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1.
Int J Mol Sci ; 25(9)2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38732012

RESUMO

Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology, and the identification of novel potential therapeutic targets and agents is an urgent clinical need. The RNA-binding protein LIN28B has been identified as an oncogene in NB and is associated with a poor prognosis. Given that LIN28B acts by negatively regulating the biogenesis of the tumor suppressor let-7 miRNAs, we reasoned that selective interference with the LIN28B/let-7 miRNA interaction would increase let-7 miRNA levels, ultimately leading to reduced NB aggressiveness. Here, we selected (-)-epigallocatechin 3-gallate (EGCG) out of 4959 molecules screened as the molecule with the best inhibitory activity on LIN28B/let-7 miRNA interaction and showed that treatment with PLC/PLGA-PEG nanoparticles containing EGCG (EGCG-NPs) led to an increase in mature let-7 miRNAs and a consequent inhibition of NB cell growth. In addition, EGCG-NP pretreatment reduced the tumorigenic potential of NB cells in vivo. These experiments suggest that the LIN28B/let-7 miRNA axis is a good therapeutic target in NB and that EGCG, which can interfere with this interaction, deserves further preclinical evaluation.


Assuntos
Catequina , MicroRNAs , Neuroblastoma , Proteínas de Ligação a RNA , Catequina/análogos & derivados , Catequina/farmacologia , Neuroblastoma/genética , Neuroblastoma/patologia , Neuroblastoma/metabolismo , Neuroblastoma/tratamento farmacológico , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Animais , Camundongos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus
2.
J Basic Microbiol ; 64(1): 50-67, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37721354

RESUMO

Saharan soil samples collected in El-Oued province have been investigated for actinobacteria as a valuable source for the production of bioactive metabolites. A total of 273 isolates were obtained and subjected to antagonistic activity tests against human pathogenic germs. A strain with a broad-spectrum antimicrobial activity was selected and identified as Nocardiopsis dassonvillei GSBS4, with high sequence similarities to N. dassonvillei subsp. dassonvilleiT X97886.1 (99%) based on polyphasic taxonomy approach and 16S ribosomal ribonucleic acid gene sequence analysis. The GSBS4 ethyl acetate crude extract showed strong antibacterial activity towards pathogenic bacteria and Candida albicans. It inhibited biofilm formation by Staphylococcus aureus and methicillin-resistant S. aureus with minimum inhibitory concentrations estimated at 0.144 and 1.15 mg·mL-1 , respectively. A 44% biofilm reduction was obtained for S. aureus and 61% for Pseudomonas aeruginosa. Furthermore, phenols composition of the crude extract showed a significant dose-dependent antioxidant activity by α-diphenyl-ß-picrylhydrazyl (57.21%) and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (64.29%) radicals scavenging assays. Although no inhibition was obtained on human coronavirus human coronavirus (HCoV) 229E and on model enterovirus (poliovirus 1) infection, a dose-dependent increase in cell viability of HCoV 229E-infected cells was noticed as the viability increased from 21% to 37%. Bioassay-guided fractionation of the crude extract gave a fraction showing antibacterial activity, which was analyzed by liquid chromatography-electrospray mass spectrometric technique, providing structural features on a major purple metabolite.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Nocardia , Humanos , Staphylococcus aureus , Solo , Bioprospecção , Antibacterianos/farmacologia , Antibacterianos/química , Bactérias , Testes de Sensibilidade Microbiana , Nocardiopsis
3.
Mar Drugs ; 21(10)2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37888446

RESUMO

The adamantane structure of arsenicin A and nor-adamantane structures of arsenicins B-D have gained attention as unique natural polyarsenicals, as well as hits showing promising anticancer activity. The purpose of this study is to apply the predictive power of NMR DFT calculations in order to identify a valid tool to be used in the structural elucidation of similar molecules. 1H- and 13C-NMR chemical shifts of twelve natural and synthetic polyarsenical analogs were calculated and validated by comparison with experimental data acquired in CDCl3 solutions, in regard to mean absolute error (MAE) values under various combinations of two methods (GIAO and CSGT), four functionals and five basis sets, also considering relativistic effects. The best computational approaches are highlighted for predicting the chemical shifts of 1H and 13C nuclei and J(1H,1H) coupling constants in the series of O- and S-polyarsenicals. This comprehensive analysis contributes to making NMR spectroscopy appealing for the structural elucidation of such molecules, contrary to the first structural elucidation of natural arsenicin A, in which the experimental NMR analysis was limited by the poor presence of proton and carbon atoms in its structure and by the shortage of reference data.


Assuntos
Adamantano , Arsenicais , Poríferos , Animais , Espectroscopia de Ressonância Magnética , Prótons
4.
Mar Drugs ; 21(3)2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36976235

RESUMO

The marine polyarsenical metabolite arsenicin A is the landmark of a series of natural and synthetic molecules characterized by an adamantane-like tetraarsenic cage. Arsenicin A and related polyarsenicals have been evaluated for their antitumor effects in vitro and have been proven more potent than the FDA-approved arsenic trioxide. In this context, we have expanded the chemical space of polyarsenicals related to arsenicin A by synthesizing dialkyl and dimethyl thio-analogs, the latter characterized with the support of simulated NMR spectra. In addition, the new natural arsenicin D, the scarcity of which in the Echinochalina bargibanti extract had previously limited its full structural characterization, has been identified by synthesis. The dialkyl analogs, which present the adamantane-like arsenicin A cage substituted with either two methyl, ethyl, or propyl chains, were efficiently and selectively produced and evaluated for their activity on glioblastoma stem cells (GSCs), a promising therapeutic target in glioblastoma treatment. These compounds inhibited the growth of nine GSC lines more potently than arsenic trioxide, with GI50 values in the submicromolar range, both under normoxic and hypoxic conditions, and presented high selectivity toward non-tumor cell lines. The diethyl and dipropyl analogs, which present favorable physical-chemical and ADME parameters, had the most promising results.


Assuntos
Adamantano , Neoplasias Encefálicas , Glioblastoma , Humanos , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Células-Tronco , Adamantano/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico
5.
Molecules ; 27(15)2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35956896

RESUMO

In recent decades, molecular hybridization has proven to be an efficient tool for obtaining new synthetic molecules to treat different diseases. Based on the core idea of covalently combining at least two pharmacophore fragments present in different drugs and/or bioactive molecules, the new hybrids have shown advantages when compared with the compounds of origin. Hybridization could be successfully applied to anticancer drug discovery, where efforts are underway to develop novel therapeutics which are safer and more effective than those currently in use. Molecules presenting naphthoquinone moieties are involved in redox processes and in other molecular mechanisms affecting cancer cells. Naphthoquinones have been shown to inhibit cancer cell growth and are considered privileged structures and useful templates in the design of hybrids. The present work aims at summarizing the current knowledge on antitumor hybrids built using 1,4- and 1,2-naphthoquinone (present in natural compounds as lawsone, napabucasin, plumbagin, lapachol, α-lapachone, and ß -lapachone), and the related quinolone- and isoquinolinedione scaffolds reported in the literature up to 2021. In detail, the design and synthetic approaches adopted to produce the reported compounds are highlighted, the structural fragments considered in hybridization and their biological activities are described, and the structure-activity relationships and the computational analyses applied are underlined.


Assuntos
Antineoplásicos , Naftoquinonas , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Naftoquinonas/química , Naftoquinonas/farmacologia , Relação Estrutura-Atividade
6.
Int J Mol Sci ; 23(1)2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-35008944

RESUMO

(1R,5S)-1-Hydroxy-3,6-dioxa-bicyclo[3.2.1]octan-2-one, available by an efficient catalytic pyrolysis of cellulose, has been applied as a chiral building block in the synthesis of seven new nucleoside analogues, with structural modifications on the nucleobase moiety and on the carboxyl- derived unit. The inverted configuration by Mitsunobu reaction used in their synthesis was verified by 2D-NOESY correlations, supported by the optimized structure employing the DFT methods. An in silico screening of these compounds as inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase has been carried out in comparison with both remdesivir, a mono-phosphoramidate prodrug recently approved for COVID-19 treatment, and its ribonucleoside metabolite GS-441524. Drug-likeness prediction and data by docking calculation indicated compound 6 [=(3S,5S)-methyl 5-(hydroxymethyl)-3-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)tetrahydrofuran-3-carboxylate] as the best candidate. Furthermore, molecular dynamics simulation showed a stable interaction of structure 6 in RNA-dependent RNA polymerase (RdRp) complex and a lower average atomic fluctuation than GS-441524, suggesting a well accommodation in the RdRp binding pocket.


Assuntos
Antivirais/síntese química , Celulose/química , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , Nucleosídeos/síntese química , SARS-CoV-2/enzimologia , Adenosina/análogos & derivados , Adenosina/química , Adenosina/farmacocinética , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacocinética , Alanina/análogos & derivados , Alanina/química , Alanina/farmacocinética , Antivirais/química , Antivirais/farmacocinética , Biologia Computacional , RNA-Polimerase RNA-Dependente de Coronavírus/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nucleosídeos/química , Nucleosídeos/farmacocinética , Pirólise , SARS-CoV-2/efeitos dos fármacos
7.
Antioxidants (Basel) ; 10(4)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924005

RESUMO

Asphodelus tenuifolius Cav. (A. tenuifolius) is a medicinal plant with a long history of traditional use to treat ailments. In this study, total phenolic and flavonoid content evaluation using LC-ESI/MS analysis and various biological activities (antioxidant, antibacterial, antifungal, antiviral and cytotoxicity) of organic extracts from the aerial parts of A. tenuifolius were analyzed. ADME tools were used to predict the potential of the identified compounds from the most potent extract as specific drugs. As shown, LC-ESI/MS results of chloroformic extract allowed the tentative identification of 12 compounds. Chloroformic extract was rich in polyphenols and flavonoids and exhibited the highest antioxidant activity given by DPPH (IC50 = 25 µg/mL) as compared to the BHT standard (11.5 µg/mL) and ß-carotene bleaching assays (IC50 = 95.692 µg/mL). Antibacterial activity results showed that chloroformic extract has a highest activity against Gram-positive and -negative bacteria, especially against Salmonella Typhimurium DT104 (IZ = 19.3 mm, MIC = 18.75 mg/mL, MBC = 37.5 mg/mL). The MBC/MIC ratio was evaluated to interpret the activity that was bacteriostatic rather than bactericidal. Conversely, weaker antifungal activity was registered, and no antiviral activity was observed for all extracts against Herpes Simplex Virus type 2 and Coxsakievirus B-3 viruses. Cytotoxic activity on VERO cell line results revealed that butanol extract was not toxic, with CC50 value of 1430 µg/mL, while chloroformic extract showed moderate cytotoxicity. Additionally, in silico studies performed proved promising pharmacokinetic and drug-likeness properties of the main compounds from the chloroformic extract. Taken together, this work highlights the potent bioactivity and acceptable drug-likeness of this plant, which supports its further preclinical development.

8.
Antibiotics (Basel) ; 8(4)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581466

RESUMO

Actinobacteria, in particular "rare actinobacteria" isolated from extreme ecosystems, remain the most inexhaustible source of novel antimicrobials, offering a chance to discover new bioactive metabolites. This is the first overview on actinobacteria isolated in Algeria since 2002 to date with the aim to present their potential in producing bioactive secondary metabolites. Twenty-nine new species and one novel genus have been isolated, mainly from the Saharan soil and palm groves, where 37.93% of the most abundant genera belong to Saccharothrix and Actinopolyspora. Several of these strains were found to produce antibiotics and antifungal metabolites, including 17 new molecules among the 50 structures reported, and some of these antibacterial metabolites have shown interesting antitumor activities. A series of approaches used to enhance the production of bioactive compounds is also presented as the manipulation of culture media by both classical methods and modeling designs through statistical strategies and the associations with diverse organisms and strains. Focusing on the Algerian natural sources of antimicrobial metabolites, this work is a representative example of the potential of a closely combined study on biology and chemistry of natural products.

9.
Molecules ; 24(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197105

RESUMO

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI50 than the ROCK inhibitor Y-27632, the Topo II inhibitor podophyllotoxin and the tubulin inhibitor combretastatin A-4. The relative position of N,N heteroatoms in the structures of the tested compounds was crucial in affecting bioactivity and selectivity. Furthermore, compound 3 (2-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(3,4,5-trimethoxyphenoxy)naphthalene-1,4-dione) emerged as the most active in the series, showing a potent and selective inhibition of breast cancer BT-549 cells (GI50 < 10 nM).


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase II/farmacologia , Moduladores de Tubulina/farmacologia , Amidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/genética , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Neoplasias/genética , Podofilotoxina/farmacologia , Piridinas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Estilbenos/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Tubulina (Proteína)/química , Tubulina (Proteína)/genética , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/química , Quinases Associadas a rho/genética
10.
Heliyon ; 5(5): e01695, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31193702

RESUMO

The novel bioactive actinobacterial strain GSBNT10 obtained from a Saharan soil, was taxonomically characterized using a polyphasic approach. 16S rRNA gene sequence analysis supported the classification of the isolate within the genus Streptomyces indicating it as a novel species. The major metabolite responsible of the bioactivity was purified and structurally characterized as actinomycin D (act-D) by mass spectrometric and nuclear magnetic resonance analyses Plackett-Burman design (PBD) and response surface methodology (RSM) were applied in order to optimize the medium formulation for the production of this bioactive metabolite. By PBD experiments, NaNO3, K2HPO4 and initial pH value were selected as significant variables affecting the metabolite production. Central Composite Design (CCD) showed that adjustment of the fermentative medium at pH 8.25, K2HPO4 at 0.2 gL-1 and NaNO3 at 3.76 gL-1 were the values suiting the production of act-D. Moreover, the results obtained by the statistical approach were confirmed by act-D detection using the HPLC equipped with a diode array detector and coupled online with electrospray-mass spectrometry (ESIMS) technique. act-D production was highly stimulated, obtaining a good yield (656.46 mgL-1) which corresponds to a 58.56% increase compared with the non-optimized conditions and data from LC-ESIMS technique efficiently confirmed the forecast from RSM.

11.
Nat Prod Res ; 33(2): 266-273, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29513090

RESUMO

The present work describes the metabolites produced by a strain identified as Streptomyces youssoufiensis, whose secondary metabolites profile has not been studied so far. The crude ethyl acetate extract was analyzed by high performance liquid chromatography-electrospray ionization mass spectrometry, leading to the detection of the ionophoric polyethers nigericin, epinigericin, abierixin and the newly isolated grisorixin methyl ester. The presence of epimeric forms of nigericin/epinigericin and grisorixin/epigrisorixin has spurred density functional theory computational calculations. This analysis was able to provide the relative stability of the most favored epimers, setting the basis for general structural considerations applicable to several other polyethers. Both nigericin sodium salt and grisorixin methyl ester showed to affect glioblastoma stem cells proliferation in a dose-dependent manner, with a higher activity for the more lipophilic grisorixin methyl ester (GI50 values of 3.85 and 3.05 µM for VIPI and COMI human glioblastoma stem cells, respectively).


Assuntos
Nigericina/análogos & derivados , Nigericina/isolamento & purificação , Nigericina/metabolismo , Streptomyces/química , Antibacterianos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Teoria da Densidade Funcional , Glioblastoma/patologia , Humanos , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Células-Tronco/patologia , Estereoisomerismo , Células Tumorais Cultivadas
12.
Molecules ; 23(8)2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30103421

RESUMO

Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1⁻3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1⁻3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Purinas/síntese química , Purinas/farmacologia , Antineoplásicos/química , Neoplasias da Mama , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Neoplasias Colorretais , Feminino , Humanos , Masculino , Micro-Ondas , Estrutura Molecular , Purinas/química , Relação Estrutura-Atividade
13.
Sci Rep ; 7(1): 11548, 2017 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28912556

RESUMO

In the light of the promising bioactivity of the tetraarsenic marine metabolite arsenicin A, the dimethyl analogue 2 and four isomeric methylene homologues (including the natural product itself) were obtained using a one-pot microwave-assisted synthesis, starting from arsenic (III) oxide. Due to the poor diagnostic value of the NMR technique in the structural elucidation of these molecules, they were fully characterized by mass spectrometry and infrared (IR)-spectroscopy, comparing density functional theory (DFT) simulated and experimental spectra. This synthetic procedure provided a fast and efficient access to the cytotoxicity evaluation of organoarsenical leads of the natural hit molecule. From in vitro screening, each tested compound resulted in being more active than the FDA-approved arsenic trioxide, with the most lipophilic molecule in the series showing the best growth inhibition of both leukemia and solid tumor cell lines. These results may open promising perspectives in the development of new more potent and selective arsenical drugs against solid tumors.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Arsenicais/síntese química , Arsenicais/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Espectrometria de Massas , Estrutura Molecular , Espectrofotometria Infravermelho
14.
Arch Pharm (Weinheim) ; 348(1): 23-33, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25523431

RESUMO

In search for more effective drugs against HIV infection acting as non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of new molecules with hybrid structures based on the natural product (+)-calanolide A and the synthetic molecule α-APA, known as potent and selective inhibitors of this enzyme, were selected by docking calculations. A convergent synthetic strategy gave 21 compounds with a 2H-pyran-2-one structural unit and bearing isosteric modifications, which were tested against HIV-infected CEM cell cultures. Only compound 6 (4-((2-(1H-indol-3-yl)ethyl)amino)-6-methyl-2H-pyran-2-one) displayed inhibitory activity (EC50 : 25-50 µM). However, it was associated with a relatively high cytostatic effect on human T lymphocyte (CEM) cell cultures, not easily predictable, neither by the chemical structure nor by the computational approach. Although this drug design has failed in selecting a novel scaffold for NNRTIs, the results have driven the interest towards new potential antitumor molecules showing activity against L1210 murine leukemia and HeLa cervix carcinoma cells, among which compound 21 (6-methyl-4-((2-(naphthalen-1-yl)ethyl)sulfonyl)-2H-pyran-2-one) was the most effective (IC50 : 0.95 and 2.9 µM, respectively).


Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Piranos/síntese química , Piranos/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Células HeLa , Humanos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Transfecção
15.
Prog Mol Subcell Biol ; 54: 175-95, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24420714

RESUMO

An overview of the biological activities of arsenic compounds containing more than one arsenic atom in their molecular structure is presented. This contribution covers the literature of the last 10-12 years concerning the in vitro and in vivo studies on arsenic species. They include inorganic oxides and sulfides, already employed for a long time in traditional Chinese medicine and currently investigated against hematological or solid malignancies, with arsenic trioxide clinically used in the treatment of acute promyelocytic leukemia. Chemical and biological aspects on the marine product arsenicin A, representing the first and only organic polyarsenical isolated from Nature, have also been reviewed, pointing out the characterization of its C3H6As4O3 molecular structure by experimental and theoretical vibrational spectroscopies, the potent antimicrobial activities, and the promising perspectives as an antitumor agent.


Assuntos
Arsênio/química , Arsenicais/química , Neoplasias/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Arsênio/uso terapêutico , Arsenicais/uso terapêutico , Humanos , Medicina Tradicional Chinesa , Estrutura Molecular , Óxidos/química , Sulfetos/química
16.
Rapid Commun Mass Spectrom ; 25(4): 526-32, 2011 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-21259361

RESUMO

Resveratrol is a polyphenolic compound found in plants and human foods which has shown biological activities including chemoprevention, acting through a mechanism which involves the reduction of Cu(II) species. By electrospray ionization (ESI) mass spectrometry we have produced and detected the resveratrol-copper complexes [Resv+Cu](+), [Resv+Cu+H(2)O](+) and [2Resv+Cu](+) by using a resveratrol/CuSO(4) solution in CH(3)CN/H(2)O. The most stable structures of the detected complexes have been calculated at the B3LYP/6-311G(d) level of theory. Resveratrol interacts with the copper ion through nucleophilic carbon atoms on the aromatic ring and the alkenyl group. The fact that only singly charged ions were observed implies that Cu(II) is reduced to Cu(I) in the ESI process. For investigating the structure-reactivity correlation, we have carried out a similar study on the synthetic analogue dihydroresveratrol (DHResv). For the latter only the [DHResv+Cu](+) complex has been detected.


Assuntos
Cobre/química , Modelos Químicos , Espectrometria de Massas por Ionização por Electrospray/métodos , Estilbenos/química , Sulfato de Cobre , Resveratrol , Termodinâmica
17.
Arch Pharm (Weinheim) ; 342(2): 80-6, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19173337

RESUMO

Our previous investigation on potential antitumor agents now got enriched by the evaluation of in-vitro activity against a full panel of NCI cancer cell lines for five new compounds. The concurrent presence in the molecular structure of a nitrogen atom in the aromatic system and a N,N-dimethylaminoethyl amide chain play a decisive role to enhance cytotoxicity. The N,N-anti compound 14 shows a higher activity than its N,N-syn isomer, exhibiting the best selective inhibition against the melanoma MALME-3M cell line, with a GI(50)-value (= 30 nM) corresponding to a 330-fold increase in activity compared to the corresponding deaza-analogue. