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1.
Biomolecules ; 9(7)2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261818

RESUMO

Triple-negative breast cancer (TNBC) is highly proliferative and metastatic, and because it lacks three major molecular targets for chemotherapy (estrogen receptor, progesterone receptor, and human epidermal receptor 2), it is extremely refractory. Differentiation-inducing factor 1 (DIF-1) and DIF-3, which are chlorinated alkylphenones, are lead anticancer compounds found in the cellular slime mold Dictyostelium discoideum. Here, we examined the in vitro effects of DIF-1, DIF-3, and 25 DIF derivatives on cell proliferation and serum-induced cell migration in human MDA-MB-231 cells, a model TNBC cell line. We found that Br-DIF-1, a chlorine-to-bromine-substituted derivative of DIF-1, strongly suppressed cell migration (IC50, 3.8 M) with negligible effects on cell proliferation (IC50, >20 M). We then synthesized 18 derivatives of Br-DIF-1 and examined the in vitro effects of these derivatives on cell proliferation and serum-induced cell migration in MDA-MB-231 cells. Among the derivatives, Br-DIF-1(+1), Br-DIF-1(+2), and Br-DIF-3(+2) exhibited strong anti-cell migration activities with IC50 values of 1.5, 1.0, and 3.1 M, respectively, without affecting cell proliferation (IC50, >20 M). These results suggest that these Br-DIF derivatives are good lead compounds for the development of anti-metastatic drugs against TNBC.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Dictyostelium/química , Halogênios/farmacologia , Hexanonas/farmacologia , Hidrocarbonetos Clorados/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Halogênios/química , Hexanonas/síntese química , Hexanonas/química , Humanos , Hidrocarbonetos Clorados/síntese química , Hidrocarbonetos Clorados/química , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
2.
Dalton Trans ; 48(28): 10488-10504, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31210199

RESUMO

Reactions between halogen substituted terpyridine ligands F- (L1), Cl- (L2), Br- (L3) and I-4'-phenyl-terpyridine (L4) and ZnBr2 or ZnI2 led to the formation of complexes [Zn(Br)2L1] (1), [Zn(i)2L1] (2), [Zn(Br)2L2] (3), [Zn(i)2L2] (4), [Zn(Br)2L3] (5), [Zn(i)2L3] (6), [Zn(Br)2L4] (7), and [Zn(i)2L4] (8), respectively, which were characterized by elemental analysis, 1H NMR, IR and single crystal X-ray diffraction. Their photoluminescence properties, solution stabilities, hydrophilicity/lipophilicity properties and anti-proliferative activity against three cancer cell lines as well as structure-function relationships are analyzed. All the complexes, which show high solution stabilities and lipophilicity under determination conditions, reveal much higher antiproliferative activities than cisplatin against the human lung carcinoma cell line (A549), human hepatocellular carcinoma cell line (Bel-7042) and human breast cancer cell line (MCF-7) in vitro. Fluorescence spectroscopy and circular dichroic analysis reveal that the compounds have strong affinity binding with ctDNA and stack onto the base pairs of the ctDNA. The results obtained are further explained in terms of the electronic properties of the compounds by density functional theory (DFT) calculations, and it is found that the halogen anions play critical roles in the antitumor activity of these compounds. Their affinities to HSP90 proteins, ALK, EGFR and HER2 kinases and the binding sites on these proteins have been determined by computational docking analysis, and the results indicate that the only form of their binding is van der Waals forces.


