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1.
J Chromatogr A ; 1644: 462121, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33845425

RESUMO

In this study, we present results obtained on the enantioseparation of some cationic compounds of pharmaceutical relevance, namely tetrahydro-ß-carboline and 1,2,3,4-tetrahydroisoquinoline analogs. In high-performance liquid chromatography, chiral stationary phases (CSPs) based on strong cation exchanger were employed using mixtures of methanol and acetonitrile or tetrahydrofuran as mobile phase systems with organic salt additives. Through the variation of the applied chromatographic conditions, the focus has been placed on the study of retention and enantioselectivity characteristics as well as elution order. Retention behavior of the studied analytes could be described by the stoichiometric displacement model related to the counter-ion effect of ammonium salts as mobile phase additives. For the thermodynamic characterization parameters, such as changes in standard enthalpy Δ(ΔH°), entropy Δ(ΔS°), and free energy Δ(ΔG°), were calculated on the basis of van't Hoff plots derived from the ln α vs. 1/T curves. In all cases, enthalpy-driven enantioseparations were observed with a slight, but consistent dependence of the calculated thermodynamic parameters on the eluent composition. Elution sequences of the studied compounds were determined in all cases. They were found to be opposite on the enantiomeric stationary phases and they were not affected by either the temperature or the eluent composition.


Assuntos
Carbolinas/química , Cromatografia Líquida de Alta Pressão/métodos , Resinas de Troca Iônica/química , Tetra-Hidroisoquinolinas/química , Acetonitrilos , Cátions , Metanol , Estereoisomerismo , Relação Estrutura-Atividade , Temperatura
2.
Eur J Med Chem ; 216: 113321, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33684825

RESUMO

ß-Carbolines are indole alkaloids having a tricyclic pyrido[3,4-b]indole ring in their structure. Since the isolation of first ß-carboline from Peganum harmala in 1841, the isolation and synthesis of various ß-carboline derivatives surged in the following centuries. ß-Carboline derivatives due to their widespread availability from natural sources, structural flexibility, quick reactivity and interaction with varied anticancer targets such as DNA (intercalation, groove binding, etc.), enzymes (GPX4, topoisomerases, kinases, etc.) and proteins (tubulin, ABCG2/BRCP1, etc.) have established themselves as promising lead compounds for the synthesis of various anticancer active agents. The current review covers the synthesis and isolation, anticancer activity, mechanism of action and SAR of various ß-carboline containing molecules, its derivatives and congeners.


Assuntos
Antineoplásicos/química , Carbolinas/química , Antineoplásicos/uso terapêutico , Carbolinas/uso terapêutico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , DNA Topoisomerases/química , DNA Topoisomerases/metabolismo , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Plantas/química , Plantas/metabolismo , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
3.
J Med Chem ; 64(3): 1392-1422, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33528252

RESUMO

The natural ß-carboline alkaloids display similarities with neurotransmitters that can be favorably exploited to design bioactive and bioavailable drugs for Alzheimer's disease (AD) therapy. Several AD targets are currently and intensively being investigated, divided in different hypotheses: mainly the cholinergic, the amyloid ß (Aß), and the Tau hypotheses. To date, only symptomatic treatments are available involving acetylcholinesterase and NMDA inhibitors. On the basis of plethoric single-target structure-activity relationship studies, the ß-carboline scaffold was identified as a powerful tool for fostering activity and molecular interactions with a wide range of AD-related targets. This knowledge can undoubtedly be used to design multitarget-directed ligands, a highly relevant strategy preferred in the context of multifactorial pathology with intricate etiology such as AD. In this review, we first individually discuss the AD targets of the ß-carbolines, and then we focus on the multitarget strategies dedicated to the deliberate design of new efficient scaffolds.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Carbolinas/química , Animais , Desenho de Fármacos , Humanos , Neurotransmissores/química , Relação Estrutura-Atividade
4.
Food Chem ; 348: 129067, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33548760

RESUMO

Pharmacologically active ß-carboline alkaloids (ßCs) such as harman, norharman and some others are naturally present in plants and occur in many foodstuffs. They have a lot of pharmacological properties, including antitumor, antioxidant, anti-inflammatory and antimicrobial effects, and possess the potential for treating Alzheimer's disease, Parkinson's disease, depression and other central nervous system diseases. Dietary intake is proven to be an important source of ßCs. Therefore, it is important to know the amounts of ßCs that can be gotten from daily diets. This review summarizes the pharmacological activities, toxicology and formation of ßCs, and gives collective information on contents of ßCs in different foodstuffs.


