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1.
Int J Mol Sci ; 22(19)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34638706

RESUMO

Breast cancer is the most common cancer of women-it affects more than 2 million women worldwide. PTP1B phosphatase can be one of the possible targets for new drugs in breast cancer therapy. In this paper, we present new curcumin derivatives featuring a 4-piperidone ring as PTP1B inhibitors and ROS inducers. We performed cytotoxicity analysis for twelve curcumin derivatives against breast cancer MCF-7 and MDA-MB-231 cell lines and the human keratinocyte HaCaT cell line. Furthermore, because curcumin is a known antioxidant, we assessed antioxidant effects in its derivatives. For the most potent cytotoxic compounds, we determined intracellular ROS and PTP1B phosphatase levels. Moreover, for curcumin and its derivatives, we performed real-time microscopy to observe the photosensitizing effect. Finally, computational analysis was performed for the curcumin derivatives with an inhibitory effect against PTP1B phosphatase to assess the potential binding mode of new inhibitors within the allosteric site of the enzyme. We observed that two tested compounds are better anticancer agents than curcumin. Moreover, we suggest that blocking the -OH group in phenolic compounds causes an increase in the cytotoxicity effect, even at a low concentration. Furthermore, due to this modification, a higher level of ROS is induced, which correlates with a lower level of PTP1B.


Assuntos
Neoplasias da Mama , Curcumina , Citotoxinas/farmacologia , Proteínas de Neoplasias/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteólise/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Feminino , Humanos , Células MCF-7
2.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638600

RESUMO

To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine derivativeshave been designed and synthesized viacyclocondensation reactions of pyrazolo-enaminone with a series of arylidenemalononitriles; compound 5 was obtained from 5-amino-4-cyanopyrazole. The structures of the target compounds were investigated by spectral techniques and elemental analysis (IR, UV-Vis, 1H NMR, 13C NMR and ESI-MS). All compounds were evaluated for their in vitro cytotoxicity employing a panel of different human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells. It has been found that the pyrazolo-pyrido-pyrimidine analog bearing a 4-Br-phenyl moiety was the most active toward many cell lines with EC50 values ranging between 9.1 and 13.5 µM. Moreover, in silico docking studies of the latter with six anticancer drug targets, i.e., DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX5, were also performed, in order to gain some insights into their putative mode of binding interaction and to estimate the free binding energy of this bioactive molecule.


Assuntos
Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Pirimidinas/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HEK293 , Células HT29 , Humanos , Células MCF-7 , Camundongos , Simulação de Acoplamento Molecular/métodos , Células NIH 3T3 , Pirazóis/farmacologia
3.
Molecules ; 26(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34641398

RESUMO

Due to the strong drug resistance of Pseudomonas aeruginosa (P. aeruginosa), the inhibition effects of conventional disinfectants and antibiotics are not obvious. Juglone extracted from discarded walnut husk, as a kind of plant-derived antimicrobial agent, has the advantages of naturalness, high efficiency, and low residue, with a potential role in the inhibition of P. aeruginosa. This study elucidated the inhibitory effect of juglone on the growth of plankton and the formation of P. aeruginosa biofilm. The results showed that juglone (35 µg/mL) had an irreversible inhibitory effect on P. aeruginosa colony formation (about 107 CFU/mL). The integrity and permeability of the cell membrane were effectively destroyed, accompanied by disorder of the membrane permeability, mass leakage of the cytoplasm, and ATP consumption. Further studies manifested that juglone could induce the abnormal accumulation of ROS in cells and block the formation of the cell membrane. In addition, RT-qPCR showed that juglone could effectively block the expression of five virulence genes and two genes involved in the production of extracellular polymers, thereby reducing the toxicity and infection of P. aeruginosa and preventing the production of extracellular polymers. This study can provide support for the innovation of antibacterial technology toward P. aeruginosa in food.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Biofilmes/crescimento & desenvolvimento , Membrana Celular/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Naftoquinonas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Proteínas de Bactérias/genética , Biofilmes/efeitos dos fármacos , Membrana Celular/patologia , Citotoxinas/farmacologia , Polímeros/metabolismo , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/metabolismo , Percepção de Quorum , Virulência
4.
PLoS One ; 16(10): e0255502, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34714855

RESUMO

We evaluated phytochemical composition, antibacterial, antifungal, anti-oxidant and cytotoxic properties of aqueous (water) and organic extracts (methanol, ethyl acetate and n-hexane) of Chenopodium glaucum. Highest phenolic content 45 mg gallic acid equivalents (GAE)/g d.w was found in aqueous extract followed by ethyl acetate (41mg GAE/g d.w) and methanol extract (34.46 mg GAE/g d.w). Antibacterial potential of aqueous and organic extracts of C. glaucum was examined against Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli and Staphylococcus epidermidis. The aqueous, methanolic, ethyl acetate, and n-hexane extract showed antibacterial activity against A. baumannii, K. pneumoniae, E. coli and S. epidermidis. However, against A. baumannii significantly higher inhibition zone (19 mm and 18.96 mm respectively) was shown by ethyl acetate and methanol extracts. Aqueous extract possessed highest growth inhibition (11 mm) against E. coli. Aqueous, ethyl acetate and methanol extracts showed 9 mm, 10 mm, and 10.33 mm zone of inhibition against the K. pneumoniae. For antifungal activity, the extracts were less effective against Aspergillus niger but showed strong antifungal activity against Aspergillus flavus (A. flavus). The antioxidant activity was measured as DPPH (2, 2-diphenyl-1-picrylhydrazyl), H2O2 and ABTS (2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) scavenging activity of free radicals. All the organic extracts of C. glaucum possessed ABTS, DPPH and H2O2 scavenging properties. The highest cytotoxic activity measured as half maximal inhibitory concentration (IC50) against human lungs carcinoma cells was recorded for methanolic (IC50 = 16 µg/mL) and n-hexane (IC50 = 25 µg/mL) extracts, respectively. The Gas chromatography-mass spectrometry (GC-MS) analysis showed 4 major and 26 minor compounds in n-hexane extract and 4 major and 7 minor compounds in methanol extract of the C. glaucum. It is concluded that aqueous and organic extracts of C. glaucum would be potential therapeutic agents and could be exploited on a pilot scale to treat human pathogenic diseases.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Chenopodium/química , Neoplasias Pulmonares/tratamento farmacológico , Extratos Vegetais/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/crescimento & desenvolvimento , Antioxidantes/farmacologia , Aspergillus/efeitos dos fármacos , Aspergillus/crescimento & desenvolvimento , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Compostos Fitoquímicos/farmacologia , Staphylococcus epidermidis/efeitos dos fármacos , Staphylococcus epidermidis/crescimento & desenvolvimento
5.
Nutrients ; 13(9)2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34578985

RESUMO

Seven derivatives of plant-derived hydroxybenzoic acid (HBA)-including 2,3-dihydroxybenzoic (2,3-DHB, pyrocatechuic), 2,4-dihydroxybenzoic (2,4-DHB, ß-resorcylic), 2,5-dihydroxybenzoic (2,5-DHB, gentisic), 2,6-dihydroxybenzoic (2,6-DHB, γ-resorcylic acid), 3,4-dihydroxybenzoic (3,4-DHB, protocatechuic), 3,5-dihydroxybenzoic (3,5-DHB, α-resorcylic), and 3,4,5-trihydroxybenzoic (3,4,5-THB, gallic) acids-were studied for their structural and biological properties. Anti-/pro-oxidant properties were evaluated by using DPPH• (2,2-diphenyl-1-picrylhydrazyl), ABTS•+ (2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), FRAP (ferric-reducing antioxidant power), CUPRAC (cupric-reducing antioxidant power), and Trolox oxidation assays. Lipophilicity was estimated by means of experimental (HPLC) and theoretical methods. The antimicrobial activity against Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Bacillus subtilis (B. subtilis), Salmonella enteritidis (S. enteritidis), and Candida albicans (C. albicans) was studied. The cytotoxicity of HBAs in MCF-7 and MDA-MB-231 cell lines was estimated. Moreover, the structure of HBAs was studied by means of experimental (FTIR, 1H, and 13C NMR) and quantum chemical DFT methods (the NBO and CHelpG charges, electrostatic potential maps, and electronic parameters based on the energy of HOMO and LUMO orbitals). The aromaticity of HBA was studied based on the calculated geometric and magnetic aromaticity indices (HOMA, Aj, BAC, I6, NICS). The biological activity of hydroxybenzoic acids was discussed in relation to their geometry, the electronic charge distribution in their molecules, their lipophilicity, and their acidity. Principal component analysis (PCA) was used in the statistical analysis of the obtained data and the discussion of the dependency between the structure and activity (SAR: structure-activity relationship) of HBAs. This work provides valuable information on the potential application of hydroxybenzoic acids as bioactive components in dietary supplements, functional foods, or even drugs.


