RESUMO
Herein we describe the structure-activity relationship of a large library of Mannich bases (MBs) synthesized from 2-hydroxy-1,4-naphthoquinone. In general, the compounds have shown high to moderate activity against the HL-60 (promyelocytic leukaemia) cell line with IC50=1.1-19.2µM. Our results suggest that the nature of the aryl moiety introduced in the structure of MBs by the aldehyde component is crucial to the cytotoxicity, and although the group originated from the primary amine has a lesser influence, aromatic ones were found to suppress the activity. Thus, MBs derived from salicylaldehydes or 2-pyridinecarboxaldehyde and aliphatic amines are the most active compounds. A satisfactory correlation of the EpIIc versus IC50 (µM) in dimethylsulfoxide was observed. The most cytotoxic MBs (Series a-c, derived from salicylaldehydes) showed the least negative EpIIc values. Noteworthy, however, Series d (derived from 2-pyridinecarboxaldehyde) did not follow this correlation. They exhibited both the lowest IC50 and the most negative EpIIc values, thus suggesting that other factors also influence the cytotoxicity of the MBs, such as lipophilicity, electronic distribution and hydrogen bonding.
Assuntos
Antineoplásicos/farmacologia , Técnicas Eletroquímicas , Naftoquinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Relação Estrutura-AtividadeRESUMO
The human immunodeficiency virus (HIV) nucleocapsid protein (NCp7) plays significant roles in the virus life cycle and has been targeted by compounds that could lead to its denaturation or block its interaction with viral RNA. Herein, we describe the interactions of platinum(II) and gold(III) complexes with NCp7 and how the reactivity/affinity of potential inhibitors can be modulated by judicious choice of ligands. The interactions of [MCl(N3)]n+ (M = Pt2+ (n = 1) and Au3+ (n = 2); N3 = tridentate chelate ligands: bis(2-pyridylmethyl)methylamine (Mebpma, L1) and bis(2-pyridylmethyl)amine (bpma, L2) with the C-terminal zinc finger of NCp7 (ZF2) were investigated by electrospray ionization-mass spectroscopy (ESI-MS). Mass spectra from the incubation of [MCl(Mebpma)]n+ complexes (PtL1 and AuL1) with ZF2 indicated that they were more reactive than the previously studied diethylenetriamine-containing analogues [MCl(dien)]n+. The initial product of reaction of PtL1 with ZF2 results in loss of all ligands and release of zinc to give the platinated apopeptide {PtF} (F = apopeptide). This is in contrast to the incubation with [PtCl(dien)]+, in which {Pt(dien)}-peptide adducts are observed. Incubation of the Au3+ complex AuL1 with ZF2 gave AuxFn+ species (x = 1, 2, 4, F = apopeptide) again with loss of all ligands. Furthermore, the formally substitution-inert analogues [Pt(N3)L]2+ (L = 4-methylpyridine (4-pic), 4-dimethylaminopyridine (dmap), and 9-ethylguanine (9-EtGua)) were prepared to examine stacking interactions with N-acetyltryptophan (N-AcTrp), the Trp-containing ZF2, and the "full" two-finger NCp7 itself using fluorescence quenching titration. Use of bpma and Mebpma gave slightly higher affinity than analogous [Pt(dien)L)]2+ complexes. The dmap-containing complexes (PtL1a and PtL2a) had the greatest association constants (Ka) for N-AcTrp and ZF2 peptide. The complex PtL1a had the highest Ka when compared with other known Pt2+ analogues: [Pt(dien)(9-EtGua)]2+ < [Pt(bpma)(9-EtGua)]2+ < [Pt(dien)(dmap)]2+< PtL2a < PtL1a. A Ka value of ca. 40.6 ± 1.0 × 103 M-1 was obtained for the full NCp7 peptide with PtL1a. In addition, the mass spectrum of the interaction between ZF2 and PtL1a confirms formation of a 1:1 PtL1a/ZF2 adduct. The reactivity of selected complexes with sulfur-containing amino acid N-acetylcysteine (N-AcCys) was also investigated by 195Pt and 1H NMR spectroscopy and ESI-MS. The precursor compounds [PtCl(N3)]+ PtL1 and PtL2 reacted readily, whereas their [Pt(N3)L]2+ analogues PtL1a and PtL2a were inert to substitution.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Ouro/química , Ouro/farmacologia , Platina/química , Platina/farmacologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Ligantes , Metilaminas/química , Metilaminas/farmacologia , Modelos MolecularesRESUMO
Trypanosoma brucei and Trypanosoma cruzi are the etiologic agents of sleeping sickness and Chagas disease, respectively, two of the 17 preventable tropical infectious diseases (NTD) which have been neglected by governments and organizations working in the health sector, as well as pharmaceutical industries. High toxicity and resistance are problems of the conventional drugs employed against trypanosomiasis, hence the need for the development of new drugs with trypanocidal activity. In this work we have evaluated the trypanocidal activity of a series of N1,N2-dibenzylethane-1,2-diamine hydrochlorides (benzyl diamines) and N1-benzyl,N2-methyferrocenylethane-1,2-diamine hydrochlorides (ferrocenyl diamines) against T. brucei and T. cruzi parasite strains. We show that incorporation of the ferrocenyl group into the benzyl diamines increases the trypanocidal activity. The molecules exhibit potential trypanocidal activity in vitro against all parasite strains. Cytotoxicity assay was also carried out to evaluate the toxicity in HepG2 cells.
