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1.
Molecules ; 27(24)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36557789

RESUMO

The Mediterranean diet is recognized as a sustainable dietary approach with beneficial health effects. This is highly relevant, although the production of typical Mediterranean food, i.e., olive oil or wine, processed tomatoes and pomegranate products, generates significant amounts of waste. Ideally, this waste should be disposed in an appropriate, eco-friendly way. A number of scientific papers were published recently showing that these by-products can be exploited as a valuable source of biologically active components with health benefits, including anticancer effects. In this review, accordingly, we elaborate on such phytochemicals recovered from the food waste generated during the processing of vegetables and fruits, typical of the Mediterranean diet, with a focus on substances with anticancer activity. The molecular mechanisms of these phytochemicals, which might be included in supporting treatment and prevention of various types of cancer, are presented. The use of bioactive components from food waste may improve the economic feasibility and sustainability of the food processing industry in the Mediterranean region and can provide a new strategy to approach prevention of cancer.


Assuntos
Dieta Mediterrânea , Neoplasias , Eliminação de Resíduos , Humanos , Frutas/química , Indústria Alimentícia , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Compostos Fitoquímicos/análise , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle
2.
Future Med Chem ; 14(16): 1187-1202, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35791783

RESUMO

Aim: The authors' aim was to improve the application of copper-catalyzed azide-alkyne cycloaddition in the synthesis of hybrids containing biologically significant nucleobases and L-ascorbic acid scaffolds by introducing an environmentally friendly and waste-free ball mill. Results: Two series of hybrids with a purine, pyrrolo[2,3-d]pyrimidine or 5-substituted pyrimidine attached to 2,3-dibenzyl-L-ascorbic acid via a hydroxyethyl- (15a-23a) or ethylidene-1,2,3-triazolyl (15b-23b) bridge were prepared by ball milling and conventional synthesis. The unsaturated 6-chloroadenine L-ascorbic acid derivative 16b can be highlighted as a lead compound and showed strong antiproliferative activity against HepG2 (hepatocellular carcinoma) and SW620 (colorectal adenocarcinoma) cells. Conclusion: Mechanochemical synthesis was superior in terms of sustainability, reaction rate and yield, highlighting the advantageous applications of ball milling over classical reactions.


Assuntos
Ácido Ascórbico , Azidas , Alcinos/química , Ácido Ascórbico/química , Ácido Ascórbico/farmacologia , Azidas/química , Pirimidinas/química , Solventes
3.
Molecules ; 27(4)2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35209235

RESUMO

Since the middle of the last century, marine organisms have been identified as producers of chemically and biologically diverse secondary metabolites which have exerted various biological activities including anticancer, anti-inflammatory, antioxidant, antimicrobial, antifouling and others. This review primarily focuses on the marine phenolic compounds and their derivatives with potent anticancer activity, isolated and/or modified in the last decade. Reports on the elucidation of their structures as well as biosynthetic studies and total synthesis are also covered. Presented phenolic compounds inhibited cancer cells proliferation or migration, at sub-micromolar or nanomolar concentrations (lamellarins D (37), M (38), K (39), aspergiolide B (41), fradimycin B (62), makulavamine J (66), mayamycin (69), N-acetyl-N-demethylmayamycin (70) or norhierridin B (75)). In addition, they exhibited anticancer properties by a diverse biological mechanism including induction of apoptosis or inhibition of cell migration and invasive potential. Finally, phlorotannins 1-7 and bromophenols 12-29 represent the most researched phenolic compounds, of which the former are recognized as protective agents against UVB or gamma radiation-induced skin damages. Finally, phenolic metabolites were assorted into six main classes: phlorotannins, bromophenols, flavonoids, coumarins, terpenophenolics, quinones and hydroquinones. The derivatives that could not be attributed to any of the above-mentioned classes were grouped in a separate class named miscellaneous compounds.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Organismos Aquáticos/química , Fenóis/química , Fenóis/farmacologia , Antineoplásicos/isolamento & purificação , Organismos Aquáticos/metabolismo , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Humanos , Redes e Vias Metabólicas , Fenóis/isolamento & purificação , Fenóis/metabolismo , Relação Estrutura-Atividade
4.
Molecules ; 26(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34641295