Assuntos
Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Citotoxinas/farmacologia , Hidroxibenzoatos/farmacologia , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Humanos , Hidroxibenzoatos/química , Células MCF-7/efeitos dos fármacos , Relação Estrutura-Atividade
6.
Life Sci ; 285: 119993, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34592231

RESUMO

AIMS: Characterizing cannabinoid receptors (CBRs) expressed in Ewing sarcoma (EWS) cell lines as potential targets for anti-cancer drug development. MAIN METHODS: CBR affinity and function were examined by competitive binding and G-protein activation, respectively. Cannabinoid-mediated cytotoxicity and cell viability were evaluated by LDH, and trypan blue assays, respectively. KEY FINDINGS: qRT-PCR detected CB1 (CB1R) and CB2 receptor (CB2R) mRNA in TC-71 cells. However, binding screens revealed that CBRs expressed exhibit atypical properties relative to canonical receptors, because specific binding in TC-71 could only be demonstrated by the established non-selective CB1/CB2R radioligand [3H]WIN-55,212-2, but not CB1/CB2R radioligand [3H]CP-55,940. Homologous receptor binding demonstrated that [3H]WIN-55,212-2 binds to a single site with nanomolar affinity, expressed at high density. Further support for non-canonical CBRs expression is provided by subsequent binding screens, revealing that only 9 out of 28 well-characterized cannabinoids with high affinity for canonical CB1 and/or CB2Rs were able to displace [3H]WIN-55,212-2, whereas two ligands enhanced [3H]WIN-55,212-2 binding. Five cannabinoids producing the greatest [3H]WIN-55,212-2 displacement exhibited high nanomolar affinity (Ki) for expressed receptors. G-protein modulation and adenylyl cyclase assays further indicate that these CBRs exhibit distinct signaling/functional profiles compared to canonical CBRs. Importantly, cannabinoids with the highest affinity for non-canonical CBRs reduced TC-71 viability and induced cytotoxicity in a time-dependent manner. Studies in a second EWS cell line (A-673) showed similar atypical binding properties of expressed CBRs, and cannabinoid treatment produced cytotoxicity. SIGNIFICANCE: Cannabinoids induce cytotoxicity in EWS cell lines via non-canonical CBRs, which might be a potential therapeutic target to treat EWS.


Assuntos
Antineoplásicos/farmacologia , Benzoxazinas/farmacologia , Canabinoides/farmacologia , Morfolinas/farmacologia , Naftalenos/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Sarcoma de Ewing/metabolismo , Ligação Competitiva , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Desenvolvimento de Medicamentos , Humanos , Ligantes , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas
7.
Molecules ; 26(15)2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34361638

RESUMO

The species Cordia verbenacea DC (Boraginaceae), known as the whaling herb and camaradinha, is a perennial shrub species native to the Atlantic Forest. Its leaves are used in folk medicine as an anti-inflammatory, analgesic, antiulcerogenic and curative agent, in the form of teas or infusions for internal or topical use. The present study aimed to verify the cytotoxicity of the essential oil and the leishmanicidal and trypanocidal potential of C. verbenacea. The essential oil was characterized by GC-MS. The in vitro biological activity was determined by anti-Leishmania and anti-Trypanosoma assays. The cytotoxixity was determined using mammalian fibroblasts. The C. verbenacea species presented α-pinene (45.71%), ß-caryophyllene (18.77%), tricyclo[2,2,1-(2.6)]heptane (12.56%) as their main compounds. The essential oil exhibited strong cytotoxicity at concentrations below 250 µg/mL (LC50 138.1 µg/mL) in mammalian fibroblasts. The potent anti-trypanosome and anti-promastigote activities occurred from the concentration of 62.5 µg/mL and was considered clinically relevant. The results also demonstrate that at low concentrations (<62.5 µg/mL), the essential oil of C. verbenacea managed to be lethal for these activities. This can be considered an indication of the power used in daily human consumption. Therefore, it can be concluded that the essential oil of C. verbenacea contains a compound with remarkable antiparasitic activities and requires further research.


