RESUMO
Leukemia is one of the most frequent types of cancer. No effective treatment currently exists, driving a search for new compounds. Simple structural modifications were made to novel triterpenes isolated from Phoradendron wattii. Of the three resulting derivatives, 3α-methoxy-24-hydroxylup-20(29)-en-28-oic acid (T1m) caused a decrease in the median inhibitory concentration (IC50) on the K562 cell line. Its mode of action was apparently apoptosis, ROS generation, and loss of mitochondrial membrane potential (MMP). Molecular docking analysis showed T1m to produce lower binding energies than its precursor for the Bcl-2 and EGFR proteins. Small, simple, and viable modifications to triterpenes can improve their activity against leukemia cell lines. T1m is a potentially promising element for future research. Clarifying the targets in its mode of action will improve its applicability.
Assuntos
Leucemia , Triterpenos , Humanos , Triterpenos/química , Lupanos , Simulação de Acoplamento Molecular , Apoptose , Leucemia/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Current antineoplastic agents present multiple disadvantages, driving an ongoing search for new and better compounds. Four lupane-type triterpenes, 3α,24-dihydroxylup-20(29)-en-28-oic acid (1), 3α,23-dihydroxy-30-oxo-lup-20(29)-en-28-oic acid (2), 3α,23-O-isopropylidenyl-3α,23-dihydroxylup-20(29)-en-28-oic acid (3), and 3α,23-dihydroxylup-20(29)-en-28-oic acid (4), previously isolated from Phoradendron wattii, were evaluated on two cell lines of chronic (K562) and acute (HL60) myeloid leukemia. Compounds 1, 2, and 4 decreased cell viability and inhibit proliferation, mainly in K562, and exhibited an apoptotic effect from 24 h of treatment. Of particular interest is compound 2, which caused arrest in active phases (G2/M) of the cell cycle, as shown by in silico study of the CDK1/Cyclin B/Csk2 complex by molecular docking. This compound [3α,23-dihydroxy-30-oxo-lup-20(29)-en-28-oic acid] s a promising candidate for incorporation into cancer treatments and deserves further study.
Assuntos
Leucemia , Phoradendron , Triterpenos , Ciclo Celular , Linhagem Celular , Humanos , Leucemia/tratamento farmacológico , Simulação de Acoplamento Molecular , Estrutura Molecular , Phoradendron/metabolismo , Folhas de Planta/metabolismoRESUMO
Amoebiasis is caused by the protozoan Entamoeba histolytica that affects millions of people throughout the world. The standard treatment is metronidazole, however, this drug causes several side effects, and is also mutagenic and carcinogenic. Therefore, the search for therapeutic alternatives is necessary. Quinoxaline 1,4-di-N-oxides (QdNOs) derivatives have been shown to exhibit activity against different protozoan. In the present study, the effects of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide (7-carboxylate QdNOs) derivatives on E. histolytica proliferation, morphology, ultrastructure, and oxidative stress were evaluated, also their potential as E. histolytica thioredoxin reductase (EhTrxR) inhibitors was analyzed. In vitro tests showed that 12 compounds from n-propyl and isopropyl series, were more active (IC50 = 0.331 to 3.56 µM) than metronidazole (IC50 = 4.5 µM). The compounds with better biological activity have a bulky, trifluoromethyl and isopropyl group at R1-, R2-, and R3-position, respectively. The main alterations found in trophozoites treated with some of these compounds included changes in chromatin, cell granularity, redistribution of vacuoles with cellular debris, and an increase in reactive oxygen species. Interestingly, docking studies suggested that 7-carboxylate QdNOs derivatives could interact with amino acid residues of the NADPH-binding domain and/or the redox-active site of EhTrxR. Enzymatic assays demonstrated that selected 7-carboxylate QdNOs inhibits EhTrxR disulfide reductase activity, and diaphorase activity shows that these compounds could act as electron acceptor substrates for the enzyme. Taken together, these data indicate that among the mechanisms involved in the antiamoebic effect of the 7-carboxylate QdNOs derivatives studied, is the induction of oxidative stress and the inhibition of EhTrxR activity.
