RESUMO
Hydroxybenzylidene hydrazines exhibit a wide spectrum of biological activities. Here, we report synthesis and free radical scavenging activity of nine new N-(hydroxybenzylidene)-N'-[2,6-dinitro-4-(trifluoromethyl)]phenylhydrazines. The chemical structures of these compounds were confirmed by 1H-NMR, 13C-NMR, 19F-NMR, IR spectroscopy, LC-MS, and elemental analysis. The prepared compounds were tested for their activity to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH), galvinoxyl radical (GOR), and 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulphonic acid (ABTS) radicals. The free radical scavenging activity expressed as SC50 values of these compounds varied in a wide range, from a strong to no radical scavenging effect. The most effective radical scavengers were hydroxybenzylidene hydrazines containing three hydroxyl groups in the benzylidene part of their molecules. The prepared compounds were also tested for their activity to inhibit photosynthetic electron transport in spinach chloroplasts. IC50 values of these compounds varied in wide range, from an intermediate to no inhibitory effect.
Assuntos
Sequestradores de Radicais Livres/química , Hidrazinas/química , Compostos de Bifenilo/química , Picratos/química , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Resveratrol (3,5,4'-trihydroxystilbene) is a phytoalexin produced by plants. Resveratrol is known for its anti-cancer, antiviral and antioxidant properties. We prepared imine analogs of resveratrol ((hydroxyphenyliminomethyl)phenols) and tested their antioxidant activity. All prepared resveratrol analogs were able to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH), galvinoxyl radical (GOR) and 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulphonic acid (ABTS) radicals. The antioxidant activity efficiency correlated with the number and position of hydroxyl groups. The most effective antioxidants were resveratrol analogs containing three hydroxyl groups in the benzylidene part of their molecules. These results provide new insights into the relationship between the chemical structure and biological activity of resveratrol analogs.
Assuntos
Compostos Benzidrílicos/antagonistas & inibidores , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Picratos/antagonistas & inibidores , Estilbenos/química , Estilbenos/farmacologia , Ácidos Sulfônicos/antagonistas & inibidores , Estrutura Molecular , ResveratrolRESUMO
Three new hydrazide and five new hydrazonoyl derivatives were synthesized. The chemical structures of these compounds were confirmed by 1H-NMR, IR spectroscopy and elemental analysis. The prepared compounds were tested for their activity to inhibit photosynthetic electron transport in spinach chloroplasts and growth of the green algae Chlorella vulgaris. IC50 values of these compounds varied in wide range, from a strong to no inhibitory effect. EPR spectroscopy showed that the active compounds interfered with intermediates Zâ¢/Dâ¢, which are localized on the donor side of photosystem II. Fluorescence spectroscopy suggested that the mechanism of inhibitory action of the prepared compounds possibly involves interactions with aromatic amino acids present in photosynthetic proteins.
Assuntos
Herbicidas/síntese química , Herbicidas/toxicidade , Hidrazinas/síntese química , Hidrazinas/toxicidade , Hidrazonas/síntese química , Hidrazonas/toxicidade , Chlorella/efeitos dos fármacos , Chlorella/crescimento & desenvolvimento , Cloroplastos/efeitos dos fármacos , Cloroplastos/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Transporte de Elétrons/efeitos dos fármacos , Herbicidas/química , Hidrazinas/química , Hidrazonas/química , Concentração Inibidora 50 , Fotossíntese/efeitos dos fármacos , Espectrometria de Fluorescência , Spinacia oleracea/efeitos dos fármacos , Spinacia oleracea/metabolismoRESUMO
The aim of this work was to analyze the antioxidant and antimutagenic/anticarcinogenic capacity of Papaver rhoeas L. water extract against standard mutagen/carcinogen methyl methanesulfonate (MMS) and radiomimetic zeocin (Zeo) on a test system Saccharomyces cerevisiae. The following assays were used: 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, quantitative determination of superoxide anion (antireactive oxygen species [antiROS test]), DNA topology assay, D7ts1 test--for antimutagenic--and Ty1 transposition test--for anticarcinogenic effects. Strong pro-oxidative capacity of Zeo was shown to correlate with its well-expressed mutagenic and carcinogenic properties. The mutagenic and carcinogenic effects of MMS were also confirmed. Our data concerning the antioxidant activity of P. rhoeas L. extract revealed that concentration corresponding to IC(50) in the DPPH assay possessed the highest antioxidant activity in the antiROS biological assay. It was also observed that a concentration with 50% scavenging activity expressed the most pronounced antimutagenic properties decreasing Zeo-induced gene conversion twofold, reverse mutation fivefold, and total aberrations fourfold. The same concentration possessed well-expressed anticarcinogenic properties measured as reduction of MMS-induced Ty1 transposition rate fivefold and fourfold when Zeo was used as an inductor. Based on the well-expressed antioxidant, antimutagenic, and anticarcinogenic properties obtained in this work, the P. rhoeas L. extract could be recommended for further investigations and possible use as a food additive.