RESUMO

Due to sedentary lifestyle and harsh environmental conditions, gorgonian coral extracts are recognized as a rich source of novel compounds with various biological activities, of interest to the pharmaceutical and cosmetic industries. The presented study aimed to perform chemical screening of organic extracts and semi-purified fractions obtained from the common Adriatic gorgonian, sea fan, Eunicella cavolini (Koch, 1887) and explore its abilities to exert different biological effects in vitro. Qualitative chemical evaluation revealed the presence of several classes of secondary metabolites extended with mass spectrometry analysis and tentative dereplication by using Global Natural Product Social Molecular Networking online platform (GNPS). Furthermore, fractions F4 and F3 showed the highest phenolic (3.28 ± 0.04 mg GAE/g sample) and carotene (23.11 ± 2.48 mg ß-CA/g sample) content, respectively. The fraction F3 inhibited 50% of DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) and ABTS (2,2'-azino-bis (3-ethylbenzthiazolin-6-yl) sulfonic acid) radicals at the concentrations of 767.09 ± 11.57 and 157.16 ± 10.83 µg/mL, respectively. The highest anti-inflammatory potential was exhibited by F2 (IC50 = 198.70 ± 28.77 µg/mL) regarding the inhibition of albumin denaturation and F1 (IC50 = 254.49 ± 49.17 µg/mL) in terms of soybean lipoxygenase inhibition. In addition, the most pronounced antiproliferative effects were observed for all samples (IC50 ranging from 0.82 ± 0.14-231.18 ± 46.13 µg/mL) against several carcinoma cell lines, but also towards non-transformed human fibroblasts pointing to a generally cytotoxic effect. In addition, the antibacterial activity was tested by broth microdilution assay against three human pathogenic bacteria: Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The latter was the most affected by fractions F2 and F3. Finally, further purification, isolation and characterization of pure compounds from the most active fractions are under investigation.


Assuntos
Antozoários/química , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Fatores Biológicos/farmacologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Fatores Biológicos/química , Fatores Biológicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Células Hep G2 , Humanos , Células MCF-7 , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa , Metabolismo Secundário , Staphylococcus aureus/efeitos dos fármacos
5.
Pharmaceuticals (Basel) ; 14(9)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34577557

RESUMO

Carbon quantum dots (CQDs) have recently emerged as innovative theranostic nanomaterials, enabling fast and effective diagnosis and treatment. In this study, a facile hydrothermal approach for N-doped biomass-derived CQDs preparation from Citrus clementina peel and amino acids glycine (Gly) and arginine (Arg) has been presented. The gradual increase in the N-dopant (amino acids) nitrogen content increased the quantum yield of synthesized CQDs. The prepared CQDs exhibited good biocompatibility, stability in aqueous, and high ionic strength media, similar optical properties, while differences were observed regarding the structural and chemical diversity, and biological and antioxidant activity. The antiproliferative effect of CQD@Gly against pancreatic cancer cell lines (CFPAC-1) was observed. At the same time, CQD@Arg has demonstrated the highest quantum yield and antioxidant activity by DPPH scavenging radical method of 81.39 ± 0.39% and has been further used for the ion sensing and cellular imaging of cancer cells. The obtained results have demonstrated selective response toward Fe3+ detection, with linear response ranging from 7.0 µmol dm-3 to 50.0 µmol dm-3 with R2 = 0.9931 and limit of detection (LOD) of 4.57 ± 0.27 µmol dm-3. This research could be a good example of sustainable biomass waste utilization with potential for biomedical analysis and ion sensing applications.

6.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206076

RESUMO

Novel symmetrical bis-pyrrolo[2,3-d]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-d]pyrimidine monomer 5f with 4,4'-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC50 = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-d]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.


Assuntos
Antineoplásicos/síntese química , Pirimidinas/síntese química , Pirróis/síntese química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reação de Cicloadição , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia
7.
Org Biomol Chem ; 19(12): 2784-2793, 2021 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-33704342

RESUMO

Unlike the closely related and widely investigated amidino-substituted benzimidazoles and benzothiazoles with a range of demonstrated biological activities, the matching benzoxazole analogues still remain a largely understudied and not systematically evaluated class of compounds. To address this challenge, we utilized the Pinner reaction to convert isomeric cyano-substituted 2-aminophenols into their amidine derivatives, which were isolated as hydrochlorides and/or zwitterions, and whose structure was confirmed by single crystal X-ray diffraction. The key step during the Pinner synthesis of the crucial carboximidate intermediates was characterized through mechanistic DFT calculations, with the obtained kinetic and thermodynamic parameters indicating full agreement with the experimental observations. The obtained amidines were subjected to a condensation reaction with aryl carboxylic acids that allowed the synthesis of a new library of 5- and 6-amidino substituted 2-arylbenzoxazoles. Their antiproliferative features against four human tumour cell lines (SW620, HepG2, CFPAC-1, HeLa) revealed sub-micromolar activities on SW620 for several cyclic amidino 2-naphthyl benzoxazoles, thus demonstrating the usefulness of the proposed synthetic strategy and promoting amidino substituted 2-aminophenols as important building blocks towards biologically active systems.