Assuntos
Alcaloides/análise , Alcaloides/química , Carbolinas/química , Análise de Alimentos , Alcaloides/farmacologia , Antioxidantes/análise , Antioxidantes/química , Antioxidantes/farmacologia , Humanos
5.
Phytomedicine ; 82: 153438, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33422953

RESUMO

BACKGROUND: 5-Hydroxy-4-methoxycanthin-6-one (PQ-A) is the main active compound in Ramulus et Folium Picrasmae, a Chinese herbal medicine commonly used in colitis treatment. PURPOSE: To clarify PQ-A's role and mechanism in colitis treatment based on a non-targeted metabolomics study. METHODS: Rats with ulcerative colitis (UC) established with 4% dextran sulfate sodium (DSS) were orally treated with PQ-A. Body weight, disease activity index (DAI), colon length, biochemical parameters (MDA and SOD), and histopathological score in colon tissue were measured. A UPLC-Q-TOF-MS/MS approach-based metabolomics analysis was conducted to explore the underlying mechanisms of PQ-A in colitis treatment. Inflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-10) concentrations in serum and their protein levels in the colon were determined. CD3 and NF-κB/p65 immunohistochemistry in the colon was semi-quantified. The related protein or mRNA in IKK-NF-κB/p65 signaling pathway was measured by Western blotting or RT-PCR, respectively. Potential molecular interactions between PQ-A and NF-κB/p65 was predicted using DS 2.5 software. RESULTS: PQ-A significantly prevented body weight loss and colonic shortening in colitic rats, and reduced the DAI and histopathologic score as well. PQ-A decreased MDA levels in the UC rat serum and increased those of SOD. Metabolomics results revealed forty-nine differential metabolites as biomarkers of DSS-induced colitis, demonstrating that the path-mechanism of colitis involved the perturbation of eight metabolic pathways, including alpha-linolenic acid and linoleic acid metabolism, sphingolipid metabolism, retinol metabolism, bile acid metabolism, et al. Thirty-six biomarkers were especially reversed to normal-like levels by PQ-A via regulation of alpha-linolenic acid and linoleic acid metabolism, sphingolipid metabolism, and retinol metabolism, which effectively hinted the potential pharmacological mechanism of PQ-A related to NF-κB/p65 inflammatory signaling. Molecular docking results predicted high affinity interaction between PQ-A and NF-κB/p65, involving hydrogen-bond interactions at five amino acid residues, suggesting NF-κB/p65 as a target. PQ-A decreased TNF-α, IL-1ß, and IL-6 concentrations in serum and their protein levels in colon tissue in colitic rats. CD3, MYD88, p-IκBα, NF-κB/p65, and p-NF-κB/p65 expression levels decreased, whereas those of IKKß and IκBα increased in colitic tissue following PQ-A treatment. PQ-A strongly inhibited nuclear translocation of NF-κB/p65. CONCLUSIONS: We provide an overview of PQ-A's possible mechanism of action in colitis treatment based on serum non-targeted metabolomics. PQ-A treatment can protect rats against DSS-induced colitis by suppressing the NF-κB/p65 signaling pathway.


Assuntos
Carbolinas/química , Carbolinas/uso terapêutico , Colite/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Animais , Biomarcadores/metabolismo , Colite/induzido quimicamente , Citocinas/metabolismo , Masculino , Metabolômica , Simulação de Acoplamento Molecular , Ratos , Espectrometria de Massas em Tandem
6.
Molecules ; 26(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513936

RESUMO

ß-Carboline alkaloids are a remarkable family of natural and synthetic indole-containing heterocyclic compounds and they are widely distributed in nature. Recently, these alkaloids have been in the focus of interest, thanks to their diverse biological activities. Their pharmacological activity makes them desirable as sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic or antimicrobial drug candidates. The growing potential inherent in them encourages many researchers to address the challenges of the synthesis of natural products containing complex ß-carboline frameworks. In this review, we describe the recent developments in the synthesis of ß-carboline alkaloids and closely related derivatives through selected examples from the last 5 years. The focus is on the key steps with improved procedures and synthetic approaches. Furthermore the pharmacological potential of the alkaloids is also highlighted.