Assuntos
Antineoplásicos/farmacologia , Teoria da Densidade Funcional , Simulação de Acoplamento Molecular , Compostos Organometálicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Halogênios/química , Halogênios/farmacologia , Humanos , Luminescência , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Processos Fotoquímicos , Proteínas/química , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , Zinco/química , Zinco/farmacologia
3.
Chembiochem ; 20(2): 282-286, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30474907

RESUMO

Deubiquitinases are important components of the protein regulatory network and, hence, constitute a tempting drug target. We report herein structure-activity relationship studies to develop halogen-substituted isoquionoline-1,3-dione-based inhibitors of the deubiquitinase USP2. In contrast to our previous reports, the best compound discovered was found to act through a reactive oxygen species independent, uncompetitive mechanism with an IC50 of 250 nm. We show the crucial role of halogens in the common scaffold to provide potency and selectivity of our compound, where the introduction of the fluorine atom completely switches the selectivity of the inhibitor between USP2 and USP7. Our cellular studies highlight the potential applicability of the reported compound for in vivo experiments. The discovery of the isoquinoline-1,3-dione core and the knowledge obtained with regard to halogen substituents provide a platform towards understanding USP2 inhibition and the development of highly selective next-generation deubiquitinase inhibitors.


Assuntos
Endopeptidases/metabolismo , Halogênios/farmacologia , Hidrocarbonetos Halogenados/farmacologia , Isoquinolinas/farmacologia , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Configuração de Carboidratos , Relação Dose-Resposta a Droga , Halogênios/química , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Hidrocarbonetos Halogenados/química , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-Atividade , Peptidase 7 Específica de Ubiquitina/metabolismo
4.
J Chem Theory Comput ; 14(10): 5383-5392, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30215528

RESUMO

Halogen bonds (XBs) are non-covalent interactions in which halogens (X), acting as electrophiles, interact with Lewis bases. XBs are able to mediate protein-ligand recognition and therefore play an important role in rational drug design. In this context, the development of molecular modeling tools that can tackle XBs is paramount. XBs are predominantly explained by the existence of a positive region on the electrostatic potential of X named the σ-hole. Typically, with molecular mechanics force fields, this region is modeled using a charged extra point (EP) linked to X along the R-X covalent bond axis. In this work, we developed the first EP-based strategy for GROMOS force fields (specifically GROMOS 54A7) using bacteriophage T4 lysozyme in complex with both iodobenzene and iodopentafluorobenzene as a prototype system. Several EP parametrization schemes were tested by adding a virtual interaction site to ligand topologies retrieved from the Automated Topology Builder (ATB) and Repository. Contrary to previous approaches using other force fields, our analysis is based on the capability of each parametrization scheme to sample XBs during MD simulations. Our results indicate that the implementation of an EP at a distance from iodine corresponding to Rmin provides a good qualitative description of XBs in MD simulations, supporting the compatibility of our approach with the GROMOS 54A7 force field.


Assuntos
Bacteriófago T4/enzimologia , Derivados de Benzeno/farmacologia , Halogênios/farmacologia , Muramidase/metabolismo , Bacteriófago T4/química , Bacteriófago T4/efeitos dos fármacos , Bacteriófago T4/metabolismo , Derivados de Benzeno/química , Cristalografia por Raios X , Desenho de Fármacos , Halogênios/química , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Muramidase/química , Eletricidade Estática
5.
Org Biomol Chem ; 16(7): 1083-1087, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29376532

RESUMO

Ortho-Phenylene bis-ureas serve as anionophores in cells expressing halide-sensitive yellow fluorescent protein, as well as in synthetic vesicles. Activities can reach high levels, and are strongly dependent on the deliverability of the transporters.


Assuntos
Transporte de Íons , Fenilenodiaminas/química , Ureia/análogos & derivados , Ânions/metabolismo , Proteínas de Bactérias , Membrana Celular/metabolismo , Halogênios/farmacologia , Membranas Intracelulares/metabolismo , Proteínas Luminescentes , Ureia/química , Ureia/metabolismo
6.
J Biol Inorg Chem ; 22(8): 1179-1186, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28975410

RESUMO

An infrared spectroelectrochemical study of Trametes hirsuta laccase and Magnaporthe oryzae bilirubin oxidase has been performed using azide, an inhibitor of multicopper oxidases, as an active infrared probe incorporated into the T2/T3 copper cluster of the enzymes. The redox potential-controlled measurements indicate that N3- stretching IR bands of azide ion bound to the T2/T3 cluster are only detected for the oxidized enzymes, confirming that azide only binds to Cu2+. Moreover, the process of binding/dissociation of azide ion is shown to be reversible. The interaction of halide anions, which also inhibit multicopper oxidases, with the active site of the enzymes was studied by measuring the changes in the azide FTIR bands. Enzymes inhibited by azide respond differently upon addition of fluoride or chloride ions to the sample solution inhibited by azide. Fluoride ions compete with azide for binding at one of the T2/T3 Cu ions, whereas competition from chloride ions is much less evident.


