harman and tryptoline

Iodobenzene diacetate was employed as a mild and efficient reagent for one-pot oxidative decarboxylation of tetrahydro-β-carboline acids and dehydrogenation of tetrahydro-β-carbolines to access the corresponding aromatic β-carbolines. To the best of our knowledge this is the first synthesis of β-carbolines via a one-pot oxidative decarboxylation at ambient temperature. The utility of this protocol has been demonstrated in the synthesis of β-carboline alkaloids norharmane (2o), harmane (2p), eudistomin U (9) and eudistomin I (12).

Topics: Acetates; Carbolines; Decarboxylation; Harmine; Iodobenzenes; Molecular Structure; Oxidation-Reduction

Beta-carboline alkaloids present in Peganum harmala (harmal) have recently drawn attention due to their antitumor activities. The mechanistic studies indicate that beta-carboline derivatives inhibit DNA topoisomerases and interfere with DNA synthesis. They interact with DNA via both groove binding and intercalative modes and cause major DNA structural changes. The aim of this study was to examine the interactions of five beta-carboline alkaloids (harmine, harmane, harmaline, harmalol and tryptoline) with calf-thymus DNA in aqueous solution at physiological conditions, using constant DNA concentration (6.25 mM) and various alkaloids/polynucleotide (phosphate) ratios of 1/240, 1/160, 1/80, 1/40, 1/20, 1/10, 1/5, 1/2 and 1/1. Fourier transform infrared (FTIR) and UV-visible spectroscopic methods were used to determine the ligand binding modes, the binding constants, and the stability of alkaloids-DNA complexes in aqueous solution. Spectroscopic evidence showed major binding of alkaloids to DNA with overall binding constants of K(harmine)-DNA=3.44x10(7) M(-1), K(harmane)-DNA=1.63x10(5) M(-1), K(harmaline)-DNA=3.82x10(5) M(-1), K(harmalol)-DNA=6.43x10(5) M(-1) and K(tryptoline)-DNA=1.11x10(5) M(-1). The affinity of alkaloids-DNA binding is in the order of harmine>harmalol>harmaline>harmane>tryptoline. No biopolymer secondary structural changes were observed upon alkaloid interaction and DNA remains in the B-family structure in these complexes.

Topics: Animals; Antineoplastic Agents; Binding Sites; Carbolines; Cattle; DNA; Harmaline; Harmine; Intercalating Agents; Nucleic Acid Conformation; Peganum; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared

β-Carboline alkaloids are present in medicinal plants such as Peganum harmala L., which have been used as folk medicine in anticancer therapy. Recently, they have drawn attention because of their antitumor activities. Despite considerable interest and investigations on alkaloid-DNA complexes, reports on alkaloid-RNA interaction are very limited. This study is the first attempt to investigate the binding of β-carboline alkaloids (harmine, harmane, harmaline, harmalol, and tryptoline) with yeast RNA. The effect of alkaloid complexation on RNA aggregation and condensation was investigated in aqueous solution at physiological conditions, using constant RNA concentration (6.25 mM) and various alkaloid:polynucleotide (phosphate) ratios of 1:240, 1:160, 1:80, 1:40, 1:20, 1:10, 1:5, 1:2, and 1:1. Fourier transform infrared and UV-visible spectroscopic methods were used to determine the ligand-binding modes, the binding constants, and the stability of alkaloid-RNA complexes in aqueous solution. Spectroscopic evidence showed major binding of alkaloids to RNA with overall binding constants of K(harmine)-RNA = 2.95 × 10⁷ M⁻¹, K(harmane)-RNA = 5.62 × 10⁵ M⁻¹, K(harmaline)-RNA = 7.47 × 10⁵ M⁻¹, K(harmalol)-RNA = 4.32 × 10⁵ M⁻¹, and K(tryptoline)-RNA = 3.21 × 10⁵ M⁻¹. The affinity of alkaloids-RNA binding is in the order of harmine > harmaline > harmane > harmalol > tryptoline. No biopolymer secondary structural changes were observed upon alkaloid interaction and RNA remains in the A-family structure in these complexes.

Topics: Carbolines; Harmaline; Harmine; Nucleic Acid Conformation; Peganum; Plants, Medicinal; RNA, Fungal

beta-Carbolines are potent modulators of GABA type A receptors and they have recently been shown to inhibit glycine receptors in a subunit-specific manner. The present study screened four structurally similar beta-carbolines, 1,2,3,4-tetrahydronorharmane, norharmane, harmane and 6-methoxyharmalan, at recombinantly expressed alpha1, alpha1beta, alpha2 and alpha3 glycine receptors with the aims of identifying structural elements of both the receptor and the compounds that are important for binding and subunit specificity. The four compounds exhibited only weak subunit specificity, rendering them unsuitable as pharmacological probes. Because they displayed competitive antagonist activity, we investigated the roles of known glycine binding residues in coordinating the four compounds. The structural similarity of the compounds, coupled with the differential effects of C-loop mutations (T204A, F207Y) on compound potency, implied direct interactions between variable beta-carboline groups and mutated residues. Mutant cycle analysis employing harmane and norharmane revealed a strong pairwise interaction between the harmane methyl group and the C-loop in the region T204 and F207. These results which define the orientation of the bound beta-carbolines were supported by molecular docking simulations. The information may also be relevant to understanding the mechanism beta-carboline of binding to GABA type A receptors where they are potent pharmacological probes.

Topics: Binding Sites; Carbolines; Cell Line; Harmine; Humans; Mutagenesis, Site-Directed; Mutation; Protein Structure, Secondary; Protein Subunits; Receptors, Glycine; Recombinant Proteins

Tetrahydro-beta-carboline alkaloids that occur in foods such as wine, seasonings, vinegar and fruit products juices, jams) acted as good radical scavengers (hydrogen- or electron donating) in the ABTS (2,2'-Azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) assay, and therefore, they could contribute to the beneficial antioxidant capacity attributed to foods. In contrast, the fully aromatic beta-carbolines norharman and harman did not show any radical scavenger activity in the same assay. During the reaction with ABTS.+ radical cation, tetrahydro-beta-carboline-3-carboxylic acid such as 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (MTCA) and 1-methyl-1,2,3,4-tetrahydro-beta-carboline-1,3-dicarboxylic acid (MTCA-COOH) were converted to harman, whereas 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (THCA) and 1,2,3,4-tetrahydro-beta-carboline-1,3-dicarboxylic acid (THCA-COOH) afforded norharman. These results suggest that food and naturally-occurring tetrahydro-beta-carboline alkaloids if accumulated in tissues, as reported elsewhere, might exhibit antioxidant activity.

Topics: Antioxidants; Benzothiazoles; Carbolines; Cations; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Food Analysis; Free Radicals; Gas Chromatography-Mass Spectrometry; Harmine; Indicators and Reagents; Models, Chemical; Sulfonic Acids; Time Factors

The beta-carbolines harmane, norharmane, tetrahydronorharmane, harmine, harmaline and harmol were administered to sheep to assess their effects on upper motor neurone function. Harmane at a dose rate of 54 mg/kg induced hypomotility, head tremors, pelvic limb paresis, hypermetria and a wide based stance. A range of similar effects were observed with norharmane at the same dose rate. Tetrahydronorharmane at a dose rate of 54 mg/kg induced hypermotility followed by hypomotility, asymmetrical pelvic limb paresis, hypermetria, a wide based stance, and stereotyped eating behaviour. Harmine and harmaline at 6 mg/kg induced mild head and body tremors, and at 18 mg/kg induced hypomotility, intense head and body tremors, pelvic limb paresis, crossing over of limbs, neck extension and head swaying. Harmol was not effective at 54 mg/kg by either the subcutaneous or intraperitoneal routes, but at an intravenous dose of 27 mg/kg it induced hypermotility followed by hypomotility, body tremors, limb paresis, muscle asynergy, a wide based stance and jumping behaviour. Harmane, tetrahydronorharmane, harmaline and harmol were convulsive in some sheep at high dose rates.

Topics: Alkaloids; Animals; Carbolines; Female; Harmaline; Harmine; Locomotion; Motor Neurons; Plants, Toxic; Sheep

Acetylcholinesterase (acetylcholine acetylhydrolase, EC 3.1.1.7) activity and muscarinic receptor binding of homogenates from several brain structures were inhibited by beta-carbolines. The inhibition was of the noncompetitive type in the case of the enzyme and of the mixed type in the case of the receptor binding. This effect was most strongly manifested by pyridoindoles(harmane, norharmane), i.e., carbolines containing an aromatic C ring than by the corresponding piperidoindoles (tetrahydroharmane, tetrahydronorharmane), i.e., those with a reduced C ring. The activity of choline acetyltransferase (acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6) was not altered. These data are further evidence of the interactions between indoleamine derivatives and the cholinergic system. The results are discussed in terms of their possible biological significance.

Topics: Acetylcholinesterase; Alkaloids; Animals; Brain; Carbolines; Cattle; Choline O-Acetyltransferase; Erythrocytes; Harmaline; Harmine; Indoles; Kinetics; Male; Rats; Rats, Inbred Strains; Receptors, Cholinergic; Receptors, Muscarinic; Structure-Activity Relationship

We have prepared a series of tetrahydro-beta-carbolines (TH beta C), beta-carbolines (beta-C), and other nitrogen heterocycles and evaluated them in vitro with respect to their ability to bind to benzodiazepine receptors. The fully aromatic beta-C's were more potent than their corresponding TH beta C derivatives. When substituents possessing a carbonyl (CO2Me, COCH3, CHO) were introduced at the beta-C 3-position the in vitro potency was augmented. Alcohol substituents (CH2OH, CHOHCH3) demonstrated decreased in vitro potency. The importance of the carbonyl moiety was further demonstrated when beta-carboline-3-carboxylic acid was shown to bind tighter to benzodiazepine receptors at lower pH. A lower pH increases the concentration of the acid and decreases the concentration of the anion. 3-(Hydroxymethyl)-beta-carboline (24), 3-formyl-beta-carboline (25) and 3-acetyl-beta-carboline (27) were benzodiazepine antagonists in vivo. Methyl isoquinoline-3-carboxylate (31a) also had in vitro activity. The same structure-activity relationships seen in beta-C's were also observed for isoquinolines.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Brain; Carbolines; Chemical Phenomena; Chemistry; Diazepam; Drug Interactions; Indoles; Male; Mice; Pentylenetetrazole; Rats; Rats, Inbred Strains; Receptors, Drug; Receptors, GABA-A