Assuntos
Entamoeba histolytica/efeitos dos fármacos , Quinoxalinas/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Óxidos N-Cíclicos , Entamoeba histolytica/enzimologia , Ésteres , Humanos , Metronidazol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Quinolinas , Espécies Reativas de Oxigênio/metabolismoRESUMO
We prepared a series of 10 carbamates derivatives based on two common antiprotozoal drugs: metronidazole (1-5) and secnidazole (6-10). The compounds were tested in vitro against a set of two amitochondriate protozoa: Giardia duodenalis and Trichomonas vaginalis. Compounds 1-10 showed strong antiprotozoal activities, with potency values in the low micromolar-to-nanomolar range, being more active than their parent drugs. Metronidazole carbamate (1) was the most active of the series, with nanomolar activities against G. duodenalis (IC50 = 460 nM) and T. vaginalis (IC50 = 60 nM). The potency of compound 1 was 10 times greater than that of metronidazole against both parasites. None of compounds showed in vitro cytotoxicity against VERO cells tested at 100 µM. Molecular dynamics of compounds 1-10, secnidazole, and metronidazole onto the ligand binding site of pyruvate-ferredoxin oxidoreductase of T. vaginalis and the modeled -tubulin of G. duodenalis revealed putative molecular interactions with key residues in the binding site of both proteins implicated in the mode of action of the parent drugs.
Assuntos
Antiprotozoários/farmacologia , Carbamatos/química , Metronidazol/análogos & derivados , Metronidazol/química , Antiprotozoários/síntese química , Antiprotozoários/química , Carbamatos/síntese química , Carbamatos/farmacologia , Giardia lamblia/efeitos dos fármacos , Giardia lamblia/patogenicidade , Giardíase/tratamento farmacológico , Giardíase/parasitologia , Metronidazol/síntese química , Metronidazol/farmacologia , Tricomoníase/tratamento farmacológico , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/patogenicidadeRESUMO
To date, several methods for the quantification of tamoxifen and its metabolites have been developed, most of which employ liquid chromatography tandem-mass spectrometry (LC-MS/MS). These methods are highly sensitive and reproducible, but are also time-consuming and require expensive equipment; one of their main disadvantages is matrix ionization effects. A more viable option, particularly in developing countries, is high-performance liquid chromatography coupled with UV or fluorescence detection. We developed and validated a method for simultaneous quantification of tamoxifen, endoxifen and 4-hydroxytamoxifen based on high-performance liquid chromatography with fluorescence detection in a reverse-phase column. The method is rapid (16 min plus 5 min of column re-equilibrium), accurate (80-100%) and precise (0.23-6.00%), and does not require any additional irradiation process. Sample pretreatment consists of protein precipitation with acetonitrile under alkaline conditions, employing only 200 µL plasma. The validated method's wide range allowed quantification of steady-state levels in patients under standard tamoxifen treatment (20 mg/day). This assay is ready for application in clinical studies and routine quantification of tamoxifen, endoxifen and 4-hydroxytamoxifen in healthcare institutions.
Assuntos
Antineoplásicos Hormonais/sangue , Neoplasias da Mama/tratamento farmacológico , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Fluorescência/métodos , Tamoxifeno/sangue , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/uso terapêutico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Tamoxifeno/análogos & derivados , Tamoxifeno/química , Tamoxifeno/uso terapêuticoRESUMO
BACKGROUND: Mucuna pruriens L. is a legume sown in the Mexican southeast with an important protein content. Studies have shown the potential use of by-products derived from Mucuna as a functional food because of the hypoglycemic and antihypertensive activities. Thus, this study aims to assess the antioxidant and protective effect of the peptide fractions derived from M. pruriens L., in vitro on the HeLa cell line. An enzymatic hydrolysis with pepsin-pancreatin was performed on the total protein concentrate, from which five peptide fractions were obtained. RESULTS: All protein derivatives from M. pruriens L., except F5-10 kDa, decreased the hydrogen peroxide production by more than 50%. The highest antioxidant activity was exhibited by F1-3 kDa, which lowered the intracellular reactive oxygen species by 207 ± 4.20%. No significant differences were found in the protective effects of the protein hydrolysate, F5-10 kDa, F3-5 kDa and F1-3 kDa relative to the N-acetylcysteine control group. CONCLUSION: This elucidated the potential action mechanisms of M. pruriens L. protein derivatives for future investigations and their role in the prevention and treatment of oxidative stress. © 2019 Society of Chemical Industry.