Assuntos
Alcaloides/química , Carbolinas/química , Produtos Biológicos/química , Compostos Heterocíclicos/química , Humanos
7.
Food Chem ; 339: 127853, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32829247

RESUMO

The correlation between potato components and Maillard reaction derivative harmful products (MRDHPs) formation during heat-processing was assessed in nine commercial potato varieties in China. Principal component analysis (PCA) combined with canonical correlation analysis (CCA) approach was performed to explore their relationships. The variables contributing most to the PCA results were extracted for CCA, and the results indicated that several amino acids, including lysine, tryptophan, alanine, phenylalanine, aspartate, and glutamate, have significant impacts on acrylamide and ß-carboline heterocyclic amine formation. Moreover, 5-O-caffeoylquinic acid, 3-O-caffeoylquinic acid, α-solanine, and α-chaconine were also important factors associated with acrylamide and ß-carboline heterocyclic amine formation. Optimally using raw potato varieties based on the impacts of these factors can help control MRDHP formation during thermal processing. For the first time, such approach was applied, which may be a useful tool for discovering the correlation of food components and MRDHPs.


Assuntos
Produtos Finais de Glicação Avançada/análise , Solanum tuberosum/química , Acrilamida/análise , Acrilamida/química , Aminas/análise , Aminas/química , Carbolinas/química , Cromatografia Líquida de Alta Pressão , Reação de Maillard , Análise de Componente Principal , Solanum tuberosum/metabolismo , Espectrometria de Massas em Tandem
8.
Biochim Biophys Acta Biomembr ; 1863(1): 183473, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937102

RESUMO

Two ß-carboline compounds, 8i and 6d, demonstrated in vitro antileishmanial activity against Leishmania (L.) amazonensis promastigotes similar to that of miltefosine (MIL). Estimates of the membrane-water partition coefficient (KM/W) and the compound concentrations in the membrane (cm50) and aqueous phase (cw50) for half maximal inhibitory concentration were made. Whereas these biophysical parameters for 6d were not significantly different from those reported for MIL, 8i showed lower affinity for the parasite membrane (lower KM/W) and a lower concentration of the compound in the membrane required to inhibit the growth of the parasite (lower cm50). A 2-hour treatment of Leishmania promastigotes with the compounds 8i and 6d caused membrane rigidity in a concentration-dependent manner, as demonstrated by the electron paramagnetic resonance (EPR) technique and spin label method. This increased rigidity of the membrane was interpreted to be associated with the occurrence of cross-linking of oxidized cytoplasmic proteins to the parasite membrane skeleton. Importantly, the two ß-carboline-oxazoline derivatives showed low hemolytic action, both in experiments with isolated red blood cells or with whole blood, denoting their great Leishmania/erythrocyte selectivity index. Using electron microscopy, changes in the membrane of both the amastigote and promastigote form of the parasite were confirmed, and it was demonstrated that compounds 8i and 6d decreased the number of amastigotes in infected murine macrophages. Furthermore, 8i and 6d were more toxic to the protozoa than to J774A.1 macrophages, with treated promastigotes exhibiting a decrease in cell volume, mitochondrial membrane potential depolarization, accumulation of lipid bodies, increased ROS production and changes in the cell cycle.


Assuntos
Antiprotozoários/farmacologia , Carbolinas/farmacologia , Membrana Celular/metabolismo , Leishmania/metabolismo , Animais , Antiprotozoários/química , Carbolinas/química , Humanos , Camundongos , Proteínas de Protozoários/metabolismo
9.
J Nat Med ; 74(4): 804-810, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32638295

RESUMO

Two new canthin-6-one alkaloids, 4,9-dimethoxy-5-hydroxycanthin-6-one (1) and 9-methoxy-(R/S)-5-(1-hydroxyethyl)-canthin-6-one (2), together with fifteen known ones were isolated from the roots of Thailand Eurycoma longifolia Jack. Among the known canthin-6-one alkaloids, compounds 9 and 16 were isolated from the Eurycoma genus for the first time. Meanwhile, the nitric oxide (NO) inhibitory activities of all isolates were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 cells at 50 µM. Moreover, a dose-dependent experiment was conducted for active compounds 1, 2, 4, 6, 7, 10, 12-17 at the concentration of 10, 25, and 50 µM, respectively. Consequently, compounds 1, 4, 6, 7, 12, 14, 15, as well as 17 were found to inhibit NO release from RAW264.7 cells in a dose-dependent manner. Two new canthin-6-one alkaloids, 4,9-dimethoxy-5-hydroxycanthin-6-one (1) and 9-methoxy-(R/S)-5-(1-hydroxyethyl)-canthin-6-one (2), together with fifteen known ones were isolated from the roots of Thailand Eurycoma longifolia Jack. Among them, 1, 4, 6, 7, 12, 14, 15, as well as 17 were found to inhibit NO release from RAW264.7 cells in a dose-dependent manner at the concentration of 10, 25, and 50 µM.