Assuntos
Anticarcinógenos/farmacologia , Antimutagênicos/farmacologia , Antioxidantes/farmacologia , Papaver/química , Extratos Vegetais/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Carcinógenos/toxicidade , Testes de Mutagenicidade , Mutagênicos/toxicidade , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismoRESUMO
VEGFR2 is an important mediator of angiogenesis and influences fate of some cancer stem cells. Here we analysed all 34 structures of VEGFR2 TK available from PDB database. From them a complex PDB: 1Y6A has an exceptional AAZ ligand bound to TK in form of two conformers (U- and S-shaped). This observation inspired us to develop three chimeric bispyridyl VEGFR2 inhibitors by combining structural features of both AAZ conformers and/or their relative ligand AAX (PDB: 1Y6B). Our most interesting inhibitor 22SYM has an enzymatic VEGFR2 TK activity (IC50: 15.1 nM) comparable or better to the active compounds from clinical drugs Nexavar and Sutent. 22SYM inhibits growth, migration and tube formation of endothelial cells (EC) and selectively induces EC apoptosis. 22SYM also inhibits in vivo angiogenesis in Zebrafish embryo assay. Additionally to the above results, we proved here that tyrosine kinases in an inactive form possessing Type I inhibitors can adopt both a closed or an opened conformation of kinase A-loop independently on their DFG-out arrangement. We proposed here that an activity of certain Type I inhibitors (e.g. 22SYM-like) in complex with DFG-out TK can be negatively influenced by collisions with a dynamically moving TK A-loop.
Assuntos
Inibidores da Angiogênese/farmacologia , Oxazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sulfonas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Apoptose/efeitos dos fármacos , Química Farmacêutica , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Neovascularização Fisiológica/efeitos dos fármacos , Oxazóis/síntese química , Oxazóis/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Peixe-ZebraRESUMO
The objectives of this study were to examine whether the methanolic and aqueous extracts from the haulm and flower of Gentiana asclepiadea exhibited free radical scavenging and protective (antigenotoxic) effect against DNA oxidation induced by H(2)O(2) in human lymphocytes and human embryonic kidney cells (HEK 293). All four extracts exhibited high scavenging effect on 1,1-diphenyl-2-picrylhydrazyl radicals at concentrations 2.5 and 25 mg ml(-1). The level of DNA damage was measured using the alkaline version of single-cell gel electrophoresis (comet assay). Challenge with H(2)O(2) shows that the pre-treatment of the cells with non-genotoxic doses of Gentiana extracts protected human DNA-either eliminated or significantly reduced H(2)O(2) induced DNA damage. The genotoxic activity of H(2)O(2) was most effectively decreased after 30 min of pre-incubation with 0.05 mg ml(-1) (range, 93.5%-96.3% of reduction in lymphocytes) and 0.25 mg ml(-1) (range, 59.5%-71.4% and 52.7%-66.4% of reduction in lymphocytes and HEK 293 cells, respectively) of G. asclepiadea extracts. These results suggest that the tested G. asclepiadea extracts could be considered as an effective natural antioxidant source.
Assuntos
Antioxidantes/farmacologia , Dano ao DNA/efeitos dos fármacos , Gentiana/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Células HEK293 , Humanos , Oxirredução/efeitos dos fármacosRESUMO
Two homologous series of racemic diastereomeric cis- and trans-(2-dimethylaminomethylcycloheptyl)-2-alkoxyphenylcarbamates with alkyl chain lengths ranging from C1 to C8 were synthesized by stereoselective reactions. The chemical structures of these compounds were confirmed by ¹H-NMR, ¹³C-NMR and IR spectroscopy and their physico-chemical properties were characterized. The two new series of diastereomeric compounds were tested for their local anesthetic activity and parabolic relationship between the local anesthetic activity and lipophilicity was found for both cis- and trans-series. Interestingly, cis-stereoisomers exhibited higher local anesthetic activity.
Assuntos
Anestésicos Locais/química , Anestésicos Locais/farmacologia , Fenilcarbamatos/química , Fenilcarbamatos/farmacologia , Anestésicos Locais/síntese química , Animais , Córnea/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Fenilcarbamatos/síntese química , Coelhos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: The purpose of this study was to assess whether a methanol extract isolated from the flower of Gentiana asclepiadea had potential cytotoxic or genotoxic effect on COS 1 (monkey kidney) cell line. Five various concentrations of the extract were investigated for cytotoxicity and genotoxicity and to determine non-cytotoxic and non-genotoxic concentrations suitable for utilization in pharmacology and medicine. METHODS: Cytotoxicity was determined using the proliferation (growth activity) and the plating efficiency (colony forming ability) assays after 24 hour incubation of COS 1 cells with different concentrations of methanolic flower extract from G. asclepiadea. To assess potential genotoxicity, the comet assay or SCGE (Single-Cell Gel Electrophoresis) was used. RESULTS: We found that only the highest (5 and 25 mg/ml) concentrations of the extract revealed cytotoxic and genotoxic effect. We have also determined concentrations that stimulated cell growth (0.25 mg/ml) and colony forming ability (0.25-2.5 mg/ml) and did not exhibit genotoxic effect (0.25-2.5 mg/ml). CONCLUSIONS: We found out that extract of G. asclepiadea was neither cytotoxic nor genotoxic in a wide range of concentrations (0.25-2.5 mg/ml) and thus can be used to further investigate potential beneficial usage in pharmacology and medicine.
