Harman products

In view of its possible interest as the mode of formation of harman, harmine and harmaline in plants, Kermack, Perkin and Robinson investigated the conversion of tryptophan (II) into harman (I) and nor-harman (IV). The latter is produced when tryptophan is condensed with formaldehyde in presence of dilute sulphuric acid and the product (III) oxidised by potassium dichromate. Harman is formed when formaldehyde in this process is replaced by acetaldehyde. 

The synthesis reported by MaGee and Beck [19] also used ester 17 as a key intermediate, though the natural product harmane 18 was used as the starting material instead of tryptamine (Fig. 7). Treatment of 18 with four equivalents... 

Sexton, A., Drake, RM., Mahmod, N., Harman, S.J., Shattock, R.J., and Ma, J.K-C. (2005). Transgenic plant production of Cyanovirin-N, an HIV microbi-cide. FASEB J. December, express article 10.1096/fj.05-4742fje... 

The simple indole alkaloids harman (27) and harmine (28) are also susceptible to biotransformation. Polystictus versicolor metabolizes both 27 and 28 to unidentified products, formed in a yield of 50% in the case of 28 (42). Mammalian liver preparations perform an oxidative O-demethylation of harmine (28) to produce harmol (29) (45). The supernatant fraction from the lO.OOOg centrifugation of liver homogenates of cow, mouse, rabbit, guinea pig, rat, and cat were all effective in O-demethylation, the highest yields (90%) being obtained after incubation for 30 min with the preparations from cow and mouse liver (45). No other products were detected from the biotransformation of harmine by the liver preparations mentioned above,... 

A variety of alkaloids bind to or intercalate with DNA or DNA/RNA processing enzymes and affect either transcription or replication (quinine, harmane alkaloids, melinone, berberine), act at the level of DNA and RNA polymerases (vinblastine, coralyne, avicine), inhibit protein synthesis (sparteine, tubulosine, vincrastine, lupanine), attack electron chains (pseudane, capsaicin, solenopsine), disrupt biomembranes and transport processes (berbamine, ellipticine, tetrandrine), and inhibit ion channels and pumps (nitidine, caffeine, saxitoxin). In addition, these natural products attack a variety of other systems that can result in serious biochemical destabilization... 

Kubicek, C., and Penttila, M. 1998. Regulation of production of plant polysaccharide degrading enzymes by Trichoderma. In Harman, G., and Kubicek, C. (Eds.), Trichoderma and Gliocladium, 2 (pp. 49-72). London Taylor and Francis Ltd. 

Note. Harman may be found in tobacco smoke and in homemade wine. It may also be found as a putrefactive base, particularly in cases where embalming has taken place. It is a condensation product of tryptophan and acetaldehyde. 

Choice between centralized and decentralized procedures in the case of many NCEs (those for which the centralized procedure is not mandatory) involves many factors, and the decision is a strategic milestone involving medical practice, manufacturing plans, the nature of product, market forces, and the size, resources, and strengths of the sponsor in the EU (see Harman, 2004, for more details). 

Figure 1. Structures of representative phototoxic plant products from various phytochemical classes. (I) 1-phenylhepta-1,2,3-triyne (acetylenic polyine) (II) 6-methoxyeuparin (benzofuran) (III) harmane (beta-carboline alkaloid) (IV) khellin (furo-chromone) (V) 8-methoxypsoralen (furocoumarin) (VI) dictamnine (furoqulnoline alkaloid) (VII) nordihydroguaiaretic acid (lignan) and (VIII) alpha-terthienyl (thiophene).

Three eudistomins display phototoxicity against several viruses, bacteria, yeast and mammalian cells (201,202) when the natural products are exposed to ultraviolet (UVA) irradiation. The activity appears to diminish with increasing side chain complexity eudistomin N (3) is most active, being similar in phototoxicity to P-carboline and harman. Eudistomins M (13) and O (4) were moderately active while eudistomins H (7) and I (8) were effectively inactive even in the presence of UVA. 

The theory and experiment of direct crystallization of enantiomers is quite well understood at present [10]. There are a number of variables which affect the resolution by direct crystallization in practice. Several technological schemes based on this principle are realized on the commercial scale. These are, for example, the Merck process used for the production of antihypertensive drug methyldopa [11], a process developed by Harman and Reimer for (-)-menthol, which is separated as an ester [12], the process patented by Industria Chimica Profarmaco for the resolution of naproxen enantiomers as the ethylamine salt [13], the production of L-glutamic acid by the Japanese company Ajinomoto on a scale in excess of 10000 tons annually as early as the 1960s [14], etc. In general, it seems that spontaneous crystallization is a very useful technique for the enantioseparation of the naturally occurring a-amino acids. All of them may be resolved either directly or as derivatives [10]. 

Rodgman also discussed the already identified and other possible theoretical relationships (Figure XVII.F-5) between tryptophan XX and 9//-pyrido[3,4-( ]indole (norharman) II its methyl homolog l-methyl-9//-pyrido[3,4-fc]indole (harman) III and other substituted norharmans VI, R = C2H5, CH3CH=CH, and -C4H9, the tryptophan pyrolysis products 3-amino-1,4-dimethyl-5/7-pyrido-[4,3-( Jindole (Trp-P-1) IV and 3-amino-l-methyl-5//-pyrido[4,3-( ] indole (Trp-P-2) V the alkyl- and dialkyl-indoles indole-... 

Detection of comutagenic compounds, harman and norharman, in pyrolysis products of proteins and food by gas chromatography-mass spectrometry Proc. 37th Ann. Mtg., Japan Cancer Assoc. (1978) 21. 

The comutagenic action of Norharman upon aryl hydrocarbon hydroxylase activity is shown to be cytochrome P-448 dependent by immunochemical analysis. The hydroxylated products of Norharman and Harman may play an important role in their comutagenic action by fluidizing the microsomal or nuclear membranes. 

The confusion on the mechanism of the comutagenesis and mutagenesis of these pyrolysis products, especially pertaining to the enhancement and inhibition effects of Harman and Norharman,centers around the problem of the lack of certain fixed variables in the experimentation, particularly, the availability of the purified enzymes involved in the metabolic activation, which constitute the cytochrome P-450 mixed function oxidase system. We, therefore, undertake this problem to elucidate the mechanism of microsomal metabolism of these oyrolysis products with the purified mixed function oxidase(MFO) system. 

Harman and coworkers have explored the reactivity of -osmium complexes of pyrroles. These complexes can react as nonaromatic species in which the Os has localized two of the Ji-electrons. For example, the complex of 1-methylpyrrole gives a conjugate addition product with methyl vinyl ketone in the presence of TBDMS triflate <93JOC4788>. Decomplexation by reaction with a base gives a 3-substituted pyrrole (Scheme 131). 

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