Assuntos
Antioxidantes/farmacologia , Mucuna/química , Peptídeos/farmacologia , Extratos Vegetais/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Hidrólise , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/química , Peptídeos/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Proteínas de Plantas/química , Proteínas de Plantas/farmacologiaRESUMO
AIM: To describe delay intervals, their impact on clinical stage and initiation of first oncologic treatment, and evaluate associated factors in breast cancer patients in Yucatan, Mexico, a low-density population region. PATIENTS & METHODS: A retrospective analysis was done of 92 medical records, and bivariate and multivariate models applied to identify associations between healthcare delay and several factors. RESULTS: System delay accounted for most of the delay (median: 86 days; 61% of delay). Socioeconomic status and delivery to tertiary-care hospital predicted delay. Clinical stage determined initiation of first oncologic treatment. CONCLUSION: Delay in treatment was largely due to system delay. Only a few variables explained this delay. Clinical stage had the strongest effect on initiation of first oncologic treatment.
Assuntos
Neoplasias da Mama/epidemiologia , Diagnóstico Tardio , Atenção à Saúde , Tempo para o Tratamento , Adulto , Algoritmos , Neoplasias da Mama/diagnóstico , Comorbidade , Feminino , Humanos , México/epidemiologia , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Vigilância da População , Estudos Retrospectivos , Classe Social , Fatores Socioeconômicos , Adulto JovemRESUMO
We designed and synthesized five new 5-nitrothiazole-NSAID chimeras as analogues of nitazoxanide, using a DCC-activated amidation. Compounds 1-5 were tested in vitro against a panel of five protozoa: 2 amitochondriates (Giardia intestinalis, Trichomonas vaginalis) and 3 kinetoplastids (Leishmania mexicana, Leishmania amazonensis and Trypanosoma cruzi). All chimeras showed broad spectrum and potent antiprotozoal activities, with IC50 values ranging from the low micromolar to nanomolar order. Compounds 1-5 were even more active than metronidazole and nitazoxanide, two marketed first-line drugs against giardiasis. In particular, compound 4 (an indomethacin hybrid) was one of the most potent of the series, inhibiting G. intestinalis growth in vitro with an IC50 of 0.145µM. Compound 4 was 38-times more potent than metronidazole and 8-times more active than nitazoxanide. The in vivo giardicidal effect of 4 was evaluated in a CD-1 mouse model obtaining a median effective dose of 1.709µg/kg (3.53nmol/kg), a 321-fold and 1015-fold increase in effectiveness after intragastric administration over metronidazole and nitazoxanide, respectively. Compounds 1 and 3 (hybrids of ibuprofen and clofibric acid), showed potent giardicidal activities in the in vitro as well as in the in vivo assays after oral administration. Therefore, compounds 1-5 constitute promising drug candidates for further testing in experimental chemotherapy against giardiasis, trichomoniasis, leishmaniasis and even trypanosomiasis infections.