Assuntos
Compostos de Benzil/farmacologia , Diaminas/farmacologia , Compostos Ferrosos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Compostos de Benzil/síntese química , Compostos de Benzil/química , Sobrevivência Celular/efeitos dos fármacos , Diaminas/síntese química , Diaminas/química , Relação Dose-Resposta a Droga , Compostos Ferrosos/síntese química , Compostos Ferrosos/química , Células Hep G2 , Humanos , Metalocenos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/químicaRESUMO
Bovine herpesvirus type 5 (BoHV-5) is an etiologic agent of meningoencephalitis in cattle. The aim of this study was to evaluate the antiviral potential of a series of synthetic Mannich bases derived from lawsone and to investigate at which stage of the BoHV-5 replicative cycle the compounds might be acting. The most potent and selective inhibitor exhibited CC50 and EC50 values of 1867 µM ± 8.3 and 3.8 µM ± 1.2, respectively (ACV: 989 µM ± 2 and 166 µM ± 2, respectively).
Assuntos
Antivirais/farmacologia , Herpesvirus Bovino 5/efeitos dos fármacos , Naftoquinonas/farmacologia , Replicação Viral/efeitos dos fármacos , Aciclovir/farmacologia , Animais , Antivirais/química , Linhagem Celular , Cães , Relação Dose-Resposta a Droga , Herpesvirus Bovino 5/fisiologia , Estrutura Molecular , Naftoquinonas/química , Ensaio de Placa ViralRESUMO
In search of a novel class of compounds against Alzheimer's disease (AD), a new series of 7-chloro-aminoquinoline derivatives containing methylene spacers of different sizes between the 7-chloro-4-aminoquinoline nucleus and imino methyl substituted phenolic rings, and also their reduced analogues, were designed, synthesized and evaluated as neuroprotective agents for AD in vitro. In spite of the multifaceted feature of AD, cholinesterases continue to be powerful and substantial targets, as their inhibition increases both the level and duration of the acetylcholine neurotransmitter action. The compounds presented inhibitory activity in the micromolar range against acetylcholinesterase (AChE) (imines and amines) and butyrylcholineterase (BChE) (amines). The SAR study revealed that elongation of the imine side chain improved AChE activity, whereas the reduction of these compounds to amines was crucial for higher activity and indispensable for BChE inhibition. The most promising selective inhibitors were not cytotoxic and did not stimulate pro-inflammatory activity in glial cells. Kinetic and molecular modeling studies indicated that they also show mixed-type inhibition for both enzymes, behaving as dual-site inhibitors, which can interact with both the peripheral anionic site and the catalytic anionic site of AChE. They could therefore restore cholinergic transmission and also may inhibit the aggregation of Aß promoted by AChE. Additionally, one compound showed promising anti-inflammatory activity by reducing the microglial release of NO⢠at a concentration that is equivalent to the IC50 against BChE (30.32 ± 0.18 µM) and 15-fold greater than the IC50 against AChE (1.97 ± 0.20 µM).Communicated by Ramaswamy H. Sarma.
Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Relação Estrutura-AtividadeRESUMO
The editors of several major journals have recently asserted the importance of combating racism and sexism in science. This is especially relevant now, as the COVID-19 pandemic may have led to a widening of the gender and racial/ethnicity gaps. Implicit bias is a crucial component in this fight. Negative stereotypes that are socially constructed in a given culture are frequently associated with implicit bias (which is unconscious or not perceived). In the present article, we point to scientific evidence that shows the presence of implicit bias in the academic community, contributing to strongly damaging unconscious evaluations and judgments of individuals or groups. Additionally, we suggest several actions aimed at (1) editors and reviewers of scientific journals (2) people in positions of power within funding agencies and research institutions, and (3) members of selection committees to mitigate this effect. These recommendations are based on the experience of a group of Latinx American scientists comprising Black and Latina women, teachers, and undergraduate students who participate in women in science working group at universities in the state of Rio de Janeiro, Brazil. With this article, we hope to contribute to reflections, actions, and the development of institutional policies that enable and consolidate diversity in science and reduce disparities based on gender and race/ethnicity.
RESUMO
The present study was designed to further evaluate a possible spasmolytic activity of synthetic lapachol derivatives, norlapachol, alpha-norlapachone, beta-norlapachone and hydro-hydroxy-norlapachol (HH-norlapachol), on guinea-pig ileum. In guinea-pig ileum, except for norlapachol, all naphthoquinones inhibited the phasic contractions induced by carbachol or histamine. Even when the ileum was pre-contracted with KCl, carbachol or histamine, all naphthoquinones induced relaxation, suggesting that these naphthoquinones could be acting on the voltage-gated calcium channels (Ca(V)). As the tonic component this contraction is maintained mainly by the opening of the Ca(V), we hypothesized that these naphthoquinones might be acting on these channels. This hypothesis was confirmed by the observation that norlapachol (pD'2 = 4.99), alpha-norlapachone (pD'2 = 4.49), beta-norlapachone (pD'2 = 6.33), and HH-norlapachol (pD'2 = 4.53) antagonized the contractions induced by CaCl2 in depolarizing medium nominally without Ca2+. As beta-norlapachone was the most potent we decided to continue the study of its action mechanism. The fact that this naphthoquinone has inhibited the tonic contractions induced by S-(-)-Bay K8644 [EC50 = (1.6 +/- 0.30) x 10(-5) M] suggests that the Ca2+ channel involved belongs to the type L (Ca(V)1.2). In addition, in the functional level, the spasmolytic effect of beta-norlapachone does not involve participation of free radicals, since its curve of relaxation was unchanged in the presence of glutathione, an antioxidant agent.
Assuntos
Íleo/fisiologia , Relaxamento Muscular/fisiologia , Naftoquinonas/farmacologia , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Animais , Agonistas dos Canais de Cálcio/farmacologia , Cobaias , Histamina/farmacologia , Íleo/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Relaxamento Muscular/efeitos dos fármacos , Naftoquinonas/isolamento & purificação , Cloreto de Potássio/farmacologia , Tabebuia/químicaRESUMO
Alzheimer's disease (AD) is one of the most common age-related neurodegenerative disorders. Aggregation of amyloid-ß peptide into extracellular plaques with incorporation of metal ions, such as Cu2+, and reduction of the neurotransmitter acetylcholine levels are among the factors associated to the AD brain. Hence, a series of 7-chloro-4-aminoquinoline Schiff bases (HLa-e) were synthesized and their cytotoxicity and anti-cholinesterase activity, assessed for Alzheimer's disease. The intrinsic relationship between Cu2+ and the amyloidogenic plaques encouraged us to investigate the chelating ability of HLa-e. Dimeric tetracationic compounds, [Cu2(NHLa-e)4]Cl4, containing quinoline protonated ligands were isolated from the reactions with CuCl2·2H2O and fully characterized in the solid state, including an X ray diffraction study, whereas EPR data showed that the complexes exist as monomers in DMSO solution. The inhibitory activity of all compounds was evaluated by Ellman's spectrophotometric method in acetylcholinesterase (AChE) from Electrophorus electricus and butyrylcholinesterase (BChE) from equine serum. HLa-e and [Cu(NHLd)2]Cl2 were selective for AChE (IC50â¯=â¯4.61-9.31⯵M) and were not neurotoxic in primary brain cultures. Docking and molecular dynamics studies of HLa-e inside AChE were performed and the results suggested that these compounds are able to bind inside AChE similarly to other AChE inhibitors, such as donepezil. Studies of the affinity of HLd for Cu2+ in DMSO/HEPES at pHâ¯6.6 and pHâ¯7.4 in µM concentrations showed formation of analogous 1:2 Cu2+/ligand complexes, which may suggest that in the AD-affected brain HLd may scavenge Cu2+ and the complex, also inhibit AChE.
