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Some studies have ascribed a protective effect against neurodegenerative diseases to the β-carbolines harman (H) and norharman (NH), which occur mostly in coffee and coffee substitutes. We determined the concentrations of β-carbolines and undesirable compounds (such as acrylamide) in roasted coffee substitute ingredients and found that chicory coffee was optimal. Two in vivo experiments were conducted with seventeen-month-old male Sprague Dawley rats fed a diet with the addition of pure carboline standards in the first stage, and chicory in the second. We observed an increase in the level of H and NH in blood plasma, as well as higher activity of animals in the battery behavioral test, particularly in the second stage. The results of in vitro studies-particularly the level of the expression in brain tissue of genes associated with aging processes and neurodegenerative diseases-clearly show the benefits of a diet rich in β-carbolines.
Herein, the synthesis and anticancer activity evaluation of a series of novel β-carbolines is reported. The reactivity of nitrosoalkenes towards indole was explored for the synthesis of novel tryptophan analogs where the carboxylic acid was replaced by a triazole moiety. This tryptamine was used in the synthesis of 3-(1,2,3-triazol-4-yl)-β-carbolines via Pictet-Spengler condensation followed by an oxidative step. A library of compounds, including the novel 3-(1,2,3-triazol-4-yl)-β-carbolines as well as methyl β-carboline-3-carboxylate and 3-tetrazolyl-β-carboline derivatives, was evaluated for their antiproliferative activity against colorectal cancer cell lines. The 3-(1H-tetrazol-5-yl)-β-carbolines stood out as the most active compounds, with values of half-maximal inhibitory concentration (IC50) ranging from 3.3 µM to 9.6 µM against colorectal adenocarcinoma HCT116 and HT29 cell lines. The results also revealed a mechanism of action independent of the p53 pathway. Further studies with the 3-tetrazolyl-β-carboline derivative, which showed high selectivity for cancer cells, revealed IC50 values below 8 μM against pancreatic adenocarcinoma PANC-1, melanoma A375, hepatocarcinoma HEPG2, and breast adenocarcinoma MCF-7 cell lines. Collectively, this work discloses the 3-tetrazolyl-β-carboline derivative as a promising anticancer agent worthy of being further explored in future works.
The present manuscript pertains to the design and synthesis of a series of 3-hydroxyindole-substituted β-carbolines/tetrahydro-β-carbolines with an aim to explore their antiproliferative structure-activity relationship against breast cancer. The conjugate with an optimum combination of a flexible tetrahydro-β-carboline core, a tertiary alcoholic group along with a chloro substituent on the indole ring, proved to be the most active compound. It displayed IC50 values of 13.61 and 22.76 μM against MCF-7 (ER+) and MDA-MB-231 (ER-) cells, respectively. The docking studies were found to be consistent with experimental results owing to the stronger binding affinity of the synthesized conjugates via hydrophobic and H-bonding interactions.
The β-carbolines, mainly including harman and norharman, are a group of naturally occurring, plant-derived alkaloids, and are also considered as nonpolar heterocyclic aromatic amines. Sesame seed oils contain a high level of β-carbolines (harman and norharman). In China, sesame seed oil blends are one of the most popular types of vegetable oils blends, which can be used as cooking oils or frying oils. Thus, it is meaningful to investigate the degradation of β-carbolines (harman and norharman) in sesame seed oil blends as frying oils during heating. In this work, the loss of harman and norharman in different types of sesame seed oil blends have been investigated. The results showed that the degradation of harman and norharman were dependent both on the type of oil blends, heating temperature and time. Harman and norharman were more degraded during heating (150 °C, 180 °C) in oleic acid-rich oil blends compared to polyunsaturated acid-rich oil blends. Mechanistic investigation suggested that the reduction in harman and norharman in oil blends during heating was mainly due to the oxidative degradation reaction between β-carbolines and lipid oxidation products. Therefore, the contents of β-carbolines (harman and norharman) in sesame seed oil blends when used as frying oils and heated can be decreased with prolonged cooking time.
Natural β-carboline alkaloids are ideal models for the discovery of pharmaceutically important entities. Various 1-substituted β-carbolines were synthesized from commercially inexpensive tryptophan and demonstrated significant in vitro antifungal activity against G. graminis. Significantly, compound 4m (EC50 = 0.45 μM) with carboxamide at 1-position displayed the best efficacy and nearly 20 folds enhancement in antifungal potential compared to Silthiopham (EC50 = 8.95 μM). Moreover, compounds 6, 7, and 4i exhibited excellent in vitro antifungal activities and in vivo protective and curative activities against B. cinerea and F. graminearum. Preliminary mechanism studies revealed that compound 4m caused reactive oxygen species accumulation, cell membrane destruction, and deregulation of histone acetylation. These findings indicated that 1-carbamoyl β-carboline can be selected as a promising model for the discovery of novel and broad-spectrum fungicide candidates.