Assuntos
Azidas/química , Cobre/metabolismo , Halogênios/farmacologia , Raios Infravermelhos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Eletroquímica , Magnaporthe/enzimologia , Sondas Moleculares/química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Trametes/enzimologia
7.
Bioorg Med Chem Lett ; 27(17): 4204-4211, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28757064

RESUMO

In the current work, 13 novel panaxadiol (PD) derivatives were synthesized by reacting with chloroacetyl chloride and bromoacetyl bromide. Their in vitro antitumor activities were evaluated on three human tumor cell lines (HCT-116, BGC-823, SW-480) and three normal cells (human gastric epithelial cell line-GES-1, hair follicle dermal papilla cell line-HHDPC and rat myocardial cell line-H9C2) by MTT assay. Compared with PD, the results demonstrated that compound 1e, 2d, 2e showed significant anti-tumor activity against three tumor cell lines, the IC50 value of compound 2d against HCT-116 was the lowest (3.836µM). The anti-tumor activity of open-ring compounds are significantly better than the compounds of C-25 cyclization. Compound 1f, 2f, 2g showed the strong anti-tumor activity. The IC50 value of compound 2g against BGC-823 and SW-480 were the lowest (0.6µM and 0.1µM, respectively). Combined with cytotoxicity test, the IC50 value of compound 1e, 2d, 2e are greater than 100. the open-ring compounds (1f, 2f, 2g) showed a strong toxicity. The toxicity of 1f is lower than 2f and 2g. These compounds may be useful for the development of novel antiproliferative agents.


Assuntos
Antineoplásicos/farmacologia , Ginsenosídeos/farmacologia , Halogênios/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 , Ginsenosídeos/síntese química , Ginsenosídeos/química , Halogênios/síntese química , Halogênios/química , Humanos , Conformação Molecular , Relação Estrutura-Atividade
8.
Org Biomol Chem ; 15(28): 6024-6032, 2017 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-28678295

RESUMO

The class D (OXA) serine ß-lactamases are a major cause of resistance to ß-lactam antibiotics. The class D enzymes are unique amongst ß-lactamases because they have a carbamylated lysine that acts as a general acid/base in catalysis. Previous crystallographic studies led to the proposal that ß-lactamase inhibitor avibactam targets OXA enzymes in part by promoting decarbamylation. Similarly, halide ions are proposed to inhibit OXA enzymes via decarbamylation. NMR analyses, in which the carbamylated lysines of OXA-10, -23 and -48 were 13C-labelled, indicate that reaction with avibactam does not ablate lysine carbamylation in solution. While halide ions did not decarbamylate the 13C-labelled OXA enzymes in the absence of substrate or inhibitor, avibactam-treated OXA enzymes were susceptible to decarbamylation mediated by halide ions, suggesting halide ions may inhibit OXA enzymes by promoting decarbamylation of acyl-enzyme complex. Crystal structures of the OXA-10 avibactam complex were obtained with bromide, iodide, and sodium ions bound between Trp-154 and Lys-70. Structures were also obtained wherein bromide and iodide ions occupy the position expected for the 'hydrolytic water' molecule. In contrast with some solution studies, Lys-70 was decarbamylated in these structures. These results reveal clear differences between crystallographic and solution studies on the interaction of class D ß-lactamases with avibactam and halides, and demonstrate the utility of 13C-NMR for studying lysine carbamylation in solution.


Assuntos
Compostos Azabicíclicos/farmacologia , Halogênios/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Compostos Azabicíclicos/química , Isótopos de Carbono , Cristalografia por Raios X , Halogênios/química , Íons/química , Íons/farmacologia , Modelos Moleculares , Conformação Molecular , Inibidores de beta-Lactamases/química
9.
Bioorg Med Chem Lett ; 27(17): 4199-4203, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28754364

RESUMO

The new lignano-9,9'-lactones (α,ß-dibenzyl-γ-butyrolactone lignans), which showed the higher cytotoxicity than arctigenin, were synthesized. The well-known cytotoxic arctigenin showed activity against HL-60 cells (EC50=12µM), however, it was inactive against HeLa cells (EC50>100µM). The synthesized (3,4-dichloro, 2'-butoxy)-derivative 55 and (3,4-dichloro, 4'-butyl)-derivative 66 bearing the lignano-9,9'-lactone structures showed the EC50 values of 10µM and 9.4µM against HL-60 cells, respectively. Against HeLa cells, the EC50 value of the derivative 66 was 27µM. By comparing the activities with the corresponding 9,9'-epoxy structure (tetrahydrofuran compounds), the importance of the lactone structure of 55 and 66 for the higher activities was shown. The substituents on the aromatic ring of the lignano-9,9'-lactones affected the cytotoxicity level, observing more than 10-fold difference.


Assuntos
Antineoplásicos/farmacologia , Furanos/farmacologia , Halogênios/farmacologia , Hidrocarbonetos Aromáticos/farmacologia , Lignanas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Células HL-60 , Halogênios/química , Células HeLa , Humanos , Hidrocarbonetos Aromáticos/química , Lignanas/síntese química , Lignanas/química , Conformação Molecular , Relação Estrutura-Atividade
10.
J Enzyme Inhib Med Chem ; 31(sup4): 125-131, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27594305

RESUMO

Phenolic bis Mannich bases having the chemical structure of 1-[3,5-bis-aminomethyl-4-hydroxyphenyl]-3-(4-halogenophenyl)-2-propen-1-ones (1a-c, 2a-c, 3a-c) were synthesized (Numbers 1, 2, and 3 represent fluorine, chlorine, and bromine bearing compounds, respectively, while a, b, and c letters represent the compounds having piperidine, morpholine, and N-methyl piperazine) and their cytotoxic and carbonic anhydrase (CA, EC 4.2.1.1) enzyme inhibitory effects were evaluated. Lead compounds should possess both marked cytotoxic potencies and selective toxicity for tumors. To reflect this potency, PSE values of the compounds were calculated. According to PSE values, the compounds 2b and 3b may serve as lead molecules for further anticancer drug candidate developments. Although the compounds showed a low inhibition potency toward hCA I (25-43%) and hCA II (6-25%) isoforms at 10 µM concentration of inhibitor, the compounds were more selective (1.5-5.2 times) toward hCA I isoenzyme. It seems that the compounds need molecular modifications for the development of better CA inhibitors.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Chalconas/síntese química , Chalconas/farmacologia , Halogênios/farmacologia , Neoplasias Bucais/tratamento farmacológico , Fenóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Halogênios/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Bases de Mannich/síntese química , Bases de Mannich/química , Bases de Mannich/farmacologia , Estrutura Molecular , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Fenóis/química , Solubilidade , Relação Estrutura-Atividade
11.
Sci Rep ; 6: 31074, 2016 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-27501852

RESUMO

Drug repositioning has been attracting increasingly attention for its advantages of reducing costs and risks. Statistics showed that around one quarter of the marketed drugs are organohalogens. However, no study has been reported, to the best of our knowledge, to aim at efficiently repositioning organohalogen drugs, which may be attributed to the lack of accurate halogen bonding scoring function. Here, we present a study to show that two organohalogen drugs were successfully repositioned as potent B-Raf V600E inhibitors via molecular docking with halogen bonding scoring function, namely D(3)DOCKxb developed in our lab, and bioassay. After virtual screening by D(3)DOCKxb against the database CMC (Comprehensive Medicinal Chemistry), 3 organohalogen drugs that were predicted to form strong halogen bonding with B-Raf V600E were purchased and tested with ELISA-based assay. In the end, 2 of them, rafoxanide and closantel, were identified as potent inhibitors with IC50 values of 0.07 µM and 1.90 µM, respectively, which are comparable to that of vemurafenib (IC50: 0.17 µM), a marketed drug targeting B-Raf V600E. Single point mutagenesis experiments confirmed the conformations predicted by D(3)DOCKxb. And comparison experiment revealed that halogen bonding scoring function is essential for repositioning those drugs with heavy halogen atoms in their molecular structures.