Assuntos
Aminoquinolinas/química , Inibidores da Colinesterase/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Bases de Schiff/química , Animais , Células Cultivadas , Inibidores da Colinesterase/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Técnicas In Vitro , Camundongos , Simulação de Acoplamento Molecular , Análise Espectral/métodosRESUMO
Resistance to benznidazole in certain strains of Trypanosoma cruzi may be caused by the increased production of enzymes that act on the oxidative metabolism, such as mitochondrial tryparedoxin peroxidase which catalyses the reduction of peroxides. This work presents cytotoxicity assays performed with ferrocenyl diamine hydrochlorides in six different strains of T. cruzi epimastigote forms (Y, Bolivia, SI1, SI8, QMII, and SIGR3). The last four strains have been recently isolated from triatominae and mammalian host (domestic cat). The expression of mitochondrial tryparedoxin peroxidase was analyzed by the Western blotting technique using polyclonal antibody anti mitochondrial tryparedoxin peroxidase obtained from a rabbit immunized with the mitochondrial tryparedoxin peroxidase recombinant protein. All the tested ferrocenyl diamine hydrochlorides were more cytotoxic than benznidazole. The expression of the 25.5kDa polypeptide of mitochondrial tryparedoxin peroxidase did not increase in strains that were more resistant to the ferrocenyl compounds (SI8 and SIGR3). In addition, a 58kDa polypeptide was also recognized in all strains. Ferrocenyl diamine hydrochlorides showed trypanocidal activity and the expression of 25.5kDa mitochondrial tryparedoxin peroxidase is not necessarily increased in some T. cruzi strains. Most likely, other mechanisms, in addition to the over expression of this antioxidative enzyme, should be involved in the escape of parasites from cytotoxic oxidant agents.
Assuntos
Diaminas/farmacologia , Compostos Ferrosos/farmacologia , Mitocôndrias/enzimologia , Oxidantes/farmacologia , Peroxidases/metabolismo , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/enzimologia , Animais , Western Blotting , Gatos , Mitocôndrias/efeitos dos fármacos , Coelhos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
BACKGROUND: Herpes simplex viruses (HSV) are leading causes of human infections which result in severe manifestations, especially in neonates, immunocompromised and/or transplanted individuals. Current HSV type-1 (HSV-1) resistance to standard antiviral agents is a therapeutic challenge, especially for treating immunocompromised patients. METHODS: Herein we describe the promising antiviral profile of three 2-aminomethyl-3-hydroxy-1,4-naphthoquinones against HSV-1 using Vero cells. RESULTS: The in silico theoretical analysis indicated that the lowest unoccupied molecular orbital (LUMO) and the conformational features of these molecules are important structural features for modulating their biological activity. Our in vitro results showed that these compounds have significant anti-HSV-1 activity comparable to acyclovir, the antiviral currently used clinically. Importantly two of them showed a lower cytotoxicity profile against Vero cells than acyclovir. The inhibitory mechanism analysis using a time-of-addition assay revealed that all compounds inhibit the late phase of lytic replication. Finally, the highest selectivity index of the first tested compound was almost twice as high as that of acyclovir. CONCLUSIONS: Since resistance is still a problem for treating HSV infections, these compounds present a promising profile toward the development of new strategies for anti-HSV-1 therapy.
