in pan-fried, minced meat, beef patties or ground beef prepared at temperatures of 175-230 °C and... 

K. Umezawa, A. Shiri, T. Matsushima, and T. Sugimura, Comutagenic effect of norharman and barman with 2-acetylaminofluorene derivatives Salmonella typhimurium/xmcTosomd enzymes/carcinogens, Proc. Natl. Acad. Sci. U.S.A. 75, 928-930 (1978). 

Norharman is uncompetitive with L-tryptophan for rabbit intestinal IDO and linearly competitive with L-tryptophan for mouse liver TPO. Some p-carbolines in 11-13 selectively inhibit one enzyme or the other. Specific inhibition effect of p-carbolines is different between TPOs from mammalian and Pseudomonad sources. Similarly, indole-3-acetamide, -acetonitrile, and -acrylic acid exhibit a potent inhibition for mammalian TPO, while they moderately inhibit the Pseudomonad enzyme. These indole derivatives show no inhibition for IDO. From these results, the difference of the structures of the active sites among these enzymes from various sources is suggested. 

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