Assuntos
Amidinas/farmacologia , Aminofenóis/farmacologia , Antineoplásicos/farmacologia , Benzoxazóis/farmacologia , Amidinas/química , Aminofenóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzoxazóis/síntese química , Benzoxazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular
8.
Curr Med Chem ; 27(8): 1367-1381, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30569844

RESUMO

The metastatic process has still not been completely elucidated, probably due to insufficient knowledge of the underlying mechanisms. Here, we provide an overview of the current findings that shed light on specific molecular alterations associated with metastasis and present novel concepts in the treatment of the metastatic process. In particular, we discuss novel pharmacological approaches in the clinical setting that target metastatic progression. New insights into the process of metastasis allow optimisation and design of new treatment strategies, especially in view of the fact that metastatic cells share common features with stem cells. Nano- and micro-technologies are herein elaborated in details as a promising therapeutic concept in targeted drug delivery for metastatic cancer. Progression in the field could provide a more efficient way to tackle metastasis and thus bring about advancements in the treatment and management of patients with advanced cancer.


Assuntos
Nanotecnologia , Neoplasias , Sistemas de Liberação de Medicamentos , Humanos , Metástase Neoplásica
9.
Eur J Med Chem ; 185: 111833, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734024

RESUMO

Herein we present and describe the design and synthesis of novel phenantrene derivatives substituted with either amino or amido side chains and their biological activity. Antiproliferative activities were assessed in vitro on a panel of human cancer cell lines. Tested compounds showed moderate activity against cancer cells in comparison with 5-fluorouracile. Among all tested compounds, some compounds substituted with cyano groups showed a pronounced and selective activity in the nanomolar range of inhibitory concentrations against HeLa and HepG2. The strongest selective activity against HeLa cells was observed for acrylonitriles 8 and 11 and their cyclic analogues 15 and 17 substituted with two cyano groups with a corresponding IC50 = 0.33, 0.21, 0.65 and 0.45 µM, respectively. Compounds 11 showed the most pronounced selectivity being almost non cytotoxic to normal fibroblasts. Additionally, mode of biological action analysis was performed in silico and in vitro by Western blot analysis of HIF-1-α relative expression for compounds 8 and 11.


Assuntos
Antineoplásicos/farmacologia , Fenantrenos/farmacologia , Tiofenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Células Hep G2 , Humanos , Estrutura Molecular , Fenantrenos/síntese química , Fenantrenos/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Células Tumorais Cultivadas
10.
Eur J Med Chem ; 184: 111739, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31586832

RESUMO

Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-l-ascorbic acid derivatives with the hydroxyethylene (8a-8u) and ethylidene linkers (10c-10p) were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and antiviral activity against a broad range of viruses. Conformationally unrestricted spacer between the lactone and 1,2,3-triazole units in 8a-8u series had a profound effect on antitumor activity. Besides, the introduction of a long side chain at C-4 of 1,2,3-triazole that led to the synthesis of decyl-substituted 2,3-dibenzyl-l-ascorbic acid 8m accounted for a selective and potent antiproliferative activity on breast cancer MCF-7 cells cells in the nM range. Further analysis showed that compound 8m strongly enhanced expression of hypoxia inducible transcription factor 1 α (HIF-1α) and to some extent decreased expression of nitric oxide synthase 2 (NOS2) suggesting its role in regulating HIF-1α signalling pathway. The p-methoxyphenyl-substituted derivative 10g displayed specific anti-cytomegalovirus (CMV) potential, whereas aliphatic-substituted derivatives 8l and 8m had the most potent, yet relatively non-specific, anti-varicella-zoster (VZV) activity.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Ácido Ascórbico/farmacologia , Triazóis/farmacologia , Vírus/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Apoptose/efeitos dos fármacos , Ácido Ascórbico/síntese química , Ácido Ascórbico/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
11.
Food Technol Biotechnol ; 57(2): 171-182, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31537966