Assuntos
Reposicionamento de Medicamentos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Substituição de Aminoácidos , Avaliação Pré-Clínica de Medicamentos , Halogênios/química , Halogênios/farmacocinética , Halogênios/farmacologia , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Estrutura Molecular , Mutagênese Sítio-Dirigida , Compostos Orgânicos/química , Compostos Orgânicos/farmacocinética , Compostos Orgânicos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Rafoxanida/química , Rafoxanida/farmacocinética , Rafoxanida/farmacologia , Salicilanilidas/química , Salicilanilidas/farmacocinética , Salicilanilidas/farmacologia , Interface Usuário-Computador
12.
Int J Biol Macromol ; 92: 293-298, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27394648

RESUMO

In this study, a group of novel water soluble chitosan ammonium salts with halogens were successfully synthesized, including chitosan-bromoacetate (CSB), chitosan-chloroacetate (CSC), chitosan-dichloroacetate (CSDC), chitosan-trichloroacetate (CSTC), and chitosan-trifluoroacetate (CSTF), and their antifungal activities against three kinds of phytopathogens were comparatively estimated by hypha measurement in vitro, respectively. The fungicidal assessment revealed that the synthesized chitosan derivatives had higher antifungal activity than chitosan. Especially, the inhibitory indices of CSTC and CSTF against three kinds of phytopathogens were higher than 70% at 1.0mg/mL. Generally, the antifungal activity decreased in the order: CSTF>CSTC>CSDC>CSC>CSB>chitosan. Apparently, the order of antifungal activity was consistent with the electronegativity of different substituted groups with halogens. The substituted groups with stronger electronegativity could augment the positive charge densities of cationic amino groups by drawing more electrons from the cationic amino groups of chitosan ammonium salts, which demonstrated that the protonation of amino groups was significant for the antifungal activity of chitosan derivatives.


Assuntos
Compostos de Amônio/síntese química , Compostos de Amônio/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Quitosana/síntese química , Quitosana/farmacologia , Halogênios/farmacologia , Sais/farmacologia , Compostos de Amônio/química , Antifúngicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Quitosana/química , Fusarium/efeitos dos fármacos , Halogênios/química , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Sais/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química
13.
J Biotechnol ; 227: 56-63, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-27059481

RESUMO

An efficient method was introduced for soluble expression of recombinant laccase (rpCotA(SL-1)) from a newly isolated halo-thermotolerant Bacillus sp. SL-1 in modified Escherichia coli, trxB2/gor2 mutant (Origami™ B (DE3)). The yield of purified soluble laccase in Origami strain under micro-aerobic condition was ∼20mg/L of bacterial culture, showing significant improvement over the laccase produced in E.coli BL21 strain under aerobic condition. The specific activity of 13U/mg for purified laccase produced in micro-aerobic condition was higher than that of 1.07U/mg observed for the purified enzyme obtained in aerobic condition in Origami. The kinetic Km and kcat parameters for laccase-induced oxidation reactions were 46µM and 23s(-1) for ABTS (2,2'-Azino-bis(3-ethylbenzthiazoline-6-sulphonic acid), and 19.6µM and 24s(-1) for SGZ (syringaldazine) substrates, respectively. The rpCotA(SL-1) displayed thermostability at 70°C and tolerance to specified concentrations of NaCl, NaN3, EDTA and SDS as inhibitors. The enzyme was relatively stable in the presence of different concentration of organic solvents, however the residual activity was adversely affected as the dipole moment of the solvents increase. Here we successfully report the production of soluble and functional laccase in Origami at the expression level suitable for industrial application.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Bacillus/enzimologia , Escherichia coli/genética , Halogênios/farmacologia , Lacase/genética , Temperatura , Sequência de Bases , Western Blotting , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos/farmacologia , Estabilidade Enzimática/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Cinética , Lacase/isolamento & purificação , Lacase/metabolismo , Proteínas Recombinantes/isolamento & purificação , Solubilidade , Solventes , Espectrofotometria Ultravioleta
14.
Mater Sci Eng C Mater Biol Appl ; 58: 396-408, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26478326