Assuntos
Carbolinas/química , Eurycoma/química , Alcaloides Indólicos/química , Extratos Vegetais/química , Raízes de Plantas/química , Tailândia
10.
Food Chem ; 332: 127387, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32629331

RESUMO

The simultaneous formation of acrylamide; ß-carboline heterocyclic amines (HAs): harmane and norharmane; and advanced glycation end products (AGEs) (Nε-(carboxymethyl)lysine (CML) and Nε-(carboxyethyl)lysine (CEL)) was analyzed based on an aqueous model system. The model systems included lysine-glucose (Lys/Glu), asparagine-glucose (Asn/Glu), tryptophan-glucose (Trp/Glu), and a mixture of these amino acids (Mix/Glu). Only AGEs were generated when heated at 100 °C, Asn and Trp competed with Lys for glucose and methylglyoxal (MGO), and glyoxal (GO) decreased AGE content. The k value of CML, CEL, and acrylamide decreased when heated at 130 °C, whereas that of harmane increased in the Mix/Glu, owing to the competition between Lys and Asn for glucose, GO, and MGO. Harmane preferably formed via the Pictet-Spengler condensation between Trp and acetaldehyde, which further reduced acrylamide formation via the acrolein pathway.


Assuntos
Acrilamida/análise , Aminas/análise , Produtos Finais de Glicação Avançada/análise , Reação de Maillard , Asparagina/química , Carbolinas/análise , Carbolinas/química , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão , Glucose/química , Harmina/análogos & derivados , Harmina/análise , Harmina/metabolismo , Temperatura Alta , Lisina/análogos & derivados , Lisina/análise , Modelos Biológicos , Aldeído Pirúvico/química
11.
Mutat Res ; 850-851: 503148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32247557

RESUMO

Norharman exists in cigarette smoke and cooked foods and is non-mutagenic among Salmonella strains but mutagenic to S. typhimurium TA98 and YG1024 in the presence of S9 mix and aniline and o-toluidine. Co-mutagenesis of ß-carbolines and aniline and o-toluidine occurs through the formation of novel mutagenic aminophenyl-ß-carboline derivatives including 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole [aminophenylnorharman] (APNH)] and 9-(4'- amino-3'-methylphenyl)-9H-pyrido[3,4-b]indole [aminomethylphenylnorharman] (AMPNH)]. Since humans are often simultaneously exposed to ß-carbolines and aniline and o-toluidine, their effects on humans should be clarified. The most potent of these, APNH, induced both point mutations and small deletions in the liver and colon of gpt delta transgenic mice. Major APNH-induced mutations in the liver occurred at a G:C base pair, suggesting that APNH-DNA adducts (dG-C8-APNH) are potentially involved in these mutations. Furthermore, APNH induced hepatic and colon tumors harboring K-ras, ß-catenin, and Apc mutations in F344 rats, with high incidence. Mutations at G:C base pairs were predominant, similar to those in the in vivo mutation assay using gpt delta mice. Moreover, APNH detected in human urine samples obtained from both healthy volunteers on a normal diet and inpatients receiving parenteral alimentation; therefore, APNH can be considered an endogenous carcinogen contributing to tumorigenesis. Exposure levels of these aminophenyl-ß-carboline derivatives may be lower than those of carcinogenic heterocyclic amines (HCAs) including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx); however, their health risks in terms of tumorigenesis may be comparable owing to stronger genotoxic effects of APNH rather than HCAs. This review summarized APNH mutagenicity/carcinogenicity, and its in vivo formation. Moreover, the effect on tumorigenesis in humans also discussed.