Assuntos
Antiprotozoários/química , Antiprotozoários/uso terapêutico , Giardia lamblia/efeitos dos fármacos , Giardíase/tratamento farmacológico , Tiazóis/química , Tiazóis/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Desenho de Fármacos , Feminino , Humanos , Leishmania/efeitos dos fármacos , Camundongos , Nitrocompostos , Infecções por Protozoários/tratamento farmacológico , Tiazóis/síntese química , Tiazóis/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Three new lupane-type triterpenes, 3α,24-dihydroxylup-20(29)-en-28-oic acid (1), 3α,23-dihydroxy-30-oxolup-20(29)-en-28-oic acid (2), and 3α,23-O-isopropylidenyl-3α,23-dihydroxylup-20(29)-en-28-oic acid (3), together with eight known compounds (4-11) were isolated from a methanol extract of Phoradendron vernicosum aerial parts. The chemical structures of 1-3 were determined on the basis of spectroscopic data interpretation. The isolated compounds were tested against seven human cancer cell lines and two normal cell lines.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Phoradendron/química , Componentes Aéreos da Planta/química , Triterpenos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células KB , Células MCF-7 , México , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Extratos Vegetais/química , Folhas de Planta/química , Triterpenos/química , Triterpenos/farmacologiaRESUMO
A series of thiazepines and diazepines having 1,3,4-oxadiazole moiety were synthesized, and they were analyzed for their in vitro antimicrobial activity against several bacteria (Staphylococcus aureus, Staphylococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa) and fungi (Candida albicans, Aspergillus niger, and Aspergillus Clavatus) and protozoa (Entamoeba histolytica, Giardia lamblia, Trypanosoma cruzi and Leishmania mexicana). Few of the selected compounds were tested for their antitubercular activity. However, it was noticed that the potency of final analogs against each strain placed reliance on the type of substituent present on aryl ring of oxadiazole as well as presence of thiophene, pyridine, and furan at benzothiazepines and benzodiazepines. The biological screening identified that some of the compounds were found to possess good antimicrobial and antitubercular (62.5-100 µg/mL of MIC) activity.
Assuntos
Anti-Infecciosos/síntese química , Azepinas/síntese química , Oxidiazóis/síntese química , Tiazepinas/síntese química , Anti-Infecciosos/farmacologia , Aspergillus/efeitos dos fármacos , Aspergillus/crescimento & desenvolvimento , Aspergillus niger/efeitos dos fármacos , Aspergillus niger/crescimento & desenvolvimento , Azepinas/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Entamoeba histolytica/efeitos dos fármacos , Entamoeba histolytica/crescimento & desenvolvimento , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Giardia lamblia/efeitos dos fármacos , Giardia lamblia/crescimento & desenvolvimento , Leishmania mexicana/efeitos dos fármacos , Leishmania mexicana/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Oxidiazóis/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Staphylococcus/efeitos dos fármacos , Staphylococcus/crescimento & desenvolvimento , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Relação Estrutura-Atividade , Tiazepinas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/crescimento & desenvolvimentoRESUMO
Parasitic diseases are a public health problem affecting millions of people worldwide. One of the scaffolds used in several drugs for the treatment of parasitic diseases is the benzimidazole moiety, a heterocyclic aromatic compound. This compound is a crucial pharmacophore group and is considered a privileged structure in medicinal chemistry. In this study, the benzimidazole core served as a model for the synthesis of a series of 2-(2-amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides 1-8 as benznidazole analogues. The in silico pharmacological results calculated with PASS platform exhibited chemical structures highly similar to known antiprotozoal drugs. Compounds 1-8 when evaluated in silico for acute toxicity by oral dosing, were less toxic than benznidazole. The synthesis of compounds 1-8 were carried out through reaction of 5(6)-nitro-1H-benzimidazol-2-amine (12) with 2-chlroactemides 10a-h, in the presence of K2CO3 and acetonitrile as solvent, showing an inseparable mixture of two regioisomers with the -NO2 group in position 5 or 6 with chemical yields of 60 to 94%. The prediction of the NMR spectra of molecule 1 coincided with the experimental chemical displacements of the regioisomers. Comparisons between the NMR prediction and the experimental data revealed that the regioisomer endo-1,6-NO2 predominated in the reaction. The in vitro antiparasitic activity of these compounds on intestinal unicellular parasites (Giardiaintestinalis and Entamoebahistolytica) and a urogenital tract parasite (Trichomonasvaginalis) were tested. Compound 7 showed an IC50 of 3.95 µM and was 7 time more active against G.intestinalis than benznidazole. Compounds 7 and 8 showed 4 times more activity against T.vaginalis compared with benznidazole.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Benzimidazóis/química , Desenho de Fármacos , Amidas/química , Antiprotozoários/química , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Testes de Sensibilidade ParasitáriaRESUMO
We synthesized four 5-nitrothiazole (1-4) and four 6-nitrobenzothiazole acetamides (5-8) using an easy two step synthetic route. All compounds were tested in vitro against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis, showing excellent antiprotozoal effects. IC50's of the most potent compounds range from nanomolar to low micromolar order, being more active than their drugs of choice. Compound 1 (IC50=122 nM), was 44-times more active than Metronidazole, and 10-fold more effective than Nitazoxanide against G. intestinalis and showed good trichomonicidal activity (IC50=2.24 µM). This compound did not display in vitro cytotoxicity against VERO cells. The in vitro inhibitory effect of compounds 1-8 and Nitazoxanide against G. intestinalis fructose-1,6-biphosphate aldolase (GiFBPA) was evaluated as potential drug target, showing a clear inhibitory effect over the enzyme activity. Molecular docking of compounds 1, 4 and Nitazoxanide into the ligand binding pocket of GiFBPA, revealed contacts with the active site residues of the enzyme. Ligand efficiency metrics of 1 revealed optimal combinations of physicochemical and antiprotozoal properties, better than Nitazoxanide.