RESUMO

The beneficial properties of polyphenols are widely recognized, and polyphenol-rich olive oil, which is part of the typical Mediterranean diet, has been identified as having positive health effects. However, over the past decade, olive leaves have been discovered as an alternative polyphenol-rich source. This is particularly interesting in the context of the growing interest in functional foods, as well as in terms of the management of biological waste, including olive leaves that are left over from the production of olive oil. Previous studies on olive leaves confirmed that they have a high phenolic content, which explains their previously described strong antibacterial, antimicrobial and antiviral activity. Therefore, the major aim of our work is to comprehensively determine olive leaf phenolic content in cultivars Istarska bjelica, Leccino and Buza as a natural source of bioactive compounds suitable for daily consumption in the form of infusion. For this purpose, we examined the influence of olive leaf cultivar, maceration time and temperature on the phenolic composition of final infusions. Phenolic compounds were analysed by liquid chromatography (LC) coupled to a triple quadrupole mass spectrometer (LC-QQQ). As expected, the results indicate the significant influence of not only the olive cultivar but also of maceration parameters on the qualitative and quantitative phenolic composition. The highest phenolic compound content was obtained in the infusion of Istarska bjelica leaves after 15 min of maceration. However, the Buza olive leaf infusion had the most diverse phenolic composition. Furthermore, we designed several functional olive leaf infusion mixtures with phenolic compositions adjusted based on the desired health effect. The results show the role of phenolic composition adjustment in the development and improvement of the quality of functional olive leaf infusions.

12.
Int J Mol Sci ; 20(19)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554245

RESUMO

The novel 4-substituted 1,2,3-triazole L-ascorbic acid (L-ASA) conjugates with hydroxyethylene spacer as well as their conformationally restricted 4,5-unsaturated analogues were synthesized as potential antioxidant and antiproliferative agents. An evaluation of the antioxidant activity of novel compounds showed that the majority of the 4,5-unsaturated L-ASA derivatives showed a better antioxidant activity compared to their saturated counterparts. m-Hydroxyphenyl (7j), p-pentylphenyl (7k) and 2-hydroxyethyl (7q) substituted 4,5-unsaturated 1,2,3-triazole L-ASA derivatives exhibited very efficient and rapid (within 5 min) 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging activity (7j, 7k: IC50 = 0.06 mM; 7q: IC50 = 0.07 mM). In vitro scavenging activity data were supported by in silico quantum-chemical modelling. Thermodynamic parameters for hydrogen-atom transfer and electron-transfer radical scavenging pathways of anions deprotonated at C2-OH or C3-OH groups of L-ASA fragments were calculated. The structure activity analysis (SAR) through principal component analysis indicated radical scavenging activity by the participation of OH group with favorable reaction parameters: the C3-OH group of saturated C4-C5(OH) derivatives and the C2-OH group of their unsaturated C4=C5 analogues. The antiproliferative evaluation showed that p-bromophenyl (4e: IC50 = 6.72 µM) and p-pentylphenyl-substituted 1,2,3-triazole L-ASA conjugate (4k: IC50 = 26.91 µM) had a selective cytotoxic effect on breast adenocarcinoma MCF-7 cells. Moreover, compound 4e did not inhibit the growth of foreskin fibroblasts (IC50 > 100 µM). In MCF-7 cells treated with 4e, a significant increase of hydroxylated hypoxia-inducible transcription factor 1 alpha (HIF-1α) expression and decreased expression of nitric oxide synthase 2 (NOS2) were observed, suggesting the involvement of 4e in the HIF-1α signaling pathway for its strong growth-inhibition effect on MCF-7 cells.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Antineoplásicos/química , Antioxidantes/química , Ácido Ascórbico/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Células MCF-7 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Teoria Quântica
13.
Anticancer Res ; 39(1): 41-56, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591439

RESUMO

Recent translational studies in cancer have produced a wealth of evidence to support an association between sphingolipid metabolism and clinical outcomes, which underscores the clinical importance of sphingolipid-related biomarkers in cancer diagnosis and prognosis. Importantly, circulating levels of bioactive sphingolipids were demonstrated to correlate with patient survival and treatment response in different tumour types, which could provide novel non-invasive cancer biomarkers. Here, we give a comprehensive overview of recent findings on bioactive sphingolipid species and protein regulators of their metabolism and signalling as novel potential biomarkers for risk assessment, prevention and prediction of treatment response in several types of solid cancers, including prostate, liver, pancreatic, breast and colon cancer, head and neck squamous cell carcinoma and gliomas. Finally, we critically discuss current issues in clinical translation of sphingolipid biomarkers and give our perspective on how these problems could be handled to facilitate implementation of sphingolipid-based diagnostics into clinical practice.