DYRK1A is a pleiotropic protein kinase with diverse functions in cellular regulation, including cell cycle control, neuronal differentiation, and synaptic transmission. Enhanced activity and overexpression of DYRK1A have been linked to altered brain development and function in Down syndrome and neurodegenerative diseases such as Alzheimer's disease. The β-carboline alkaloid harmine is a high affinity inhibitor of DYRK1A but suffers from the drawback of inhibiting monoamine oxidase A (MAO-A) with even higher potency. Here we characterized a series of novel harmine analogs with minimal or absent MAO-A inhibitory activity. We identified several inhibitors with submicromolar potencies for DYRK1A and selectivity for DYRK1A and DYRK1B over the related kinases DYRK2 and HIPK2. An optimized inhibitor, AnnH75, inhibited CLK1, CLK4, and haspin/GSG2 as the only off-targets in a panel of 300 protein kinases. In cellular assays, AnnH75 dose-dependently reduced the phosphorylation of three known DYRK1A substrates (SF3B1, SEPT4, and tau) without negative effects on cell viability. AnnH75 inhibited the cotranslational tyrosine autophosphorylation of DYRK1A and threonine phosphorylation of an exogenous substrate protein with similar potency. In conclusion, we have characterized an optimized β-carboline inhibitor as a highly selective chemical probe that complies with desirable properties of drug-like molecules and is suitable to interrogate the function of DYRK1A in biological studies.
Wnt signaling pathway is aberrantly activated in a variety of cancers, especially in colorectal cancer (CRC), because of mutations in the genes encoding adenomatous polyposis coli (APC), β-catenin and Axin. Small-molecule antagonists of Wnt/β-catenin signaling are attractive candidates for developing effective therapeutics for CRC. In this study, we have identified a novel Wnt signaling inhibitor, isopropyl 9-ethyl-1- (naphthalen-1-yl)-9H-pyrido[3,4-b]indole-3- carboxylate (Z86). Z86 inhibited Wnt reporter activities and the expression of endogenous Wnt signaling target genes in mammalian cells and antagonized the second axis formation of Xenopus embryos induced by Wnt8. We showed that Z86 treatment inhibits GSK3β (Ser9) phosphorylation, leading to its overactivation and promoting the phosphorylation and degradation of β-catenin. In vitro, Z86 selectively inhibited the growth of CRC cells with constitutive Wnt signaling and caused obvious G1-phase arrest of the cell cycle. Notably, in a nude mouse model, Z86 inhibited dramatically the xenografted tumor growth of CRC. Daily intraperitoneal injection of Z86 at 5 mg/kg resulted in >70% reduction in the tumor weight of HCT116 cell origin that was associated with decreased GSK3β (Ser9) phosphorylation and increased β-catenin phosphorylation. Taken together, our findings provide a novel promising chemotype for CRC therapeutics development targeting the canonical Wnt signaling.
1,5-Disubstituted indole-2-carboxaldehyde derivatives 1a-h and glycine alkyl esters 2a-c are shown to undergo a novel cascade imination-heterocylization in the presence of the organic base DIPEA to provide 1-indolyl-3,5,8-substituted γ-carbolines 3aa-ea in good yields. The γ-carbolines are fluorescent and exhibit anticancer activities against cervical, lung, breast, skin, and kidney cancer cells.
Utilizing a pharmacophore hybridization approach, we have designed and synthesized a novel series of 28 new heterobivalent β-carbolines. The in vitro cytotoxic potential of each compound was evaluated against the five cancer cell lines (LLC, BGC-823, CT-26, Bel-7402, and MCF-7) of different origin-murine and human, with the aim of determining the potency and selectivity of the compounds. Compound 8z showed antitumor activities with half-maximal inhibitory concentration (IC50) values of 9.9 ± 0.9, 8.6 ± 1.4, 6.2 ± 2.5, 9.9 ± 0.5, and 5.7 ± 1.2 µM against the tested five cancer cell lines. Moreover, the effect of compound 8z on the angiogenesis process was investigated using a chicken chorioallantoic membrane (CAM) in vivo model. At a concentration of 5 μM, compound 8z showed a positive effect on angiogenesis. The results of this study contribute to the further elucidation of the biological regulatory role of heterobivalent β-carbolines and provide helpful information on the development of vascular targeting antitumor drugs.