Assuntos
Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Naftoquinonas/farmacologia , Aciclovir/farmacologia , Animais , Antivirais/química , Antivirais/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Simulação por Computador , Farmacorresistência Viral , Herpes Simples/tratamento farmacológico , Herpes Simples/imunologia , Herpes Simples/virologia , Humanos , Hospedeiro Imunocomprometido , Testes de Sensibilidade Microbiana , Naftoquinonas/química , Naftoquinonas/toxicidade , Células Vero , Ensaio de Placa ViralRESUMO
BACKGROUND: A deeper knowledge on the effects of the degradation of magnetic nanoparticles on their magnetic properties is required to develop tools for the identification and quantification of magnetic nanoparticles in biological media by magnetic means. METHODS: Citric acid and phosphonoacetic acid-coated magnetic nanoparticles have been degraded in a medium that mimics lysosomal conditions. Magnetic measurements and transmission electron microscopy have been used to follow up the degradation process. RESULTS: Particle size is reduced significantly in 24 h at pH 4.5 and body temperature. These transformations affect the magnetic properties of the compounds. A reduction of the interparticle interactions is observed just 4 h after the beginning of the degradation process. A strong paramagnetic contribution coming from the degradation products appears with time. CONCLUSIONS: A model for the in vivo degradation of magnetic nanoparticles has been followed to gain insight on the changes of the magnetic properties of iron oxides during their degradation. The degradation kinetics is affected by the particle coating, in our case being the phosphonoacetic acid-coated particles degraded faster than the citric acid-coated ones.
Assuntos
Ácido Cítrico/química , Lisossomos/química , Lisossomos/ultraestrutura , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/ultraestrutura , Ácido Fosfonoacéticos/química , Materiais Biomiméticos/química , Materiais Biomiméticos/efeitos da radiação , Líquidos Corporais/química , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/efeitos da radiação , Impedância Elétrica , Cinética , Nanopartículas de Magnetita/efeitos da radiação , Teste de Materiais , Tamanho da Partícula , TemperaturaRESUMO
Several chlorido and amino Pt(2+) complexes of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases HL exhibiting moderate to high cytotoxicity against cancer cell lines were studied in order to investigate their modes of DNA binding, in vitro DNA strand breaks, mechanism of topoisomerase (Topo I) inhibition and cellular accumulation. DNA model base studies have shown that complex 1a [Pt(HL1)Cl(2)] was capable of binding covalently to 9-ethylguanine (9-EtG) and 5'-GMP. (1)H NMR and mass spectrometry studies have shown that both chlorides were substituted by 9-EtG ligands, whereas 5'-GMP was able to replace only one chlorido ligand, due to steric hindrance. The chlorido Pt(2+) complexes [Pt(HL)Cl(2)] highly accumulate in prostate (PC-3) and melanoma (MDA-MB-435) cell lines, being able to induce DNA strand breaks in vitro and inhibit Topo I by a catalytic mode. On the other hand, the free 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinones HL and the amino Pt(2+) complexes [Pt(L(-))(NH(3))(2)]NO(3) neither cause DNA strand breakage nor exhibit strong DNA interaction, nevertheless the latter were also found to be catalytic inhibitors of Topo I at 100µM. Thus, coordination of the Mannich bases HL to the "PtCl(2)" fragment substantially affects the chemical and biophysical properties of the pro-ligands, leading to an improvement of their DNA binding properties and generating compounds that cleave DNA and catalytically inhibit Topo I. Finally, the high cytotoxicity exhibited by the free (uncomplexed) 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinones might be associated with their decomposition in solution, which is not observed for the Pt(2+) complexes.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , DNA Topoisomerases Tipo I/química , DNA/química , Bases de Mannich/química , Naftoquinonas/farmacologia , Platina/química , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Sítios de Ligação , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Complexos de Coordenação/síntese química , Clivagem do DNA/efeitos dos fármacos , Guanina/análogos & derivados , Guanina/química , Guanosina Monofosfato/química , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Naftoquinonas/síntese química , Inibidores da Topoisomerase I/síntese químicaRESUMO
Zinc(II) and copper(II) complexes of a tridentate Mannich base L1 derived from 2-hydroxy-1,4-naphthoquinone, pyridinecarboxyaldehyde and 2-aminomethylpyridine, [ZnL1Cl(2)]·H(2)O 1 and [CuL1Cl(2)]·2H(2)O 2, have been synthesized and fully characterized. The structure of complex 1 has been elucidated by a single crystal X-ray diffraction study: the zinc atom is pentacoordinate and the coordination geometry is a distorted square base pyramid, with a geometric structural parameter τ equal to 0.149. Vibrational spectroscopy and ab initio DFT calculations of both compounds have confirmed that the two complexes exhibit similar structures. Full assignment of the vibrational spectra was also supported by careful analysis of the distorted geometries generated by the normal modes.
