- Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic β-carboline alkaloids harmaline and harmine
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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.
- Yu, Al-Ming,Idle, Jeffrey R.,Krausz, Kristopher W.,Kuepfer, Adrian,Gonzalez, Frank J.
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- Structure–activity relationships and biological evaluation of 7-substituted harmine analogs for human β-cell proliferation
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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.
- Kumar, Kunal,Wang, Peng,Swartz, Ethan A.,Khamrui, Susmita,Secor, Cody,Lazarus, Michael B.,Sanchez, Roberto,Stewart, Andrew F.,DeVita, Robert J.
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- Antitumor agents 201. Cytotoxicity of harmine and β-carboline analogs
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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).
- Ishida, Junko,Wang, Hui-Kang,Bastow, Kenneth F.,Hu, Chang-Qi,Lee, Kuo-Hsiung
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- Synthesis and isolation of chloro-β-carbolines obtained by chlorination of β-carboline alkaloids in solution and in solid state
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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)
- Ponce, Maria A.,Tarzi, Olga I.,Erra-Balsells, Rosa
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- KINASE INHIBITOR COMPOUNDS AND COMPOSITIONS AND METHODS OF USE
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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.
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Paragraph 0232
(2019/10/15)
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- ?-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
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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.
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Paragraph 0115-0117
(2016/11/28)
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- Β dephosphorizing compd. carbocation-screw, its manufacturing method, and use a pharmaceutical composition
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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.
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Paragraph 0139; 140
(2016/10/07)
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- Selective binding to monoamine oxidase A: In vitro and in vivo evaluation of 18F-labeled β-carboline derivatives
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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.
- Schieferstein, Hanno,Piel, Markus,Beyerlein, Friderike,Lüddens, Hartmut,Bausbacher, Nicole,Buchholz, Hans-Georg,Ross, Tobias L.,R?sch, Frank
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p. 612 - 623
(2015/01/30)
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- Exploiting the polypharmacology of ?-carbolines to disrupt o. volvulus molting
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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.
- Gooyit, Major,Tricoche, Nancy,Javor, Sacha,Lustigman, Sara,Janda, Kim D.
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p. 339 - 343
(2015/03/30)
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- Synthesis and antiviral and fungicidal activity evaluation of β-carboline, dihydro-β-carboline, tetrahydro-β-carboline alkaloids, and their derivatives
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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.
- Song, Hongjian,Liu, Yongxian,Liu, Yuxiu,Wang, Lizhong,Wang, Qingmin
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p. 1010 - 1018
(2014/03/21)
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- Synthesis and antiviral and fungicidal activity evaluation of β-carboline, dihydro-β-carboline, tetrahydro-β-carboline alkaloids, and their derivatives
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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.
- Song, Hongjian,Liu, Yongxian,Liu, Yuxiu,Wang, Lizhong,Wang, Qingmin
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p. 1010 - 1018
(2015/04/22)
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- Design, synthesis and in vitro and in vivo antitumor activities of novel bivalent β-carbolines
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A series of bivalent β-carbolines with a spacer of three to ten methylene units between the indole nitrogen was synthesized and evaluated as antitumor agents. The results demonstrated that compounds 18c, 21b, 25a and 31b exhibited strong cytotoxic activities with IC50 value of lower than 20 μM against four tumor cell lines. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, compounds 18b, 21b, 26a and 31b exhibited potent antitumor activities with tumor inhibition rate of over 40% in animal models. Preliminary structure-activity relationships analysis indicated that (1) the spacer length affected antitumor potencies, and four to six methylene units were more favorable; (2) the introduction of appropriate substituent into position-1 of β-carboline facilitated antitumor potencies.
- Shi, Buxi,Cao, Rihui,Fan, Wenxi,Guo, Liang,Ma, Qin,Chen, Xuemei,Zhang, Guoxian,Qiu, Liqin,Song, Huacan
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- Nanoporous metal oxides with tunable and nanocrystalline frameworks via conversion of metal-organic frameworks
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Nanoporous metal oxide materials are ubiquitous in the material sciences because of their numerous potential applications in various areas, including adsorption, catalysis, energy conversion and storage, optoelectronics, and drug delivery. While synthetic
- Kim, Tae Kyung,Lee, Kyung Joo,Cheon, Jae Yeong,Lee, Jae Hwa,Joo, Sang Hoon,Moon, Hoi Ri
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supporting information
p. 8940 - 8946
(2013/07/26)
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- Novel trisubstituted harmine derivatives with original in vitro anticancer activity
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To overcome the intrinsic resistance of cancer cells to apoptotic stimuli, we designed and synthesized approximately 50 novel β-carbolines structurally related to harmine. Harmine is known for its anticancer properties and is a DYRK1A inhibitor. Of the synthesized compounds, the most active in terms of growth inhibition of five cancer cell lines are cytostatic and approximately 100 times more potent than harmine but demonstrated no DYRK1A inhibitory activity. These novel β-carbolines display similar growth inhibitory activity in cancer cells that are sensitive and resistant to apoptotic stimuli. Using ChemGPS-NP, we found that the more active β-carbolines are all more lipophilic and larger than the less active compounds. Lastly, on the basis of the NCI human tumor cell line anticancer drug screen and the NCI COMPARE algorithm, it appears that some of these compounds, including 5a and 5k, seem to act as protein synthesis inhibitors.
- Frédérick, Rapha?l,Bruyére, Céline,Vancraeynest, Christelle,Reniers, Jérémy,Meinguet, Céline,Pochet, Lionel,Backlund, Anders,Masereel, Bernard,Kiss, Robert,Wouters, Johan
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scheme or table
p. 6489 - 6501
(2012/09/07)
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- Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors
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Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure-activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.
- Cuny, Gregory D.,Ulyanova, Natalia P.,Patnaik, Debasis,Liu, Ji-Feng,Lin, Xiangjie,Auerbach, Ken,Ray, Soumya S.,Xian, Jun,Glicksman, Marcie A.,Stein, Ross L.,Higgins, Jonathan M.G.
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scheme or table
p. 2015 - 2019
(2012/04/05)
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- BETA CARBOLINE DERIVATIVES USEFUL IN THE TREATMENT OF PROLIFERATIVE DISORDERS
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The invention provides novel beta-carboline derivatives of formulae (la) and (lb) useful in the treatment of proliferative disorders including cancer, intermediates used in their preparation, processes for preparing the same and uses thereof.
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Page/Page column 98
(2012/01/13)
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- Substituted beta-carbolines
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Compounds of the formula I are suitable for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of IκB kinase is involved.
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- Spectroscopic study of molecular associations between FMN and β-carbolines
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The spectrophotometric and thermodynamic properties of molecular complexes of flavin mononucleotide (FMN) (riboflavin 5'-phosphate) with some β-carboline derivatives have been investigated in aqueous solution.The molecular associations have been examined by means of electronic absorption spectra, since in each a new charge-transfer band has been located, and also the variation of the fluorescenece emission of FMN on the solutions has been observed.The formation constants for the molecular complexes were determined from absorption data using the Foster-Hammick-Wardley method.The quenching phenomenon observed in FMN fluorescence is related to the concentration of the β-carboline derivatives, allowing the calculation of the quenching constants for FMN-β-carboline complexes.Thermodynamic parameters have been determined from the values of association constants for the molecular complexes at various temperatures.The influence of substituents in the β-carboline molecule on the stability of the complexes formed was also investigated.
- Codoner, Armando,Medina, Piedad,Jover, Enrique,Sanchez, Jesus A.
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p. 1793 - 1800
(2007/10/02)
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