A series of novel 1-(substituted phenyl)-3-(2-oxo-1,3,4-oxadiazol-5-yl) β-carbolines (4a-e) and the corresponding Mannich bases 5-9(a-c) were synthesized and evaluated for their in vitro antitumor activity against seven human cancer cell lines. Compounds of 4a-e series showed a broad spectrum of antitumor activity, with GI50 values lower than 15μM for five cell lines. The derivative 4b, having the N,N-dimethylaminophenyl group at C-1, displayed the highest activity with GI50 in the range of 0.67-3.20μM. A high selectivity and potent activity were observed for some Mannich bases, particularly towards resistant ovarian (NCI-ADR/RES) cell lines (5a, 5b, 6a, 6c and 9b), and ovarian (OVCAR-03) cell lines (5b, 6a, 6c, 9a, 9b and 9c). In addition, the interaction of compound 4b with DNA was investigated by using UV and fluorescence spectroscopic analysis. These studies indicated that 4b interact with ctDNA by intercalation binding.
β-Carbolines are naturally occurring bioactive alkaloids. In this work, carbohydrate-derived β-carbolines (βCs), 1-(1,3,4,5-tetrahydroxypent-1-yl)-β-carboline isomers (1a/b), 1-(1,4,5-trihydroxypent-1-yl)-β-carboline (2), 1-(1,5-dihydroxypent-3-en-1-yl)-β-carboline (3), and 1-(1,2,3,4,5-pentahydroxypent-1-yl)-β-carboline (4) were identified and analyzed in commercial foods. The concentrations of βCs 1-4 in foods ranged from undetectable to 11.4 μg/g levels, suggesting their intake in the diet. Processed foods contained higher amounts than fresh or unprocessed foods, and the highest content was found in processed tomato and fruit products, sauces, and baked foods. βCs 1-3 were formed in foods during heating, and 1a/b were the main compounds. The formation of carbohydrate-derived βCs was studied in model reactions of tryptophan and carbohydrates. They formed in reactions of tryptophan with glucose under acidic conditions at temperatures higher than 80 °C. The formation of 1a/b was favored, but 2-3 increased at high temperatures. Noticeably, the βCs 1-3 formed in the reactions of tryptophan with fructose or sucrose, and the formation from fructose was much higher than from glucose. Thus, fructose was the main carbohydrate involved in the formation of 1-3, whereas sucrose gave these βCs after acid hydrolysis. It is shown for the first time that the mechanism of formation of βCs 1-3 occurs from the sugar intermediate 3-deoxyglucosone that reacts with tryptophan affording these carbohydrate-derived βCs. A mechanism of reaction to give βCs 1-3 is proposed that relies on the tautomerism (keto-enediol or enamine-imine) of intermediates involved in the reaction. Carbohydrate βCs 1-4 were assessed as inhibitors of monoamine oxidase (MAO), as antioxidants, and for their interaction with DNA. They were not good inhibitors of MAO-A or -B, were poor antioxidants, and did not appreciably interact with DNA.
Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule γ-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is π-π stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions.
The aim of this study was to investigate the inhibitory effect of non-precursors amino acids (histidine, leucine, proline and methionine) which have advantages of safety, inexpensiveness and high standardization on the formation of β-carbolines in roast beef patties and glucose/creatine/creatinine/tryptophan model system, and the possible pathway of inhibition by monitoring the scavenging of free radicals by electron paramagnetic resonance (EPR) spectroscopy and the consumption of tryptophan by HPLC in a glucose/tryptophan model system. Almost all amino acids can inhibit β-carbolines in roast beef patties (up to 80.62%) and model system (up to 67.01%). Histidine showed an excellent alkyl radical scavenging ability (up to 82.59%) and a highly competitive inhibition ability (up to 65.60%) against β-carbolines generation. The corresponding abilities of leucine and methionine were less remarkable. Proline could only suppress β-carbolines through competitive inhibition. The results could shed light on the reduction of β-carbolines during meat processing.
The membrane permeability transition of mitochondria has been suggested to be involved in toxic and oxidative forms of cell injury. Mitochondrial dysfunction is considered to play a critical role in neurodegeneration in Parkinson's disease. Despite the suggestion that indole beta-carbolines may be neurotoxic, these compounds provide a protective effect against cytotoxicity of other neurotoxins. In addition, the effect of indole beta-carbolines on change in the mitochondrial membrane permeability due to reactive nitrogen species (RNS), which may lead to cell death, has not been clarified.
Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-β-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.
Heat treatment of meat can lead to the formation of carcinogenic organic compounds. The influence of dried fruits on the formation of non-polar heterocyclic aromatic amines (carbolines) and nitrogen derivatives of polycyclic aromatic hydrocarbons (azaarenes) in roasted pork loin was elucidated. Two hundred grams of fruit per 1 kg of meat were used as stuffing. Carbolines, derivatives of pyridoimidazole and pyridoindole, and azaarenes (benzoacridines and dibenzoacridines) were determined by means of high-performance liquid chromatography with fluorescence detection. The total concentration of six δ-, γ- and α-carbolines in roasted pork loin was 1.3 ng/g. This content decreased by 64%, 58%, and 54% in pork loin stuffed with prunes, apricots, and cranberries, respectively. Concentrations of β-carbolines (harmane and norharmane) increased under the influence of added fruits. The norharmane content increased the most, from 2.2 ng/g in the control sample to 12.3 ng/g in meat prepared with cranberries. The harmane content increased from 1.0 ng/g to 3.6 ng/g in meat with prunes. The total concentration of azaarenes (two benzoacridines and dibenzo[a,c]acridine), which was close to 0.1 ng/g, decreased in dishes with prunes and apricots by 54% and 12%, respectively. Azaarenes were not found in samples of meat stuffed with cranberries.
The emission properties of three 4-azafluorenone and five new α-carboline fluorophores in both solution and thin solid films were investigated. Fluorescence of the azafluorenone is clearly enhanced in thin solid films due to the presence of phenyl/biphenyl rotors, and these derivatives can be classified as green Aggregation-Induced Emission luminogens (AIEgens) with a non-emissive heteroaromatic core structure. Compared to azafluorenones, emission of α-carbolines is hypsochromically shifted to the blue region of the electromagnetic spectrum, and most of these derivatives exhibit strong violet-blue fluorescence in both solution and thin solid film layers. Further, the effective mobility and electroluminescence of new α-carbolines were investigated in prepared organic field-effect transistors and organic light-emitting diodes, respectively.
Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO-A), preventing extensive first-pass degradation of DMT into 3-indole-acetic acid (3-IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non-serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5-HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged.
New brominated β-carbolines irenecarbolines A (1) and B (4) along with known β-carbolines 2 and 3 and a new 8-oxoisoguanine derivative, 5, were isolated from a solitary ascidian, Cnemidocarpa irene. The structures of these compounds were determined on the basis of their spectral data. All, except for 3, inhibited the action of acetylcholinesterase (AchE). The activities of 1 and 5 were comparable to those of galantamine, a clinically used AchE inhibitor. Compounds 1 and 2 were found to be present in high concentrations in blood, and fluorescence was observed in certain types of cells found in the blood of the tunicate.
Ayahuasca is a psychoactive infusion with a large pharmacological application normally prepared with Banisteriopsis caapi, which contains the monoamine oxidase inhibitors β-carbolines, and Psichotria virids, which contains the serotonin receptor agonist N,N dimethyltryptamine (DMT). The objectives of this study were to investigate the chemical profile of B. caapi and of ayahuasca collected in various Brazilian regions. In total, 176 plant lianas, of which 159 B. caapi and 33 ayahuasca samples were analyzed. Dried liana samples were powdered, extracted with methanol, diluted, and analyzed by LC-MS/MS. Ayahuasca samples were diluted and analyzed. Mean concentrations in B. caapi were 4.79 mg/g harmine, 0.451 mg/g harmaline, and 2.18 mg/g tetrahydroharmine (THH), with a high variability among the samples (RSD from 78.9 to 170%). Native B. caapi samples showed significantly higher harmine concentrations than cultivated ones, and samples from the Federal District/Goiás had higher THH content than those collected in the State of Acre. The other Malpighiaceae samples did not contain β-carbolines, except for one D. pubipetala sample. Concentrations in ayahuasca samples ranged from 0.109 to 7.11 mg/mL harmine, 0.012 to 0.945 mg/mL harmaline, 0.09 to 3.05 mg/mL THH, and 0.10 to 3.12 mg/mL DMT. The analysis of paired ayahuasca/B. caapi confirmed that harmine is reduced to harmaline and to THH during the brew preparation. This is the largest study conducted with Malpighiaceae samples and showed a large variability in the main β-carbolines present in B. caapi. This biodiversity is a challenge for standardization of the material used in ethnopharmacological studies of B. caapi and ayahuasca.
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