Assuntos
Cordia/química , Citotoxinas , Leishmania braziliensis/crescimento & desenvolvimento , Óleos Voláteis , Tripanossomicidas , Trypanosoma cruzi/crescimento & desenvolvimento , Animais , Linhagem Celular , Citotoxinas/química , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Camundongos , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/farmacologia , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificação , Tripanossomicidas/farmacologia
8.
Int J Mol Sci ; 22(16)2021 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-34445240

RESUMO

Nitroaromatic compounds (ArNO2) maintain their importance in relation to industrial processes, environmental pollution, and pharmaceutical application. The manifestation of toxicity/therapeutic action of nitroaromatics may involve their single- or two-electron reduction performed by various flavoenzymes and/or their physiological redox partners, metalloproteins. The pivotal and still incompletely resolved questions in this area are the identification and characterization of the specific enzymes that are involved in the bioreduction of ArNO2 and the establishment of their contribution to cytotoxic/therapeutic action of nitroaromatics. This review addresses the following topics: (i) the intrinsic redox properties of ArNO2, in particular, the energetics of their single- and two-electron reduction in aqueous medium; (ii) the mechanisms and structure-activity relationships of reduction in ArNO2 by flavoenzymes of different groups, dehydrogenases-electrontransferases (NADPH:cytochrome P-450 reductase, ferredoxin:NADP(H) oxidoreductase and their analogs), mammalian NAD(P)H:quinone oxidoreductase, bacterial nitroreductases, and disulfide reductases of different origin (glutathione, trypanothione, and thioredoxin reductases, lipoamide dehydrogenase), and (iii) the relationships between the enzymatic reactivity of compounds and their activity in mammalian cells, bacteria, and parasites.


Assuntos
Bactérias/enzimologia , Proteínas de Bactérias , Citotoxinas , Elétrons , Flavoproteínas , Nitrocompostos , Oxirredutases , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Citotoxinas/química , Citotoxinas/farmacologia , Flavoproteínas/química , Flavoproteínas/metabolismo , Humanos , Nitrocompostos/química , Nitrocompostos/farmacologia , Oxirredução , Oxirredutases/química , Oxirredutases/metabolismo
9.
Molecules ; 26(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34361566

RESUMO

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome, and currently no effective targeted therapies are available. Indole compounds have been shown to have potential antitumor activity against various cancer cells. In the present study, we found that new four benzo[f]indole-4,9-dione derivatives reduce TNBC cell viability by reactive oxygen species (ROS) accumulation stress in vitro. Further analyses showed that LACBio1, LACBio2, LACBio3 and LACBio4 exert cytotoxic effects on MDA-MB 231 cancer cell line by inducing the intrinsic apoptosis pathway, activating caspase 9 and Bax/Bcl-2 pathway in vitro. These results provide evidence that these new four benzo[f]indole-4,9-dione derivatives could be potential therapeutic agents against TNBC by promoting ROS stress-mediated apoptosis through intrinsic-pathway caspase activation.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Citotoxinas , Indóis , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Feminino , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo
10.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361797

RESUMO

Carpesium divaricatum Sieb. & Zucc., a traditional medicinal plant used as an inflammation-relieving remedy, is a rich source of terpenoids. At least 40 germacrane-type sesquiterpene lactones, representatives of four different structural groups, were isolated from the plant. Cytotoxicity against cancer cells in vitro is the most frequently described biological activity of the compounds. However, little is known about the selectivity of the cytotoxic effect. The anti-inflammatory activity of the germacranolides is also poorly documented. The objective of the present study was to assess the cytotoxic activity of selected C. divaricatum germacranolides-derivatives of 4,5,8,9-tetrahydroxy-3-oxo-germacran-6,12-olide towards cancer and normal cell lines (including cells of different p53 status). Moreover, to assess the anti-inflammatory effect of the compounds, the release of four proinflammatory cytokines/chemokines (IL-1ß, IL-8, TNF-α and CCL2) by lipopolysaccharide-stimulated human neutrophils was measured by ELISA. The investigated sesquiterpene lactones demonstrated nonselective activity towards prostate cancer (Du145 and PC3) and normal prostate epithelial cells (PNT2) as well as against melanoma cells (A375 and HTB140) and keratinocytes (HaCaT). Cytotoxic activity against osteosarcoma cells was independent of their p53 status. In sub-cytotoxic concentrations (0.5-2.5 µM) the studied compounds significantly decreased cytokine/chemokine release by lipopolysaccharide-stimulated human leukocytes.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Citotoxinas/farmacologia , Sesquiterpenos de Germacrano/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/classificação , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/classificação , Antineoplásicos Fitogênicos/isolamento & purificação , Asteraceae/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Citotoxinas/química , Citotoxinas/classificação , Citotoxinas/isolamento & purificação , Doxorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Concentração Inibidora 50 , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Extratos Vegetais/química , Plantas Medicinais , Polônia , Cultura Primária de Células , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/classificação , Sesquiterpenos de Germacrano/isolamento & purificação , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
11.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361724