Assuntos
Carbolinas/química , Indóis/toxicidade , Mutagênese/efeitos dos fármacos , Piridinas/toxicidade , Toluidinas/química , Compostos de Anilina/toxicidade , Animais , Carbolinas/toxicidade , Colo/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Mutação Puntual/efeitos dos fármacos , Toluidinas/toxicidade
12.
J Chromatogr A ; 1620: 461036, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32201039

RESUMO

Leaves, flowers, fruits and stems (44 sample groups) were collected from mature Camptotheca acuminate during 2017.3-2018.3 and classified by ultra-high performance liquid chromatography coupled with quadrupole-time of flight-mass spectrometry based metabolomics. One hundred metabolites including forty-seven alkaloids, fifteen terpenes, thirty-two polyphenols and six other metabolites were rapidly identified through the in-house database alignment at first glance. Thirty-three alkaloids classified into five groups including camptothecin group (CG1-13), pumiloside group (PG1-5), strictosidinic acid group (SG1-3), vincosamide group (VG1-7), and a new hybrid group, vincosamide-camptothecin group (VC1-5) were mined and further characterized by MS/MS analyses. The identification of two untapped biosynthetic precursors, 2-hydroxypumiloside (PG2) and 16­hydroxy­15, 16-dihydrocamptothecoside (CG3), along with sixteen new alkaloids enables us for a better understanding of camptothecin biogenetic reasoning. The underlying enzymes involved in camptothecin biosynthesis were also proposed according to the guiding metabolic map, thus purposefully mining of enzymes involved in the downstream biosynthetic pathway of camptothecin could be initiated with the help of this map.


Assuntos
Alcaloides/análise , Vias Biossintéticas , Camptotheca/química , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Camptotecina/análogos & derivados , Camptotecina/análise , Camptotecina/química , Camptotecina/metabolismo , Carbolinas/análise , Carbolinas/química , Bases de Dados como Assunto , Análise Discriminante , Glicosídeos/análise , Glicosídeos/química , Alcaloides Indólicos/análise , Alcaloides Indólicos/química , Análise dos Mínimos Quadrados , Redes e Vias Metabólicas , Metaboloma , Metabolômica , Análise Multivariada , Análise de Componente Principal
13.
Int J Nanomedicine ; 15: 465-481, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021191

RESUMO

Background: 1-(4-isopropylphenyl)-ß-carboline-3-carboxylic acid (ICCA) was modified by Trp-Phe-Phe to form 1-(4-isopropylphenyl)-ß-carboline-3-carbonyl-Trp-Phe-Phe (ICCA-WFF). Purpose: The object of preparing ICCA-WFF was to enhance the in vivo efficacy of ICCA, to explore the possible targeting action, and to visualize the nano-feature. Methods: The advantages of ICCA-WFF over ICCA were demonstrated by a series of in vivo assays, such as anti-tumor assay, anti-arterial thrombosis assay, anti-venous thrombosis assay, P-selectin expression assay, and GPIIb/IIIa expression assay. The nano-features of ICCA-WFF were visualized by TEM, SEM and AFM images. The thrombus targeting and tumor-targeting actions were evidenced by FT-MS spectrum analysis. Results: The minimal effective dose of ICCA-WFF slowing tumor growth and inhibiting thrombosis was 10-fold lower than that of ICCA. ICCA-WFF, but not ICCA, formed nano-particles capable of safe delivery in blood circulation. In vivo ICCA-WFF, but not ICCA, can target thrombus and tumor. In thrombus and tumor, ICCA-WFF released Trp-Phe-Phe and/or ICCA. Conclusion: Modifying ICCA with Trp-Phe-Phe successfully enhanced the anti-tumor activity, improved the anti-thrombotic action, formed nano-particles, targeted tumor tissue and thrombus, and provided an oligopeptide modification strategy for heterocyclic compounds.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Fibrinolíticos/farmacologia , Peptídeos/química , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fibrinolíticos/química , Humanos , Masculino , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Nanopartículas/química , Selectina-P/química , Selectina-P/metabolismo , Peptídeos/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ratos Sprague-Dawley , Trombose/sangue , Trombose/tratamento farmacológico
14.
Eur J Med Chem ; 187: 111935, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31816556