RESUMO

Antimony(III) halide complexes of the formulae {[SbBr(Me2DTC)2]n} (1), {[SbI(Me2DTC)2]n} (2) and {[(Me2DTC)2Sb(µ2-I)Sb(Me2DTC)2](+).I3(-)} (3) (Me2DTC = dimethyldithiocarbomate) were synthesized from SbX3, (X = Br or I) and tetramethylthiuram monosulfide (Me4tms) or tetramethylthiuram disulfide (Me4tds). The complexes were characterized by melting point (m.p.), elemental analysis (e.a.), Fourier-transform Infra-Red (FT-IR), Fourier-transform Raman (FT-Raman), Nuclear Magnetic Resonance ((1)H,(13)C-NMR) spectroscopy and Thermogravimetric-Differential Thermal Analysis (TG-DTA). Crystal structures of complexes 1-3 were determined with single crystal X-ray diffraction analysis. Complexes 1 and 2 are polymers with distorted square pyramidal (SP) geometry in each monomeric unit, whereas complex 3 is ionic, containing an iodonium linkage Sb-I(+)-Sb and an I3(-) counter anion; to the best of our knowledge, this is the first ionic antimony(III) iodide complex. The in vitro cytotoxic activity of 1-3 against human adenocarcinoma cells: breast (MCF-7) and cervix (HeLa) cells and non-cancerous cells: MRC-5 (normal human fetal lung fibroblast cells) was evaluated with trypan blue (TB) and sulforhodamine B (SRB) assays. Among antimony(III) compounds with sulfur containing ligand, those of dithiocarbamates exhibit significant cytotoxic activity. Hirshfeld surface volumes were analyzed to clarify the nature of the intermolecular interactions by the 2D fingerprint plot. Molecules with lower H-all atoms inter-molecular interactions exhibit the higher activity against MCF-7 cells. The in vivo genotoxicity of 1-3 was evaluated by the mean of Allium cepa test. Alterations in the mitotic index values due to the chromosomal aberrations were observed in the case of complexes 2 and 3. Since, no such alteration is caused by 1, it makes this compound candidate for further study as potential drug.


Assuntos
Antimônio/farmacologia , Ditiocarb/farmacologia , Halogênios/farmacologia , Tiram/química , Allium/citologia , Allium/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Aberrações Cromossômicas , Cristalografia por Raios X , Ditiocarb/síntese química , Ditiocarb/química , Células HeLa , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Ligantes , Células MCF-7 , Espectroscopia de Ressonância Magnética , Conformação Molecular , Mutagênicos/toxicidade , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Temperatura , Tiram/síntese química , Tiram/toxicidade , Vibração
15.
Bioresour Technol ; 201: 253-60, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26684174

RESUMO

A halophilic mangrove isolate identified by 16S rRNA sequence as a Bacillus spp. was found to be capable of using a broad range of carbon sources including monosaccharides (glucose and fructose), disaccharides (sucrose), pentoses (xylose and arabinose), various organic acids (acetic acid, propionic acid and octanoic acid) and even the acid pre-treated liquor (APL) of sugarcane trash, a lignocellulosic biomass, for growth and the production of polyhydroxyalkanoates (PHAs) such as poly(3-hydroxybutyrate, P3HB), poly(3-hydroxybutyrate-co-3-hydroxyvalerate, PHBV), and 4-hydroxyhexanoate, 4HHX). The study describes the innate ability of a wild-type culture for PHBV production by both propionate dependent and propionate independent pathways. The biopolymer was extracted and characterized physico-chemically. The PHBV yield from glucose was estimated to be 73% of biomass weight with a high 3-hydroxyvalerate fraction of 48mol%. Thereafter, spherical homogenous PHBV nanoparticles of ∼164nm size were prepared for future applications.