Assuntos
Cobre/química , Bases de Mannich/síntese química , Modelos Moleculares , Naftoquinonas/síntese química , Teoria Quântica , Vibração , Zinco/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Espectroscopia de Ressonância de Spin Eletrônica , Elétrons , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Bases de Mannich/química , Conformação Molecular , Naftoquinonas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , TermodinâmicaRESUMO
Abstract Resistance to benznidazole in certain strains of Trypanosoma cruzi may be caused by the increased production of enzymes that act on the oxidative metabolism, such as mitochondrial tryparedoxin peroxidase which catalyses the reduction of peroxides. This work presents cytotoxicity assays performed with ferrocenyl diamine hydrochlorides in six different strains of T. cruzi epimastigote forms (Y, Bolivia, SI1, SI8, QMII, and SIGR3). The last four strains have been recently isolated from triatominae and mammalian host (domestic cat). The expression of mitochondrial tryparedoxin peroxidase was analyzed by the Western blotting technique using polyclonal antibody anti mitochondrial tryparedoxin peroxidase obtained from a rabbit immunized with the mitochondrial tryparedoxin peroxidase recombinant protein. All the tested ferrocenyl diamine hydrochlorides were more cytotoxic than benznidazole. The expression of the 25.5 kDa polypeptide of mitochondrial tryparedoxin peroxidase did not increase in strains that were more resistant to the ferrocenyl compounds (SI8 and SIGR3). In addition, a 58 kDa polypeptide was also recognized in all strains. Ferrocenyl diamine hydrochlorides showed trypanocidal activity and the expression of 25.5 kDa mitochondrial tryparedoxin peroxidase is not necessarily increased in some T. cruzi strains. Most likely, other mechanisms, in addition to the over expression of this antioxidative enzyme, should be involved in the escape of parasites from cytotoxic oxidant agents.
Assuntos
Animais , Gatos , Coelhos , Peroxidases/metabolismo , Compostos Ferrosos/farmacologia , Proteínas de Protozoários/metabolismo , Oxidantes/farmacologia , Diaminas/farmacologia , Mitocôndrias/enzimologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia , Western Blotting , Mitocôndrias/efeitos dos fármacosRESUMO
Semi-empirical (AM1 and PM3) and DFT (B3LYP/6-31G(d)) calculations were employed to study the tautomeric equilibrium between the aminequinone A and hydroxylquinoneimine B forms of 4-(4-R-phenylamino)naphthalene-1,2-diones. Substituent effects on the tautomeric equilibrium as well as on geometric and electronic parameters were also determined. In the gas phase the hydroxylquinoneimine B form is the most stable, whereas in water the aminequinone A form becomes more stable. The substituents do not modify the relative energies of the two tautomers. These results are in accordance with experimental data reported in the literature.
Assuntos
Modelos Químicos , Naftalenos/química , Gases/química , Isomerismo , Simulação de Dinâmica Molecular , Água/químicaRESUMO
A series of (E) and (Z)-ferrocenyl oxindoles were prepared by coupling substituted oxindoles to ferrocenylcarboxyaldehyde in the presence of morpholine as a catalyst. The redox behavior of these isomers was determined by cyclic voltammetry. The effects of the oxindole derivatives on the migration of human breast cancer cells were evaluated using the wound-healing assay and the Boyden chamber cell-migration assay. The most potent Z isomers 11b (IC(50) = 0.89 microM), 12b (IC(50) = 0.49 microM) and 17b (IC(50) = 0.64 microM) could represent attractive new lead compounds for further development for cancer therapy.