Assuntos
Biomarcadores Farmacológicos/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias/genética , Esfingolipídeos/genética , Ceramidas/metabolismo , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Medição de Risco , Esfingolipídeos/metabolismo , Taxa de Sobrevida
14.
Biochem Biophys Res Commun ; 503(2): 843-848, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-29920241

RESUMO

Acid ceramidase (ASAH1) has been implicated in the progression and chemoresistance in different cancers. Its role in colon cancer biology and response to standard chemotherapy has been poorly addressed so far. Here, we have investigated ASAH1 expression at the protein level in human colon cancer cell lines and tissues from colon cancer patients, and have examined in vitro the possible link between ASAH1 expression and functional activity of p53 protein whose inactivation is associated with the progression from adenoma to malignant tumour in colon cancer. Finally, we have explored the role of ASAH1 in response and resistance mechanisms to oxaliplatin (OXA) in HCT 116 colon cancer cells. We have demonstrated that human colon cancer cells and colorectal adenocarcinoma tissues constitutively express ASAH1, and that its expression is higher in tumour tissues than in normal colonic mucosa. Furthermore, we found an inverse correlation between ASAH1 expression and p53 functional activity. Obtained data revealed that ASAH1 was involved in HCT 116 cell response to OXA and that anti-proliferative, pro-apoptotic, anti-migratory and anti-clonogenic effects of OXA could be significantly increased by combination treatment with ASAH1 inhibitor carmofur. Increased OXA sensitivity was associated with downregulation of signalling involved in acquired resistance to OXA in colon cancer, in particular transglutaminase 2 and ß1 integrin/FAK, which resulted in the suppression of NF-κB and Akt. Thus, combination of OXA with ASAH1 inhibitors could be a promising strategy to counter chemoresistance and improve treatment outcome in advanced colon cancer.


Assuntos
Ceramidase Ácida/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Integrina beta1/metabolismo , Oxaliplatina/farmacologia , Transglutaminases/metabolismo , Ceramidase Ácida/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação para Baixo/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , Proteína 2 Glutamina gama-Glutamiltransferase , Transdução de Sinais/efeitos dos fármacos
15.
ChemMedChem ; 13(4): 360-372, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29381258

RESUMO

A series of N-methylated and N-oxidised tripyridyl porphyrins were synthesised, characterised, and their PDT activity was studied with six cell lines. All the tested porphyrins with a long alkyl chain, except one, were more efficient for PDT than an N-methylated hydrophilic porphyrin and N-oxidised porphyrin without the long alkyl chain. Generally, N-methylated tripyridyl porphyrins were more active than those N-oxidised, but IC50 values for phototoxicity of two N-oxides, named TOPyP3-C17 H33 O and TOPyP3-C17 H35 , were still in the nanomolar concentration range for most of the tested cell lines. However, TOPyP3-C17 H35 did not show phototoxicity on human foreskin fibroblast cells. Two methylated amphiphilic porphyrins, named TMPyP3-C17 H33 and TMPyP4-C17 H35, showed significant dark toxicity, whereas none of the oxidopyridyl porphyrins were toxic without light activation. The selected photosensitisers were shown to be apoptosis inducers, and had inhibitory effects on the clonogenic growth of HCT116 and HeLa cells. All three N-methylated amphiphilic porphyrins significantly reduced the migratory potential of HCT116 cells. Porphyrins TMPyP3-C17 H35 and TOPyP3-C17 H35 reduced the activity of acid ceramidase, whereas TOPyP3-C17 H33 O had a significant inhibitory effect on sphingosine kinase 1 activity in HeLa cells. Compounds with this dual activity were shown to be the most promising photosensitisers, with potential to treat invasive cancers.