Assuntos
Bacillus/isolamento & purificação , Halogênios/farmacologia , Ácidos Pentanoicos/metabolismo , Poliésteres/metabolismo , Áreas Alagadas , Bacillus/efeitos dos fármacos , Bacillus/metabolismo , Biomassa , Varredura Diferencial de Calorimetria , Carbono/farmacologia , Nanopartículas/química , Filogenia , Propionatos/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , RNA Ribossômico 16S/genética , Saccharum/química , Espectroscopia de Infravermelho com Transformada de Fourier , Resíduos
16.
EBioMedicine ; 2(6): 544-53, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26351651

RESUMO

Based on a molecular-mechanism-based anticancer drug discovery program enabled by an innovative femtomedicine approach, we have found a previously unknown class of non-platinum-based halogenated molecules (called FMD compounds) as potent antitumor agents for effective treatment of cancers. Here, we present in vitro and in vivo studies of the compounds for targeted chemotherapy of cervical, breast, ovarian, and lung cancers. Our results show that these FMD agents led to DNA damage, cell cycle arrest in the S phase, and apoptosis in cancer cells. We also observed that such a FMD compound caused an increase of reduced glutathione (GSH, an endogenous antioxidant) levels in human normal cells, while it largely depleted GSH in cancer cells. We correspondingly found that these FMD agents exhibited no or little toxicity toward normal cells/tissues, while causing significant cytotoxicity against cancer cells, as well as suppression and delay in tumor growth in mouse xenograft models of cervical, ovarian, breast and lung cancers. These compounds are therefore a previously undiscovered class of potent antitumor agents that can be translated into clinical trials for natural targeted chemotherapy of multiple cancers.


Assuntos
Antineoplásicos/farmacologia , Halogênios/farmacologia , Neoplasias/tratamento farmacológico , Compostos de Platina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Descoberta de Drogas , Citometria de Fluxo , Glutationa/metabolismo , Humanos , Camundongos , Camundongos SCID , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Testes de Toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Environ Sci Technol ; 49(15): 9212-21, 2015 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-26154624

RESUMO

Bioremoval of H2S from gas streams became popular in recent years because of high process efficiency and low operational costs. To expand the scope of these processes to gas streams containing volatile organic sulfur compounds, like thiols, it is necessary to provide new insights into their impact on overall biodesulfurization process. Published data on the effect of thiols on biodesulfurization processes are scarce. In this study, we investigated the effect of methanethiol on the selectivity for sulfur production in a bioreactor integrated with a gas absorber. This is the first time that the inhibition of biological sulfur formation by methanethiol is investigated. In our reactor system, inhibition of sulfur production started to occur at a methanethiol loading rate of 0.3 mmol L(-1) d(-1). The experimental results were also described by a mathematical model that includes recent findings on the mode of biomass inhibition by methanethiol. We also found that the negative effect of methanethiol can be mitigated by lowering the salinity of the bioreactor medium. Furthermore, we developed a novel approach to measure the biological activity by sulfide measurements using UV-spectrophotometry. On the basis of this measurement method, it is possible to accurately estimate the unknown kinetic parameters in the mathematical model.


Assuntos
Álcalis/farmacologia , Bactérias/metabolismo , Halogênios/farmacologia , Compostos de Sulfidrila/farmacologia , Enxofre/metabolismo , Biomassa , Reatores Biológicos/microbiologia , Sulfeto de Hidrogênio/isolamento & purificação , Cinética , Modelos Teóricos , Oxirredução/efeitos dos fármacos , Oxigênio/análise , Reprodutibilidade dos Testes , Salinidade , Solubilidade , Compostos de Sulfidrila/isolamento & purificação , Sulfetos/análise
19.
Environ Sci Technol ; 49(11): 6554-63, 2015 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-25941832