RESUMO

A series of methyl ß-carboline carboxylates (2a-g) and of imide-ß-carboline derivatives containing the phthalimide (4a-g), maleimide (5b, g) and succinimide (6b, e, g) moiety were synthesized, and evaluated for their activity against Mycobacterium tuberculosis H37Rv. The most active ß-carboline derivatives against the reference strain were assayed for their cytotoxicity and the activity against resistant M. tuberculosis clinical isolates. Farther, structure-activity relationship (SAR) studies were carried out using the three and four-dimensional approaches for starting to understand the way of ß-carboline activity in M. tuberculosis. All 19 ß-carboline derivatives were assayed, firstly, by determining the minimum inhibitory concentration (MIC) using resazurin microtiter assay plate (REMA) in M. tuberculosis H37Rv. Then, five derivatives (2c, 4a, 4e, 4g, 6g), which showed MIC ≤ 125 µg/mL, were assayed in nine resistant M. tuberculosis clinical isolates (five MDR, three isoniazid monoresistant and one isoniazid plus streptomycin resistant). The MIC values against the resistant clinical isolates ranged from 31.25 to >250 µg/mL. All five derivatives were non-cytotoxic to the VERO cell line, determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, at the tested concentration (selectivity index ranged from <1.74 to 14.4). Our study demonstrated that (2c) and (6g) derivatives had better anti-M. tuberculosis activity, especially against resistant clinical isolates, what makes them scaffold candidates for further investigations about their anti-tuberculosis activity. The SAR study conducted with the 19 ß-carboline derivatives showed the importance of steric effects for the synthesized ß-carbolines against M tuberculosis, and these models can be used for future proposition of new derivatives, increasing the chances of obtaining potentially anti-tuberculosis compounds.


Assuntos
Antituberculosos/farmacologia , Carbolinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antituberculosos/síntese química , Antituberculosos/química , Carbolinas/síntese química , Carbolinas/química , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Células Vero
15.
Chemistry ; 26(3): 729-734, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31729089

RESUMO

The psychotropic effects of Psilocybe "magic" mushrooms are caused by the l-tryptophan-derived alkaloid psilocybin. Despite their significance, the secondary metabolome of these fungi is poorly understood in general. Our analysis of four Psilocybe species identified harmane, harmine, and a range of other l-tryptophan-derived ß-carbolines as their natural products, which was confirmed by 1D and 2D NMR spectroscopy. Stable-isotope labeling with 13 C11 -l-tryptophan verified the ß-carbolines as biosynthetic products of these fungi. In addition, MALDI-MS imaging showed that ß-carbolines accumulate toward the hyphal apices. As potent inhibitors of monoamine oxidases, ß-carbolines are neuroactive compounds and interfere with psilocybin degradation. Therefore, our findings represent an unprecedented scenario of natural product pathways that diverge from the same building block and produce dissimilar compounds, yet contribute directly or indirectly to the same pharmacological effects.


Assuntos
Agaricales/metabolismo , Alcaloides/química , Carbolinas/química , Inibidores da Monoaminoxidase/química , Monoaminoxidase/metabolismo , Psilocibina/química , Triptofano/química , Agaricales/química , Monoaminoxidase/química
16.
Drug Dev Res ; 81(1): 32-42, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31498913

RESUMO

Gliomas remain highly fatal due to their high resistance to current therapies. Deregulation of protein synthesis contributes to cancer onset and progression and is a source of rising interest for new drugs. CM16, a harmine derivative with predicted high blood-brain barrier penetration, exerts antiproliferative effects partly through translation inhibition. We evaluated herein how CM16 alters the proteome of glioma cells. The analysis of the gel-free LC/MS and auto-MS/MS data showed that CM16 induces time- and concentration-dependent significant changes in the total ion current chromatograms. In addition, we observed spontaneous clustering of the samples according to their treatment condition and their proper classification by unsupervised and supervised analyses, respectively. A two-dimensional gel-based approach analysis allowed us to identify that treatment with CM16 may downregulate four key proteins involved in glioma aggressiveness and associated with poor patient survival (HspB1, BTF3, PGAM1, and cofilin), while it may upregulate galectin-1 and Ebp1. Consistently with the protein synthesis inhibition properties of CM16, HspB1, Ebp1, and BTF3 exert known roles in protein synthesis. In conclusion, the downregulation of HspB1, BTF3, PGAM1 and cofilin bring new insights in CM16 antiproliferative effects, further supporting CM16 as an interesting protein synthesis inhibitor to combat glioma.