Assuntos
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fármacos Fotossensibilizantes/química , Porfirinas/química , Esfingolipídeos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HeLa , Humanos , Luz , Metilação , Nitrogênio/química , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 143: 1616-1634, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29133046

RESUMO

A series of novel amidino 2-substituted benzimidazoles linked to 1,4-disubstituted 1,2,3-triazoles were synthesized by implementation of microwave and ultrasound irradiation in click reaction and subsequent condensation of thus obtained 4-(1,2,3-triazol-1-yl)benzaldehyde with o-phenylenediamines. In vitro antiproliferative screening of compounds performed on human cancer cell lines revealed that p-chlorophenyl-substituted 1,2,3-triazolyl N-isopropylamidine 10c and benzyl-substituted 1,2,3-triazolyl imidazoline 11f benzimidazoles had selective and potent cytostatic activities in the low nM range against non-small cell lung cancer cell line A549, which could be attributed to induction of apoptosis and primary necrosis. Additional Western blot analyses showed different mechanisms of cytostatic activity between compounds 10c and 11f that could be associated with the nature of aromatic substituent at 1-(1,2,3-triazolyl) and amidino moiety at C-5 position of benzimidazole ring. Specifically, compound 11f abrogated the activity of several protein kinases including TGM2, CDK9, SK1 and p38 MAPK, whereas compound 10c did not have profound effect on the activities of CDK9 and TGM2, but instead showed moderate downregulation of SK1 activity concomitant with a significant reduction in p38 MAPK. Further in silico structural analysis demonstrated that compound 11f bound slightly better to the ATP binding site of p38 MAPK compared to 10c, which correlated well with observed stronger decrement in the expression level of phospho-p38 MAPK elicited by 11f in comparison with 10c.


Assuntos
Amidinas/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desenho de Fármacos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Amidinas/síntese química , Amidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzimidazóis/síntese química , Benzimidazóis/química , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/patologia , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Quinases , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia
17.
Exp Biol Med (Maywood) ; 242(15): 1553-1558, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28799406

RESUMO

Circadian clock regulation in mammals is controlled by feedback loops of a set of circadian genes. One of these circadian genes, NPAS2, encodes for a member of the bHLH-PAS class of transcription factors and is expressed in the forebrain and in some peripheral organs such as liver and skin. Other biological processes are also regulated by circadian genes. For example, NPAS2 is involved in cell proliferation, DNA damage repair and malignant transformation. Aberrant expression of clock genes has been previously observed in melanoma which led to our effort to sequence the NPAS2 promoter region in this cancer type. The NPAS2 putative promoter and 5' untranslated region of ninety-three melanoma patients and ninety-six control subjects were sequenced and several variants were identified. Among these is a novel microsatellite comprising a GGC repeat with different alleles ranging from 7 to 13 repeats located in the 5' untranslated exon. Homozygosity of an allele with nine repeats (9/9) was more prevalent in melanoma than in control subjects (22.6% and 13.5%, respectively, P: 0.0206) suggesting that some NPAS2 variants might contribute to melanoma susceptibility. Impact statement This report describes a variable microsatellite repeat sequence located in the 5' untranslated exon of NSPAS2, a gene encoding a clock transcription factor. Significantly, this study is the first to show that a variant copy number GGC repeat sequence in the NPAS2 clock gene associates with melanoma risk and which may be useful in the assessment of melanoma predisposition.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Predisposição Genética para Doença , Melanoma/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Regiões 5' não Traduzidas , Alelos , Feminino , Humanos , Masculino , Repetições de Microssatélites , Regiões Promotoras Genéticas , Sequências Repetitivas de Ácido Nucleico
18.
Mol Divers ; 21(1): 201-210, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27677735

RESUMO

A series of pyrido[1,2-a]benzimidazoles has been designed, and novel examples are synthesized and evaluated for their potential antiproliferative activity against four human tumour cell lines-cervical (HeLa), colorectal (SW620), breast (MCF-7) and hepatocellular carcinoma (HepG2). In addition, their antioxidative potency has been evaluated by in vitro spectrophotometric assays. Preliminary structure-activity relationships among the synthesized compounds are discussed. Evaluation of their antioxidative capacity has shown that two compounds (25 and 26) possess promising reducing characteristics and free radical scavenging activity. Selective antiproliferative effect in the single-digit micromolar range was observed for compound 25 on MCF-7 [Formula: see text] and HeLa [Formula: see text] cell lines, comparable to the standards 5-fluorouracil and cisplatin. The combination of the radical scavenging activity and antiproliferative activity of compound 25 positions this compound as a potential lead candidate for further optimization.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade
19.
Anticancer Agents Med Chem ; 17(1): 57-66, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27141878