Assuntos
Citotoxinas/farmacologia , Gentiana , Rim/citologia , Rim/efeitos dos fármacos , Mutagênicos/farmacologia , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Células COS , Chlorocebus aethiops , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Flores , Modelos AnimaisRESUMO
OBJECTIVES: The purpose of this study was to assess whether a methanol extract isolated from the greater celandine Chelidonium majus L. (CME) had antioxidant effect and was able to inhibit proliferation and to induce apoptosis in leukemia cells in vitro. METHODS: The potential antioxidant activity of CME was proved by the 1,1-diphenyl- 2-picrylhydrazyl (DPPH) radical scavenging assay. The cytotoxicity of CME was measured by the cell growth inhibition assay using murine leukemia L1210 cell line and human promyelocytic HL-60 leukemia cells. Apoptosis-inducing effect was determined by fluorescence microscopy (chromatin condensation and nuclear DNA fragmentation). RESULTS: In the DPPH assay CME acted as a scavenger of DPPH free radical. The results on antiproliferative properties assessment clearly demonstrated that CME had a cytotoxic effect towards both leukemia cell lines in a dose-dependent manner. In addition, the human promyelocytic HL-60 cells were more sensitive to CME treatment than the L1210 cells. CONCLUSIONS: We concluded that the extract of C. majus L. had a strong antioxidant potential and exerted the antiproliferative activity via apoptosis on leukemia cells. CME due to the presence of the isoquinoline alkaloids and the flavonoid components may play an important role in both cancer chemoprevention through its antioxidant activity and modern cancer chemotherapy as cytotoxic and apoptosis-inducing agent.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Chelidonium/química , Leucemia/tratamento farmacológico , Animais , Compostos de Bifenilo , Relação Dose-Resposta a Droga , Sequestradores de Radicais Livres , Células HL-60 , Humanos , Leucemia/patologia , Leucemia L1210/tratamento farmacológico , Leucemia L1210/patologia , Camundongos , Microscopia de Fluorescência , Picratos/química , Extratos Vegetais/farmacologiaRESUMO
The stability constants of the 1:1 complexes formed between Mg(2+), Ca(2+), Sr(2+), Ba(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), or Cd(2+) and the pyrimidine-nucleoside 5'-diphosphates CDP(3)(-), UDP(3)(-), and dTDP(3)(-) (= NDP(3)(-)) were determined by potentiometric pH titration in aqueous solution (I = 0.1 M, NaNO(3); 25 degrees C). For comparison, the same values were measured for the corresponding complexes with the simple diphosphate monoesters (R-DP(3)(-)) phenyl diphosphate, methyl diphosphate, and n-butyl diphosphate. The acidity constants for H(3)(CDP)(+/-), H(2)(UDP)(-), H(2)(dTDP)(-), and H(2)(R-DP)(-) were measured also via potentiometric pH titration and various comparisons with related constants are made. By plotting log versus for the complexes of all six diphosphates mentioned and by a careful evaluation of the deviation of the various data pairs from the straight-line correlations, the expectation is confirmed that in the M(UDP)(-) and M(dTDP)(-) complexes the metal ion is only diphosphate-coordinated. The straight-line equations, which result from the mentioned correlations, together with the pK(a) value of a given monoprotonated diphosphate monoester allow now to predict the stability of the corresponding M(R-DP)(-) complexes. In this way, the experimentally determined stability constants for the M(CDP)(-) complexes are evaluated and it is concluded that the pyridine-like N3 of the cytosine residue does not participate in complex formation; i.e., the stability of the M(CDP)(-) complexes is also solely determined by the coordination tendency of the diphosphate residue. In all the monoprotonated M(H;NDP) and M(H;R-DP) complexes both, H(+) and M(2+), are bound at the diphosphate group. Only the Cu(H;CDP) complex exists in aqueous solution in the form of three different isomers: about 15% of the species have Cu(2+) and H(+) at the diphosphate residue, in about 13% Cu(2+) is bound at N3 and H(+) at the terminal beta-phosphate group, and the dominating isomer with about 72% carries the proton at N3 and the metal ion at the diphosphate residue. Several general features of phosphate-metal ion coordination are discussed, and estimations for the stabilities of the Fe(2+) complexes formed with mono-, di-, and triphosphate monoesters are provided.