Assuntos
Neoplasias Encefálicas/metabolismo , Carbolinas/farmacologia , Glioma/metabolismo , Proteômica/métodos , Neoplasias Encefálicas/tratamento farmacológico , Carbolinas/síntese química , Carbolinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Humanos , Aprendizado de Máquina , Estrutura Molecular , Espectrometria de Massas em Tandem
17.
Future Med Chem ; 12(3): 183-192, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31813284

RESUMO

Aim: Cancer is a major health burden and a leading cause of death worldwide. We sought to discover potential anticancer molecules with novel scaffold for further development of more active agents to address the issue. Methodology: A series of ß-carboline-1-one hydantoins were designed according to a conformational restriction strategy, synthesized via a one-pot Knoevenagel condensation-intramolecular cyclization, and tested in cytotoxicity assays. Results: The study culminated in the identification of 6b and 6c, both of which were found to potently inhibit breast and lung cancer cell lines. Of particular interest was 6c, which was 83 times more potent an inhibitor than 5-fluorouracil in inhibiting MCF-7. Conclusion: This work establishes ß-carboline-1-one hydantoin as a promising scaffold in the investigation of anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Desenho de Fármacos , Hidantoínas/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Carbolinas/síntese química , Carbolinas/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidantoínas/síntese química , Hidantoínas/química , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Nat Prod Res ; 34(4): 489-493, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30369253

RESUMO

(±)-Quassidine K (1), a pair of new bis-ß-carboline alkaloid enantiomers, were isolated from Picrasma quassioides. Their structures were determined on the basis of detailed spectroscopic data analysis. The absolute configurations of (+)-S-quassidine K (1a) and (-)-R-quassidine K (1b) were determined by comparing with the reported experimental ECD spectra after chiral separation. The cytotoxicity assay showed activity against HeLa cells with IC50 values of 15.8 and 20.1 µM, respectively.


Assuntos
Alcaloides/isolamento & purificação , Antineoplásicos/isolamento & purificação , Carbolinas/isolamento & purificação , Picrasma/química , Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Estereoisomerismo
19.
Nat Commun ; 10(1): 5553, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804483

RESUMO

Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.


Assuntos
Carbolinas/química , Ciclização , Alcaloides Indólicos/química , Indóis/química , Carbolinas/síntese química , Catálise , Cromatografia Líquida de Alta Pressão , Sinergismo Farmacológico , Alcaloides Indólicos/síntese química , Indóis/síntese química , Modelos Químicos , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Estereoisomerismo
20.
Molecules ; 24(22)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703464

RESUMO

Portulaca oleracea is as a medicinal plant known for its neuroprotective, hepatoprotective, antidiabetic, antioxidant, anticancer, antimicrobial, antiulcerogenic, and anti-inflammatory activities. However, the specific active compounds responsible for the individual pharmacological effects of P. oleracea extract (95% EtOH) remain unknown. Here, we hypothesized that alkaloids, the most abundant constituents in P. oleracea extract, are responsible for its anti-inflammatory activity. We investigated the phytochemical substituents (compounds 1-22) using nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI-MS) and screened their effects on NO production in lipopolysaccharide (LPS)-induced macrophages. Compound 20, 1-carbomethoxy-ß-carboline, as an alkaloid structure, ameliorated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and proinflammatory cytokines associated with the mitogen-activated protein kinase (MAPK) pathways, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Subsequently, we observed that compound 20 suppressed nuclear translocation of nuclear factor κB (NF-κB) using immunocytochemistry. Moreover, we recently reported that compound 8, trans-N-feruloyl-3', 7'-dimethoxytyramine, was originally purified from P. oleracea extracts. Our results suggest that 1-carbomethoxy-ß-carboline, the most effective anti-inflammatory agent among alkaloids in the 95% EtOH extract of P. oleracea, was suppressing the MAPK pathway and nuclear translocation of NF-κB. Therefore, P. oleracea extracts and specifically 1-carbomethoxy-ß-carboline may be novel therapeutic candidates for the treatment of inflammatory diseases associated with the activation of MAPKs and NF-κB.


Assuntos
Anti-Inflamatórios , Carbolinas , Núcleo Celular/metabolismo , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Portulaca/química , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Carbolinas/química , Carbolinas/isolamento & purificação , Carbolinas/farmacologia , Núcleo Celular/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , MAP Quinase Quinase 4/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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