Assuntos
Antineoplásicos/síntese química , Compostos Ferrosos/química , Indóis/química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Catálise , Linhagem Celular Tumoral , Técnicas Eletroquímicas , Feminino , Humanos , Isomerismo , Metalocenos , Morfolinas/química , Oxirredução , OxindóisRESUMO
The first examples of platinum(II) complexes of 3-(aminomethyl)naphthoquinone Mannich bases have been synthesised and their crystal structures are described. Neutral and charged complexes have been obtained, fully characterised and their cytotoxic activities have also been investigated. 3-[(R(1)-amino)(pyridin-2-yl)methyl]-2-hydroxy-1,4-naphthoquinones (R(1) = n-Bu, HL1; Bn, HL2; furfuryl, HL3; n-heptyl, HL4 and n-decyl, HL5) coordinate to platinum(II) through the two nitrogen atoms. The neutral complexes cis-[Pt(HL)Cl(2)] 1a-5a are analogous to cisplatin with the bidentate ligand HL and two chlorine atoms occupying cis positions. In the charged complexes cis-[Pt(L(-))(NH(3))(2)]NO(3)1b-5b the deprotonated form of the ligand L(-) also coordinates via the nitrogen atoms, and the other two positions around the platinum(II) ion are completed with NH(3) ligands. The cytotoxic activities of all compounds have been tested for six different cancer cell lines: MDA-MB-435 (melanoma), HL-60 (promyelocytic leukaemia), HCT-8 (colon), SF-295 (brain), OVCAR-8 (ovary) and PC-3 (prostate). Proligands HL4 and HL5 have exhibited high activity against HL-60 (IC(50) = 1.9 and 3.8 µmol L(-1), respectively), HCT-8 (IC(50) = 1.6 and 1.7 µmol L(-1), respectively) and SF-295 (IC(50) = 1.1 and 1.7 µmol L(-1), respectively). The chlorido complexes 1a-5a have shown high to moderate cytotoxic activities, complex 4a (R(1) = n-heptyl) being more active than proligand HL4 against melanoma (IC(50) = 6.4 and > 40 µmol L(-1), respectively) and more active than cisplatin against all tested cell lines. Among the amine charged complexes only 4b and 5b have exhibited significant cytotoxic activity against the tested cell lines, although they were only moderately active against the PC-3 cell line (IC(50) = 29.9 and 15.6 µmol L(-1), respectively). In general the compounds with the longest carbon chains (R(1) = n-heptyl and n-decyl) have exhibited the highest activities.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Bases de Mannich/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Platina/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Cristalografia por Raios X , Eletroquímica , Humanos , Concentração Inibidora 50 , Compostos Organometálicos/síntese químicaRESUMO
The toxic profile of lawsone (2-hydroxy-[1,4]naphthoquinone) and a series of [1,4]naphthoquinone derivatives was evaluated against the brine shrimp Artemia salina and against the mollusk Biomphalaria glabrata, the main transmitting vector of schistosomiasis in Brazil. Of the seventeen compounds tested nine fell below the threshold of 100 microg/mL set for potential molluscicidal activity by the World Health Organization. As a general rule derivatives with non-polar substituents presented the highest molluscicidal activities. These substances showed significant toxicity in A. salina lethality bioassay.
Assuntos
Artemia/efeitos dos fármacos , Biomphalaria/efeitos dos fármacos , Moluscocidas/farmacologia , Naftoquinonas/farmacologia , Animais , Moluscocidas/síntese química , Naftoquinonas/síntese químicaRESUMO
New nitrogen derivatives from norlapachol, including four new diastereomeric 1,2,3,4-tetrahydro-1-aza-anthraquinones obtained from the Prins cyclization on suitable aminoacetaldehyde dimethylacetal derivatives with formic acid, were found to exhibit molluscicidal activity against Biomphalaria glabrata. These derivatives showed low to medium LC(50) values, similar to those reported previously for the homologous series of nitrogen derivatives of lapachol. The toxicity profile against Artemia salina was also determined for all compounds.
Assuntos
Antraquinonas/química , Antraquinonas/toxicidade , Compostos Aza/síntese química , Compostos Aza/toxicidade , Moluscos/efeitos dos fármacos , Moluscocidas/síntese química , Moluscocidas/toxicidade , Naftoquinonas/química , Alquilação , Aminação , Animais , Antraquinonas/síntese química , Compostos Aza/química , Hidroxilação , Estrutura Molecular , Moluscocidas/química , Relação Estrutura-AtividadeRESUMO
A series of new amino derivatives and a new partially hydrogenated derivative of the natural naphthoquinone lapachol were assayed for molluscicidal activity against Biomphalaria glabrata. These derivatives showed low to medium LC(50) values, and a 3.1 microg/mL value for the most potent derivative of the series. The toxicity is in agreement with the decrease of polar character of the tested compounds.