Assuntos
Acetamidas/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Benzotiazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Giardia lamblia/efeitos dos fármacos , Nitrocompostos/farmacologia , Tiazóis/farmacologia , Trichomonas vaginalis/efeitos dos fármacos , Acetamidas/síntese química , Acetamidas/química , Animais , Antiprotozoários/química , Benzotiazóis/síntese química , Benzotiazóis/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Frutose-Bifosfato Aldolase/antagonistas & inibidores , Frutose-Bifosfato Aldolase/metabolismo , Giardia lamblia/enzimologia , Simulação de Dinâmica Molecular , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Trichomonas vaginalis/enzimologia , Células VeroRESUMO
The plant Aeschynomene fascicularis (Fabaceae) has been used in Mayan traditional medicine in the Yucatan peninsula. However, the compounds present in the plant responsible for its curative properties have not yet been investigated. Aeschynomene fascicularis root bark was extracted with 100% methanol to obtain a crude extract. The methanol extract was partitioned successively with solvents with increasing polarity to obtain the corresponding hexane (Hx), dichloromethane (DCM) and ethyl acetate fractions (EtOAc), as well as a residual water-alcoholic fraction. These fractions were tested for their cytotoxic activities using an MTT assay against Hep-2 cancer cell lines. The Hx fraction led to the isolation of spinochalcone C (1), spinochalcone A (2), isocordoin (3) and secundiflorol G (4). Their structures were identified based on spectroscopic evidence and chemical properties. All compounds were subjected to cytotoxicity and antiproliferative assays against a panel of seven cell lines, including one normal-type cell line. Spinochalcone A (2) exhibited cytotoxic activity against DU-145 cell line and antiproliferative activity against the KB cell line. Secundiflorol G (4) showed strong cytotoxic activity towards KB and Hep-2 cell lines. In addition, isocordoin (3) showed moderate activity on KB, Hep-2 and DU-145 cell lines. The active Compounds 2, 3 and 4 are potential therapeutic entities against cancer.
Assuntos
Antineoplásicos , Citotoxinas , Fabaceae/química , Casca de Planta/química , Raízes de Plantas/química , Plantas Medicinais/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Citotoxinas/química , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Células Hep G2 , HumanosRESUMO
The 2-acylamino-5-nitro-1,3-thiazole derivatives (1-14) were prepared using a one step reaction. All compounds were tested in vitro against four neglected protozoan parasites (Giardia intestinalis, Trichomonas vaginalis, Leishmania amazonensis and Trypanosoma cruzi). Acetamide (9), valeroylamide (10), benzamide (12), methylcarbamate (13) and ethyloxamate (14) derivatives were the most active compounds against G. intestinalis and T. vaginalis, showing nanomolar inhibition. Compound 13 (IC50=10nM), was 536-times more active than metronidazole, and 121-fold more effective than nitazoxanide against G. intestinalis. Compound 14 was 29-times more active than metronidazole and 6.5-fold more potent than nitazoxanide against T. vaginalis. Ureic derivatives 2, 3 and 5 showed moderate activity against L. amazonensis. None of them were active against T. cruzi. Ligand efficiency indexes analysis revealed higher intrinsic quality of the most active 2-acylamino derivatives than nitazoxanide and metronidazole. In silico toxicity profile was also computed for the most active compounds. A very low in vitro mammalian cytotoxicity was obtained for 13 and 14, showing selectivity indexes (SI) of 246,300 and 141,500, respectively. Nitazoxanide showed an excellent leishmanicidal and trypanocidal effect, repurposing this drug as potential new antikinetoplastid parasite compound.
