Harmine derivatives

The N-alkylated harmine derivatives were prepared by simple alkylation of harmine anions (generated using sodium hydride) with alkyl halides and bromides. For example, 56 was prepared in 83% yield in this manner, and the N-methyl analog (which had similar antitumor activity to that of 56) was obtained in 80% yield using methyl iodide. 

Chen Q, Chao R, Chen H, Hou X, Yan H, Zhou S, Peng W, Xu A (2005) Antitumor and neurotoxic effects of novel harmine derivatives and structure-activity relationship analysis. Int J Cancer 114 675-682... 

Spath and Lederer have published a simplified synthesis of harmaline consisting in treating the acetyl derivative of 6-methoxytryptamine (XXIX) with phosphorus pentoxide in boiling xylene, the harmaline thus produced being converted into harmine by catalytic dehydrogenation at 200°. 

The alkylation of carboline derivatives has been repeatedly studied. The first quaternary A-alkyl carbolinium salts to be described were those prepared in connection with the elucidation of the structure of harmine (methiodide, methochloride, and methosulfate Other j8-carbolinium salts were subsequently prepared in connection with systematic studies of the site of alkylation and of the... 

These authors formulated the major steps in the biogenesis of the harmala bases as a condensation of a tryptamine derivative (460) with acetaldehyde to yield a l,2,3,4-tetrahydro-)3-carboline (461), which on oxidation in two stages would give harmaline (462 R = OCH3) and then harmine (463 R = OCH3). 

Although harmine 52 is frequently obtained by isolation (or purchase order), a synthesis of this compound as well as a number of analogs has recently appeared [47,48]. The key step to this synthesis was the thermal electrocyclization of oxime intermediate 55, which was prepared by acylation of vinylindole derivative 54 followed by treatment with hydroxylamine hydrochloride. Neither oxime 55 nor its ketone precursor were isolated— instead, the crude reaction mixture was heated at reflux in o-dichlorobenzene to ultimately yield harmine in 56% yield overall starting from 54 (Fig. 18). 

Seven groups of these drugs can be separated based on their various chemical f structures (a) lysergic acid derivatives, of which lysergide (LSD) is the prototype (b) phenylethylamine derivatives, of which 3,4,5-trihydroxyphenylethylamine (mescaline) is the prototype (c) indolealkylamines, such as 4-phosphorodi-methyltryptamine (psilocybin) (d) other indolic derivatives, such as the harmine... 

In summary, based on the results of relatively limited studies, the dihydro beta-carboline, harmaline (80), is more active than either its fully unsaturated derivative harmine (79) or its reduced derivative tetrahydroharmine (81). The positional isomer of harmine, 6-methoxyharmalan (85), is slightly more potent than harmaline. Reduction to the tetrahydro derivative 86 reduces potency. Although thorough dose-effect studies have not yet been performed, none of the beta-carboline derivatives has been found to be significantly more potent than DMT (37). 

Anthranilic acid-derived Zygophyllaceae Peganum harmala Harmin... 

Harmin14 derived an approximate form of the transformation of Eq. (6.18) which is particularly useful. The information contained in the quantum numbers nx and n2 always appears as ( , — n2) and can also be represented by Zx and Z, the separation constants, a notion which easily passes into the regime in which n2 is not a well defined quantum number. (In a field nx is always a good quantum number.) Explicitly, Harmin showed that Eq. (6.18) can also be written as14... 

Back to the individual chemical stories. This commentary will cover the scatter of beta-carbolines that might play some major role in the human nervous system, other than the harmine trilogy. Harmine, harmaline and tetrahydroharmine all have the oxygen at the 7-position, and mostly have their origins in the botanical world. The 6-position oxygen can come directly from serotonin or hydroxy-tryptophan, and are found both in plants and animals. Similarly, the hydrogen derivatives (unsubstituted) derive from tryptamine and tryptophan, again from both plants and animals. 

During their early investigations of harmine, Perkin and Robinson attempted a synthesis of what they thought to be isoharman. The 2-quinolone amide (74) was cyclized with phosphoryl chloride to a chloro compound (75), which gave 2.ff-pyrrolo[2,3-6]quinoline (76, R = H) with tin and hydrochloric acid, and its 3-methyl derivative (75, R = Me) with methylmagnesium iodide. The name quinindole ... 

Of much interest is the recent discovery of substances closely related to the harmala alkaloids in animals. One of these is adrenoglomerulotropine, a hormone of the pineal body, the chemical identity of which has been indicated as 2,3,4,9-tetrahydro-6-methoxy-i-methyl-iH-pyrido (3,4,6) indole. This substance is identical to 6-methoxyletrahydroharman which has been shown to be formed in vivo from 5-methoxy tryptamine and acetaldehyde. 6-methoxytetrahydroharman is an isomer of tetrahydro-harmine, one of the alkaloids in Banisteriopsis, and in the African Leptactinia densillora. One more substance, 6-methoxyharmalan, has been shown to derive, at least in vitro, from melatonin, which results from the methylation of acetylserotonin. The enzyme which makes this possible, hydroxyindole O-methyl transferase, has only been found in the pineal body. (Naranjo, in Efron et al. 

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