RESUMO

Orchids are rich treasure troves of various important phytomolecules. Among the various medicinal orchids, Ansellia africana stands out prominently in the preparing of various herbal medicines due to its high therapeutic importance. The nodal explants of A. africana were sampled from asymbiotically germinated seedlings on basal Murashige and Skoog (MS) medium and were micropropagated in MS medium supplemented with 3% sucrose and 10 µM meta topolin (mT) + 5 µM naphthalene acetic acid (NAA) +15 µM indole butyric acid (IBA) + 30 µM phloroglucinol (PG). In the present study, the essential oil was extracted by hydrodistillation and the oleoresins by the solvent extraction method from the micropropagated A. africana. The essential oil and the oleoresins were analysed by Gas Chromatography (GC) and GC/MS (Mass spectrometry). A total of 84 compounds were identified. The most predominant components among them were linoleic acid (18.42%), l-ascorbyl 2,6-dipalmitate (11.50%), linolenic acid (10.98%) and p-cresol (9.99%) in the essential oil; and eicosane (26.34%), n-butyl acetate (21.13%), heptadecane (16.48%) and 2-pentanone, 4-hydroxy-4-methyl (11.13%) were detected in the acetone extract; heptadecane (9.40%), heneicosane (9.45%), eicosane (6.40%), n-butyl acetate (14.34%) and styrene (22.20%) were identified and quantified in the ethyl acetate extract. The cytotoxic activity of essential oil and oleoresins of micropropagated A. africana was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide) assay on Vero cells compared to the standard drug doxorubicin chloride. The present research contains primary information about the therapeutic utility of the essential oil and oleoresins of A. africana with a promising future research potential of qualitative and quantitative improvement through synchronised use of biotechnological techniques.


Assuntos
Citotoxinas/isolamento & purificação , Óleos Voláteis/isolamento & purificação , Orchidaceae/química , Extratos Vegetais/isolamento & purificação , Plântula/química , Acrilatos/isolamento & purificação , Alcanos/isolamento & purificação , Animais , Ácido Ascórbico/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cresóis/isolamento & purificação , Meios de Cultura/química , Meios de Cultura/farmacologia , Citotoxinas/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Hidroponia/métodos , Ácido Linoleico/isolamento & purificação , Extração Líquido-Líquido/métodos , Óleos Voláteis/farmacologia , Orchidaceae/metabolismo , Palmitatos/isolamento & purificação , Pentanóis/isolamento & purificação , Pentanonas/isolamento & purificação , Extratos Vegetais/farmacologia , Plantas Medicinais , Plântula/metabolismo , África do Sul , Estireno/isolamento & purificação , Células Vero , Ácido alfa-Linoleico/isolamento & purificação
12.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361728

RESUMO

Glycyrrhetinic acid (GA) is one of many interesting pentacyclic triterpenoids showing significant anticancer activity by triggering apoptosis in tumor cell lines. This study deals with the design and synthesis of new glycyrrhetinic acid (GA)-amino acid peptides and peptide ester derivatives. The structures of the new derivatives were established through various spectral and microanalytical data. The novel compounds were screened for their in vitro cytotoxic activity. The evaluation results showed that the new peptides produced promising cytotoxic activity against the human breast MCF-7 cancer cell line while comparing to doxorubicin. On the other hand, only compounds 3, 5, and 7 produced potent activity against human colon HCT-116 cancer cell line. The human liver cancer (HepG-2) cell line represented a higher sensitivity to peptide 7 (IC50; 3.30 µg/mL), while it appeared insensitive to the rest of the tested peptides. Furthermore, compounds 1, 3, and 5 exhibited a promising safety profile against human normal skin fibroblasts cell line BJ-1. In order to investigate the mode of action, compound 5 was selected as a representative example to study its in vitro effect against the apoptotic parameters and Bax/BCL-2/p53/caspase-7/caspase-3/tubulin, and DNA fragmentation to investigate beta (TUBb). Additionally, all the new analogues were subjected to antimicrobial assay against a panel of Gram-positive and Gram-negative bacteria and the yeast candida Albicans. All the tested GA analogues 1-8 exhibited more antibacterial effect against Micrococcus Luteus than gentamicin, but they exhibited moderate antimicrobial activity against the tested bacterial and yeast strains. Molecular docking studies were also simulated for compound 5 to give better rationalization and put insight to the features of its structure.