Assuntos
Antiprotozoários/farmacologia , Infecções por Protozoários/imunologia , Tiazóis/química , Animais , Desenho de Fármacos , HumanosRESUMO
CONTEXT: The hexane extracts of Dictyota ciliolata Sonder ex Kützing (Dictyotaceae), Padina sanctae-crucis Børgesen (Dictyotaceae), and Turbinaria tricostata E.S. Barton (Sargassaceae) were found to exhibit cytotoxic and antiproliferative activities in vitro. Bioactive compounds responsible for these activities have not been studied in detail for these species and phytochemical studies are very limited. OBJECTIVE: Isolate, evaluate, and elucidate the bioactive constituents of D. ciliolata, P. sanctae-crucis, and T. tricostata. MATERIALS AND METHODS: Bioassay-guided cytotoxicity fractionations using the Hep-2 cell line of the hexane extracts from these brown algae were analyzed using various chromatographic techniques. Cytotoxic and antiproliferative activities of all isolated compounds were also evaluated on a panel of cell lines (KB, Hep-2, MCF-7, and SiHa). Furthermore, their selectivity index, the ratio of cytotoxicity on normal cells to cancer cells, was evaluated using the HEK-293 cell line. RESULTS: Four compounds were isolated from studied species: two sterol, fucosterol (1) and 24ξ-hydroperoxy-24-vinylcholesterol (2); and two diterpenes, pachydictyol A (3) and dictyol B acetate (4). The major bioactive components of the hexane extracts of T. tricostata and P. sanctae-crucis were compounds 1 and 2 (with CC50 varying around 3.1-25.6 µg/mL) on cell lines tested. Whereas compounds 1, 3, and 4 showed cytotoxic activity against cancer cell lines (CC50 varying between 14.8 and 41.2 µg/mL) and were major bioactive constituents of hexane extract of D. ciliolata. Compounds 1 and 4 showed antiproliferative activity on MCF-7 (IC50 = 43.3 µg/mL for compound 1 and 38.3 µg/mL for compound 2) and SiHa (IC50 = 43.3 µg/mL for compound 1 and 38.3 µg/mL for compound 2) cell lines. CONCLUSION: This study is the first investigation on the bioactive components of D. ciliolata, P. sanctae-crucis, and T. tricostata. Although compounds 1-3 were described previously, the pharmacological activity of compound 4 is presented here for the first time.
Assuntos
Proliferação de Células/efeitos dos fármacos , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Alga Marinha , Citotoxinas/química , Células HEK293 , Humanos , Células MCF-7 , Extratos Vegetais/químicaRESUMO
In this study, twenty-four organic extracts from six marine sponge species, collected at shallows of Yucatan, Mexico, were evaluated against Giardia lamblia trophozoites and Vero cells. The dichloromethane and hexane extracts of Haliclona tubifera exhibited the highest antigiardiasic activity (IC50 = 1.00 and 2.11 µg/mL, respectively), as well as high selectivity (SI = 41.8 and > 47.4, respectively), while ethyl acetate and methanol extracts of Cinachyrella alloclada, and methanol extract of Suberites aurantiaca showed moderate activity. Contrastingly, the extracts of Halichondria magniculosa and Oceanapia nodosa were considered non actives. Consequently, the dichloromethane extract of H. tubifera were subject to an exploratory chemical study, isolating cholesterol, two benzaldehyde derivatives, three benzoic acid derivatives, cytosine, and thymine.