RESUMO

A novel chemolithotrophic metabolism based on a mixed arsenic-sulfur species has been discovered for the anaerobic deltaproteobacterium, strain MLMS-1, a haloalkaliphile isolated from Mono Lake, California, U.S. Strain MLMS-1 is the first reported obligate arsenate-respiring chemoautotroph which grows by coupling arsenate reduction to arsenite with the oxidation of sulfide to sulfate. In that pathway the formation of a mixed arsenic-sulfur species was reported. That species was assumed to be monothioarsenite ([H2As(III)S(-II)O2](-)), formed as an intermediate by abiotic reaction of arsenite with sulfide. We now report that this species is monothioarsenate ([HAs(V)S(-II)O3](2-)) as revealed by X-ray absorption spectroscopy. Monothioarsenate forms by abiotic reaction of arsenite with zerovalent sulfur. Monothioarsenate is kinetically stable under a wide range of pH and redox conditions. However, it was metabolized rapidly by strain MLMS-1 when incubated with arsenate. Incubations using monothioarsenate confirmed that strain MLMS-1 was able to grow (µ = 0.017 h(-1)) on this substrate via a disproportionation reaction by oxidizing the thio-group-sulfur (S(-II)) to zerovalent sulfur or sulfate while concurrently reducing the central arsenic atom (As(V)) to arsenite. Monothioarsenate disproportionation could be widespread in nature beyond the already studied arsenic and sulfide rich hot springs and soda lakes where it was discovered.


Assuntos
Álcalis/farmacologia , Arseniatos/farmacologia , Crescimento Quimioautotrófico , Deltaproteobacteria/crescimento & desenvolvimento , Halogênios/farmacologia , Anaerobiose/efeitos dos fármacos , Arsênico/isolamento & purificação , Arsenitos/farmacologia , Biotransformação/efeitos dos fármacos , Crescimento Quimioautotrófico/efeitos dos fármacos , Deltaproteobacteria/efeitos dos fármacos , Deltaproteobacteria/metabolismo , Oxirredução , Soluções , Espectrofotometria Atômica , Sulfetos/farmacologia , Enxofre/metabolismo , Espectroscopia por Absorção de Raios X
20.
Ann Clin Microbiol Antimicrob ; 14: 16, 2015 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-25857255

RESUMO

Brucellosis is a zoonosis that disseminated by a variety of ways between animals and humans. The effective disinfection of contaminated environments, soil, feces, and animal bodies plays an irreplaceable role in the prevention and control of brucellosis. To kill Brucella effectively, the bactericidal effects of frequently used disinfectants (including aldehydes, halogens, quaternary ammonium compound, phenolics, and alkalines) and the potential factors that influence disinfection effects were determined in the present study. The results revealed that the minimum bactericidal concentrations (MBCs) of the six disinfectants were all significantly lower than the routinely used concentrations, and all the tested disinfectants were effective against B. melitensis NI. The results of quantitative determination showed that the bactericidal effects of the disinfectants were influenced by their concentration, exposure time, dirty condition and the temperature. Under dirty conditions and a low temperatures, sodium hypochlorite and sodium hydroxide showed better bactericidal effect, while benzalkonium chloride was almost without bactericidal ability. In addition, increasing the disinfectant concentration at low temperatures can improve the bactericidal effect. The present study suggested that Brucella is sensitive to commonly used disinfectants. However, the bactericidal effect is vulnerable to dirty conditions and low temperatures. Thus, it is necessary to test the in vitro sensitivity of disinfectants that are commonly used on farms or the new disinfectant formulations periodically, with the aim of improving the efficacy of animal and human brucellosis prevention programs.


Assuntos
Brucella melitensis/efeitos dos fármacos , Desinfetantes/farmacologia , Desinfecção/métodos , Aldeídos/farmacologia , Álcalis/farmacologia , Brucella melitensis/crescimento & desenvolvimento , Brucelose/microbiologia , Avaliação de Medicamentos , Halogênios/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Fenol/farmacologia , Compostos de Amônio Quaternário/farmacologia
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