Assuntos
Antibacterianos/síntese química , Antifúngicos/síntese química , Antineoplásicos/síntese química , Citotoxinas/síntese química , Ácido Glicirretínico/química , Peptídeos/química , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Caspase 3/química , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/farmacologia , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ácido Glicirretínico/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Células HCT116 , Células Hep G2 , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Peptídeos/farmacologia , Conformação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
13.
Sci Rep ; 11(1): 16281, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381064

RESUMO

Essential oils and their active components, referred here as plant derived antimicrobials (PDAs), have been used for their antimicrobial, anti-inflammatory and antioxidant properties. Many reports also document PDAs' cytotoxic effects on cancerous cells, raising the hope that they could be used for cancer treatments. Due to the lack of specificity, we hypothesize that PDAs are cytotoxic to both cancerous and non-cancerous cells. Trans-cinnamaldehyde (TCA), carvacrol, and eugenol were assessed for their cytotoxicity on cancerous HeLa cells and normal skin fibroblasts (CCD-1123Sk, CCD) by MTT and LDH assays, flow cytometry, and reverse transcription quantitative PCR (RT-qPCR). After 24 h of treatment, carvacrol and TCA significantly decreased cell viability (by more than 50%) at 100 µg/ml, whereas eugenol was ineffective up to 400 µg/ml. Cell detachment and significantly increased apoptosis were observed with 100 µg/ml of TCA on both cell types. RT-qPCR for apoptotic genes (BCL2, CASP3 and CASP8) and necrosis genes (MLKL, RIPK1 and RIPK3) did not show significant differences between control and treated cells of both types, with the exception of eugenol-treated HeLa cells in which expression of BCL2, MLKL and RIPK1 was significantly higher than controls. Taken together, we conclude that the three PDAs studied here exhibited similar cytotoxic effects on both cancerous and non-cancerous cells.


Assuntos
Acroleína/análogos & derivados , Cimenos/farmacologia , Citotoxinas/farmacologia , Eugenol/farmacologia , Acroleína/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Células HeLa , Humanos , Óleos Voláteis/farmacologia
14.
Molecules ; 26(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198523

RESUMO

It is crucial to establish relationship between nanoparticle structures (or properties) and nanotoxicity. Previous investigations have shown that a nanoparticle's size, shape, surface and core materials all impact its toxicity. However, the relationship between the redox property of nanoparticles and their toxicity has not been established when all other nanoparticle properties are identical. Here, by synthesizing an 80-membered combinatorial gold nanoparticle (GNP) library with diverse redox properties, we systematically explored this causal relationship. The compelling results revealed that the oxidative reactivity of GNPs, rather than their other physicochemical properties, directly caused cytotoxicity via induction of cellular oxidative stress. Our results show that the redox diversity of nanoparticles is regulated by GNPs modified with redox reactive ligands.


Assuntos
Técnicas de Química Combinatória/métodos , Citotoxinas/farmacologia , Ouro/química , Nanopartículas Metálicas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Células A549 , Proliferação de Células/efeitos dos fármacos , Citotoxinas/química , Humanos , Nanopartículas Metálicas/química , Oxirredução , Tamanho da Partícula
15.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201912

RESUMO

Ethnobotanical surveys indicate that the Masai and Kikuyu in Kenya, the Venda in South Africa, and the Gumuz people of Ethiopia use Pappea capensis for the treatment of malaria. The present study aimed to investigate the phytochemical and antiplasmodial properties of the plant leaves. The bioactive compounds were isolated using chromatographic techniques. The structures were established using NMR, HRMS, and UV spectroscopy. Antiplasmodial activity of P. capensis leaf extract and isolated compounds against chloroquine-sensitive 3D7 P. falciparum was evaluated using the parasite lactate dehydrogenase assay. Cytotoxicity against HeLa (human cervix adenocarcinoma) cells was determined using the resazurin assay. The extract inhibited the viability of Plasmodium falciparum by more than 80% at 50 µg/mL, but it was also cytotoxic against HeLa cells at the same concentration. Chromatographic purification of the extract led to the isolation of four flavonoid glycosides and epicatechin. The compounds displayed a similar activity pattern with the extract against P. falciparum and HeLa cells. The results from this study suggest that the widespread use of P. capensis in traditional medicine for the treatment of malaria might have some merits. However, more selectivity studies are needed to determine whether the leaf extract is cytotoxic against noncancerous cells.


