487-03-6

Usage

InChI:InChI=1/C12H10N2O/c1-7-12-10(4-5-13-7)9-3-2-8(15)6-11(9)14-12/h2-6,14-15H,1H3

Upstream product

• 442-51-3 harmine 
• 17952-75-9 Tetrahydroharmol 
• 443-31-2 6-hydroxytryptamine 
• 1362736-69-3 C₁₀H₈N₂O₃ 
• 304-21-2 harmaline 
• 7647-01-0 hydrogenchloride 
• 257938-78-6 7-acetyloxy-1-methyl-9H-pyrido[3,4-b]indole 

Downstream Products

• 1207519-31-0 2-benzyl-7-hydroxy-1-methyl-9H-pyrido[3,4-b]indole-2-ium trifluoroacetate 
• 1207519-30-9 2-benzyl-7-benzyloxy-1-methyl-9H-pyrido[3,4-b]indol-2-ium trifluoroacetate 
• 1118607-50-3 3-[(1-methyl-9H-β-carbolin-7-yl)oxy]propyl 4-methylbenzenesulfonate 
• 1118607-48-9 2-[(1-methyl-9H-β-carbolin-7-yl)oxy]ethyl 4-methylbenzenesulfonate 

Relevant academic research and scientific papers

Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic β-carboline alkaloids harmaline and harmine

The psychotropic β-carboline alkaloids, showing high affinity for 5-hydroxytryptamine, dopamine, benzodiazepine, and imidazoline receptors and the stimulation of locus coeruleus neurons, are formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with aldehydes in both plants and mammals. Cytochromes P450 1A1 (18.5), 1A2 (20), and 2D6 (100) catalyzed the O-demethylation of harmaline, and CYP1A1 (98.5), CYP1A2 (35), CYP2C9 (16), CYP2C19 (30), and CYP2D6 (115) catalyzed that of harmine (relative activities). The dehydrogenation/aromatization of harmaline to harmine was not carried out by aromatase (CYP19), CYP1A2, CYP2C9, CYP2D6, CYP3A4, pooled recombinant cytochromes P450, or human liver microsomes (HLMs). Kinetic parameters were calculated for the O-demethylations mediated by each isozyme and by pooled HLMs. Kcat (min-1) and Km (μM) values for harmaline were: CYP1A1, 10.8 and 11.8; CYP1A2, 12.3 and 13.3; CYP2C9, 5.3 and 175; CYP2C19, 10.3 and 160; and CYP2D6, 39.9 and 1.4. Values for harmine were: CYP1A1, 45.2 and 52.2; CYP1A2, 9.2 and 14.7; CYP2C9, 11.9 and 117; CYP2C19, 21.4 and 121; and CYP2D6, 29.7 and 7.4. Inhibition studies using monoclonal antibodies confirmed that CYP1A2 and CYP2D6 were the major isozymes contributing to both harmaline (20% and 50%, respectively) and harmine (20% and 30%) O-demethylations in pooled HLMS. The turnover numbers for CYP2D6 are among the highest ever reported for a CYP2D6 substrate. Finally, CYP2D6-transgenic mice were found to have increased harmaline and harmine O-demethylase activities as compared with wild-type mice. These findings suggest a role for polymorphic CYP2D6 in the pharmacology and toxicology of harmine and harmaline.

Structure–activity relationships and biological evaluation of 7-substituted harmine analogs for human β-cell proliferation

Recently, we have shown that harmine induces β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. We explore structure–activity relationships of the 7-position of harmine for both DYRK1A kinase inhibition and β-cell proliferation based on our related previous structure–activity relationship studies of harmine in the context of diabetes and β-cell specific targeting strategies. 33 harmine analogs of the 7-position substituent were synthesized and evaluated for biological activity. Two novel inhibitors were identified which showed DYRK1A inhibition and human β-cell proliferation capability. The DYRK1A inhibitor, compound 1-2b, induced β-cell proliferation half that of harmine at three times higher concentration. From these studies we can draw the inference that 7-position modification is limited for further harmine optimization focused on β-cell proliferation and cell-specific targeting approach for diabetes therapeutics.

Antitumor agents 201. Cytotoxicity of harmine and β-carboline analogs

Twenty-six β-carbolines were evaluated for in vitro cytotoxicity in a human tumor cell line panel. Harmine (3) showed significant activity against several cell lines including three drug-resistant KB sublines with various resistance mechanisms. α-(4-Nitrobenzylidine) harmine (16) had a broad cytotoxicity spectrum (ED50 values from 0.3-1.2 μg/mL against 1A9, KB, SaOS-2, A549, SK-MEL-2, U-87-MG, and MCF-7 cells).

Synthesis and isolation of chloro-β-carbolines obtained by chlorination of β-carboline alkaloids in solution and in solid state

β-Carbolines (1-5) undergo electrophilic aromatic substitution with N-chlorosuccinimide and N-chlorobenzotriazole under different experimental conditions. Although 6-chloro and 8-chloro-nor-harmane (1a and 1b) and 6-chloro and 8-chloro-harmane (2a and 2b)

KINASE INHIBITOR COMPOUNDS AND COMPOSITIONS AND METHODS OF USE

Described herein are compounds having the following structure: formula (I) or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof. Also disclosed are compositions containing the compounds, methods of inhibiting activity of DYRKl A in a cell, methods of increasing cell proliferation in a population of pancreatic beta cells, methods of treating a subject for a condition associated with insufficient insulin secretion, and methods of treating a subject for a neurological disorder.

?-CARBOLINE, DIHYDRO-?-CARBOLINE AND TETRAHYDRO-?-CARBOLINE ALKALOID DERIVATIVES AND PREPARATION METHODS SAME AND USE IN ASPECTS OF PREVENTING AND TREATING PLANT VIRUSES, FUNGICIDES AND INSECTICIDES

The present invention relates to β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives (I) and a method for preparing same and the use in the aspects of preventing and treating plant viruses, fungicides and insecticides. For the meaning of each group in formula (I) see the description. The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives of the present invention show a particularly ourstanding anti-plant virus activity, and also have fungicidal and insecticidal activities.

Β dephosphorizing compd. carbocation-screw, its manufacturing method, and use a pharmaceutical composition

Disclosed in the present invention are a bis-2-carboline compound and a preparation method, a pharmaceutical composition and the use thereof. In particular, the bis-2-carboline compound and a pharmaceutical salt thereof are described as general formula I, and the bis-2-carboline compound is prepared through the condensation of 2-carboline intermediate and dihaloalkane. Also disclosed in the present invention are a pharmaceutical composition comprising an effective dose of the bis-2-carboline compound as shown in formula I and a pharmaceutically acceptable carrier, and the use of the bis-2-carboline compound in preparing drugs resistant to tumours such as melanoma, stomach cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermoid carcinoma, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, and colon cancer.

Selective binding to monoamine oxidase A: In vitro and in vivo evaluation of 18F-labeled β-carboline derivatives

In this study we synthesized four different 18F-labeling precursors for the visualization of the monoamino oxidase A using harmol derivatives. Whereas two are for prosthetic group labeling using [18F]fluoro-d2-methyl tosylate and 2-[18F]fluoroethyl-tosylate, the other three precursors are for direct nucleophilic 18F-labeling. Additionally the corresponding reference compounds were synthesized. The syntheses of [18F]fluoro-d2-methyl-harmol and 2-[18F]fluoroethyl-harmol were carried out using harmol as starting material. For direct nucleophilic 18F-labeling of the tracers carrying oligoethyled spacers (PEG), a toluenesulfonyl leaving group was employed. The radiolabeling, purification and formulation for each tracer was optimized and evaluated in vitro and in vivo. Stability tests in human serum showed that all tracers were stable over the observation period of 60 min. μPET studies using of the synthesized tracers revealed that the tracers carrying PEG spacers showed no sufficient brain uptake. Consequently, the 18F-fuoro alkylated tracers [18F]fluoro-d2-methyl-harmol and 2-[18F]fluoroethyl-harmol were further evaluated showing SUVs in the brain of 1.0 ± 0.2 g/mL and 3.4 ± 0.5 g/mL after 45 min, respectively. In blockade studies the selectivity and specificity of both tracers were demonstrated. However, for [18F]fluoro-d2-methyl-harmol a rapid washout from the brain was also observed. In vitro binding assays revealed that 2-[18F]fluoroethyl-harmol (IC50 = 0.54 ± 0.06 nM) has a higher affinity than the 18F-fluoro-d2-methylated ligand (IC50 = 12.2 ± 0.6 nM), making 2-[18F]fluoroethyl-harmol superior to the other evaluated compounds and a promising tracer for PET imaging of the MAO A.

Exploiting the polypharmacology of ?-carbolines to disrupt o. volvulus molting

Onchocerciasis is an infection caused by the filarial worm Onchocerca volvulus, which can eventually result in blindness. The lack of an effective macrofilaricide and the possible development of ivermectin-resistant strains of O. volvulus necessitate the need for alternative treatment strategies. We have shown that targeting the L3-stage-specific chitinase OvCHT1 impairs the shedding of the filarial cuticle. In our continued efforts to discover OvCHT1 inhibitors, we identified the β-carboline alkaloid scaffolding as a chitinase inhibitor that is capable of penetrating the worm cuticle. Herein, we disclose the rich polypharmacology of the β-carboline class of compounds as an approach to abrogate the molting of the parasite and thus the initiation of infection in the human host.

Synthesis and antiviral and fungicidal activity evaluation of β-carboline, dihydro-β-carboline, tetrahydro-β-carboline alkaloids, and their derivatives

Six known β-carboline, dihydro-β-carboline, and tetrahydro-β-carboline alkaloids and a series of their derivatives were designed, synthesized, and evaluated for their anti-tobacco mosaic virus (TMV) and fungicidal activities for the first time. All of the alkaloids and some of their derivatives (compounds 3, 4, 14, and 19) exhibited higher anti-TMV activity than the commercial antiviral agent Ribavirin both in vitro and in vivo. Especially, the inactivation, curative, and protection activities of alkaloids Harmalan (62.3, 55.1, and 60.3% at 500 μg/mL) and tetrahydroharmane (64.2, 57.2, and 59.5% at 500 μg/mL) in vivo were much higher than those of Ribavirin (37.4, 36.2, and 38.5% at 500 μg/mL). A new derivative, 14, with optimized physicochemical properties, obviously exhibited higher activities in vivo (50.4, 43.9, and 47.9% at 500 μg/mL) than Ribavirin and other derivatives; therefore, 14 can be used as a new lead structure for the development of anti-TMV drugs. Moreover, most of these compounds exhibited good fungicidal activity against 14 kinds of fungi, especially compounds 4, 7, and 11.