Assuntos
Giardia lamblia , Haliclona , Chlorocebus aethiops , Animais , México , Metanol , Cloreto de Metileno , Células VeroRESUMO
Ethanol extracts of Senna villosa, Serjania yucatanensis, Byrsonima bucidaefolia, and Bourreria pulchra were evaluated for their in vitro activity against epimastigotes and trypomastigotes of Trypanosoma cruzi. Results showed that the leaf extracts of S. yucatanensis and B. pulchra were the most active against epimastigotes (IC(100) = 100 µg/mL) and trypomastigotes of T. cruzi (95% or more reduction in the number of parasites at 100 and 50 µg/mL). However, only the leaf extract of S. yucatanensis showed significant trypanocidal activity when tested in vivo, reducing 75% of the parasitemia in infected mice at 100 mg/kg. This same extract inhibited the egress of trypomastigotes from infected cells and proved not to be cytotoxic (IC(50) = 318.8 ± 2.3 µg/mL).
Assuntos
Antiprotozoários/administração & dosagem , Antiprotozoários/farmacologia , Gleiquênias/química , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/isolamento & purificação , Doença de Chagas/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Humanos , Concentração Inibidora 50 , México , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/tratamento farmacológico , Testes de Sensibilidade Parasitária , Extratos Vegetais/isolamento & purificação , Resultado do TratamentoRESUMO
Background: The gastrointestinal parasite Giardia lamblia causes giardiasis. Its treatment with standard drugs produces side effects and improper treatment can generate resistant strains. New antigiardial compounds are needed. An analysis was done to identify the antigiardial activity of Morinda royoc, a plant used in traditional Mayan medicine to treat stomach and bowel pain. We aimed to assess the efficacy of M. royoc roots against G. lamblia and their effect on cells viability. Methods: A methanol extract was done of the root and then fractionated. The extract and fractions were tested in vitro on G. lamblia trophozoites and their effect on cell viability was quantified by flow cytometry. The active extract and fractions were analyzed by gas chromatography-mass spectrometry and high-performance liquid chromatography. Results: The hexane fraction exhibited potent activity against G. lamblia (IC50 = 0.08 µg/mL). Its principal component was an anthraquinone-type compound. None of the fractions were toxic to human promyelocytic leukemia, chronic myelogenous leukemia and human mononuclear cells. Conclusion: The medicinal plant M. royoc contains promising bioactive agents with antigiardial activity and deserves further research.
RESUMO
Plant-derived secondary metabolites are a source of promising bioactive molecules in the search for safer more selective cancer drugs. Mexico's flora is extremely diverse and many species, such as Phoradendron wattii, form part of traditional medicine. Compounds with notable cytotoxic activity have been isolated from P. wattii, but their concentrations may vary seasonally. The aim was to identify any variation in active metabolite concentrations in Phoradendron wattii methanol extracts in response to season. Betulin exhibited the most evident seasonal variations, being most abundant during the midsummer drought. Cytotoxic activity was highest (29 ± 1 µg/mL) in the rainy season methanol extract. Though not the most abundant metabolite in the extracts, 3α,24-dihydroxylup-20(29)-en-28-oic acid is apparently one of the most active among them and is a promising chemotaxonomic biomarker for this species. In summary, secondary metabolite concentrations in P. wattii methanol extracts varied in response to season, and these variations influenced cytotoxic activity.
Assuntos
Antineoplásicos , Phoradendron , Antineoplásicos/farmacologia , Metanol , Extratos Vegetais/farmacologia , Estações do AnoRESUMO
A series of 15 novel 1,3-thiazole amide derivatives of the pentacyclic triterpene Ochraceolide A (1) was synthesized, characterized, and evaluated in vitro against three human cancer cell lines (MCF-7, MDA-MB-231 and SiHa) and a normal cell line (Vero). Synthetic derivatives were obtained by acylation of the 2-aminothiazole triterpene 2, previously reported. Remarkably, the 5-nitrofuramide derivative (2o) showed better cytotoxic and antiproliferative activity than compound 2 and the other derivatives against the three cancer cell lines with CC50 and IC50 values of 1.6-12.7 µM. Furthermore, butyramide derivative (2c) was approximately 25 times more selective than 2, as well as 3.4 times more selective than Docetaxel, against SiHa cells in the cytotoxic assay, while the phenyl amide derivatives were inactive against the three cancer cell lines.