RESUMO

BACKGROUND: Differently substituted thiophenes are largely studied due to their diverse pharmacological properties, especially anticancer activity. Recent studies have reported on interesting benzothiophene compounds antitumor properties and we also recently reported on the synthesis, strong antitumor activities and DNA binding features of substituted thieno[3',2':4,5]thieno- and benzo[b]thieno[2,3-c]quinolones, containing different substituents, mostly amidino- or substituted amidino- groups. OBJECTIVE: The objective of presented paper was to prepare a series of novel cationic 2-thiophene and 2- benzothiophene substituted 6-(2- imidazolinyl)benzothiazole derivatives and to test their antiproliferative activity against several human cancer cell lines. METHOD: Synthesis of 2-thiophene and 2-benzothiophene substituted 6-(2-imidazolinyl)benzothiazole derivatives was carried out by condensation reaction of 2-amino-5-(2-imidazolinium)benzenethiolate with aldehydes or carbonyl chloride derivatives followed by two simple acid-base reaction steps was used for their conversion into targeted mesylates. Evaluation of antiproliferative effects and cell death was done by use of MTT assay and annexin-V test, while expression of sphingosine kinase 1 was studied by Western blot and gluthatione intracellular levels were measured by use of a luminescence-based assay. RESULTS: Preparation of water soluble mesylate salts 3a-3j was successfully achieved. In general, all compounds showed pronounced anticancer activities in vitro. Compound 3f showed strong and selective cytostatic activity in cervical carcinoma cells (HeLa) with moderate toxicity on normal fibroblasts. Similar to all other tested compounds, 3f cannot be considered a mitochondrial toxicant. One of the major mechanisms accounting for observed cytostatic effects of 3f was induction of apoptosis, probably due to specific inhibition of acid ceramidase activity. Compound 3h negatively regulated activity of sphingosine kinase 1 in HeLa cells. CONCLUSION: Design of novel inhibitors targeting enzymes that regulate sphingolipid biosynthesis and turnover could change the landscape for the development of new anticancer drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Benzotiazóis/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Tiofenos/síntese química
20.
Eur J Med Chem ; 124: 794-808, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27639370

RESUMO

The 4-substituted 1,2,3-triazole core in designed coumarin hybrids (4-35) with diverse physicochemical properties was introduced by eco-friendly copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition under microwave irradiation. Coumarin-1,2,3-triazole-benzofused heterocycle hybrids emerged as the class of compounds exhibiting the highest antiproliferative activity. The strong relationship between lipophilicity and antiproliferative activities was observed indicating that lipophilic 1,2,3-triazole-coumarin hybrids containing phenylethyl (13), 3,5-difluorophenyl (14), 5-iodoindole (30) and benzimidazole (33 and 35) subunits showed the most potent cytostatic effects. The 7-methylcoumarin-1,2,3-triazole-2-methylbenzimidazole hybrid 33 can be highlighted as a lead that exerted the highest cytotoxicity against hepatocellular carcinoma HepG2 cells with IC50 value of 0.9 µM and high selectivity (SI = 50). This compound induced cell death, mainly due to early apoptosis. Strong antiproliferative effect of 33 could be associated with its inhibition of 5-lipoxygenase (5-LO) activity and perturbation of sphingolipid signaling by interfering with intracellular acid ceramidase (ASAH) activity. Outlined considerable effect of lipophilicity on antiproliferative activity was not observed for antibacterial activity. The compounds with p-pentylphenyl (17), 2-chloro-4-fluorobenzenesulfonamide (23) and dithiocarbamate (27) moiety were endowed with high selectivity against Enterococcus species. Moreover, these compounds were found to be superior in inhibiting the growth of clinically isolated vancomycin-resistant Enterococcus faecium, while the reference antibiotics exhibited the lack of activity. Our findings indicate that coumarin-1,2,3-triazole could be used as the scaffold for structural optimization to develop more potent and selective anticancer agents and encourage further development of novel structurally related analogs of 33 as more effective 5-LO inhibitors.


Assuntos
Simulação por Computador , Cumarínicos/síntese química , Cumarínicos/farmacologia , Desenho de Fármacos , Triazóis/química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Cumarínicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
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