Assuntos
Antimaláricos , Apiaceae/química , Citotoxinas , Flavonoides , Malária Falciparum/tratamento farmacológico , Folhas de Planta/química , Plasmodium falciparum/crescimento & desenvolvimento , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Citotoxinas/química , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Células HeLa , Humanos , Malária Falciparum/metabolismo
16.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203562

RESUMO

Nucleic acids are essential biomolecules in living systems and represent one of the main targets of chemists, biophysics, biologists, and nanotechnologists. New small molecules are continuously developed to target the duplex (ds) structure of DNA and, most recently, RNA to be used as therapeutics and/or biological tools. Stimuli-triggered systems can promote and hamper the interaction to biomolecules through external stimuli such as light and metal coordination. In this work, we report on the interaction with ds-DNA and ds-RNA of two aza-macrocycles able to coordinate Zn2+ metal ions and form binuclear complexes. The interaction of the aza-macrocycles and the Zn2+ metal complexes with duplex DNA and RNA was studied using UV thermal and fluorescence indicator displacement assays in combination with theoretical studies. Both ligands show a high affinity for ds-DNA/RNA and selectivity for ds-RNA. The ability to interact with these duplexes is blocked upon Zn2+ coordination, which was confirmed by the low variation in the melting temperature and poor displacement of the fluorescent dye from the ds-DNA/RNA. Cell viability assays show a decrease in the cytotoxicity of the metal complexes in comparison with the free ligands, which can be associated with the observed binding to the nucleic acids.


Assuntos
Complexos de Coordenação , Citotoxinas , DNA/química , RNA de Cadeia Dupla/química , Zinco , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Humanos , Ligantes , Células Vero , Zinco/química , Zinco/farmacologia
17.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299358

RESUMO

In vitro cytotoxicity of polymer-carriers, which in the side chains contain the cholinum ionic liquid units with chloride (Cl) or pharmaceutical anions dedicated for antituberculosis therapy, i.e., p-aminosalicylate (PAS) and clavulanate (CLV), was investigated. The carriers and drug conjugates were examined, in the concentration range of 3.125-100 µg/mL, against human bronchial epithelial cells (BEAS-2B) and adenocarcinomic human alveolar basal epithelial cells (A549) as an experimental model cancer cell line possibly coexisting in tuberculosis. The cytotoxicity was evaluated by MTT test and confluency index, as well as by the cytometric analyses, including Annexin-V FITC apoptosis assay. The polymer systems showed supporting activity towards the normal cells and no tumor progress, especially at the highest concentration (100 µg/mL). The analysis of cell death did not show meaningful changes in the case of the BEAS-2B, whereas in the A549 cell line, the cytostatic activity was observed, especially for the drug-free carriers, causing death in up to 80% of cells. This can be regulated by the polymer structure, including the content of cationic units, side-chain length and density, as well as the type and content of pharmaceutical anions. The results of MTT tests, confluency, as well as cytometric analyses, distinguished the polymer systems with Cl/PAS/CLV containing 26% of grafting degree and 43% of ionic units or 46% of grafting degree and 18% of ionic units as the optimal systems.


Assuntos
Citotoxinas/farmacologia , Portadores de Fármacos/farmacologia , Líquidos Iônicos/farmacologia , Polímeros/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Citostáticos/farmacocinética , Células Epiteliais/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Mucosa Respiratória/efeitos dos fármacos
18.
Biomolecules ; 11(7)2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206656

RESUMO

Antibody-drug conjugates (ADCs) are currently used for the targeted delivery of drugs to diseased cells, but intracellular drug delivery and therefore efficacy may be suboptimal because of the large size, slow internalization and ineffective intracellular trafficking of the antibody. Using a phage display method selecting internalizing phages only, we developed internalizing single domain antibodies (sdAbs) with high binding affinity to rat PDGFRß, a receptor involved in different types of diseases. We demonstrate that these constructs have different characteristics with respect to internalization rates but all traffic to lysosomes. To compare their efficacy in targeted drug delivery, we conjugated the sdAbs to a cytotoxic drug. The conjugates showed improved cytotoxicity correlating to their internalization speed. The efficacy of the conjugates was inhibited in the presence of vacuolin-1, an inhibitor of lysosomal maturation, suggesting lysosomal trafficking is needed for efficient drug release. In conclusion, sdAb constructs with different internalization rates can be designed against the same target, and sdAbs with a high internalization rate induce more cell killing than sdAbs with a lower internalization rate in vitro. Even though the overall efficacy should also be tested in vivo, sdAbs are particularly interesting formats to be explored to obtain different internalization rates.


Assuntos
Portadores de Fármacos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Anticorpos de Cadeia Única , Animais , Linhagem Celular Tumoral , Citotoxinas/química , Citotoxinas/farmacocinética , Citotoxinas/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Lisossomos/metabolismo , Camundongos , Estudo de Prova de Conceito , Ratos , Anticorpos de Cadeia Única/química , Anticorpos de Cadeia Única/farmacocinética , Anticorpos de Cadeia Única/farmacologia
19.
Molecules ; 26(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299583

RESUMO

Background: G-quadruplex (G4) forming sequences are recurrent in telomeres and promoter regions of several protooncogenes. In normal cells, the transient arrangements of DNA in G-tetrads may regulate replication, transcription, and translation processes. Tumors are characterized by uncontrolled cell growth and tissue invasiveness and some of them are possibly mediated by gene expression involving G-quadruplexes. The stabilization of G-quadruplex sequences with small molecules is considered a promising strategy in anticancer targeted therapy. Methods: Molecular virtual screening allowed us identifying novel symmetric bifunctionalized naphtho[1,2-b:8,7-b']dithiophene ligands as interesting candidates targeting h-Telo and c-MYC G-quadruplexes. A set of unexplored naphtho-dithiophene derivatives has been synthesized and biologically tested through in vitro antiproliferative assays and spectroscopic experiments in solution. Results: The analysis of biological and spectroscopic data highlighted noteworthy cytotoxic effects on HeLa cancer cell line (GI50 in the low µM range), but weak interactions with G-quadruplex c-MYC promoter. Conclusions: The new series of naphtho[1,2-b:8,7-b']dithiophene derivatives, bearing the pharmacophoric assumptions necessary to stabilize G-quadruplexes, have been designed and successfully synthesized. The interesting antiproliferative results supported by computer aided rational approaches suggest that these studies are a significant starting point for a lead optimization process and the isolation of a more efficacious set of G-quadruplexes stabilizers.


Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Citotoxinas , Quadruplex G/efeitos dos fármacos , Naftóis , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Células HeLa , Humanos , Naftóis/síntese química , Naftóis/química , Naftóis/farmacologia , Proteínas Proto-Oncogênicas c-myc/biossíntese
20.
Molecules ; 26(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299644

RESUMO

Metallodrugs form a large family of therapeutic agents against cancer, among which is cisplatin, a paradigmatic member. Therapeutic resistance and undesired side effects to Pt(II) related drugs, prompts research on different metal-ligand combinations with potentially enhanced biological activity. We present the synthesis and biological tests of novel palladium(II) complexes containing bisdemethoxycurcumin (BDMC) 1 and 2. Complexes were fully characterized and their structures were determined by X-ray diffraction. Their biological activity was assessed for several selected human tumor cell lines: Jurkat (human leukaemic T-cell lymphoma), HCT-116 (human colorectal carcinoma), HeLa (human cervix epitheloid carcinoma), MCF-7 (human breast adenocarcinoma), MDA-MB-231 (human mammary gland adenocarcinoma), A549 (human alveolar adenocarcinoma), Caco-2 (human colorectal carcinoma), and for non-cancerous 3T3 cells (murine fibroblasts). The cytotoxicity of 1 is comparable to that of cisplatin, and superior to that of 2 in all cell lines. It is a correlation between IC50 values of 1 and 2 in the eight studied cell types, promising a potential use as anti-proliferative drugs. Moreover, for Jurkat cell line, complexes 1 and 2, show an enhanced activity. DFT and docking calculations on the NF-κB protein, Human Serum Albumin (HSA), and DNA were performed for 1 and 2 to correlate with their biological activities.


Assuntos
Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação , Citotoxinas , DNA de Neoplasias , Diarileptanoides , Simulação de Acoplamento Molecular , Paládio , Células 3T3 , Animais , Células CACO-2 , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Diarileptanoides/química , Diarileptanoides/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HeLa , Humanos , Células Jurkat , Células MCF-7 , Camundongos , Paládio/química , Paládio/farmacologia
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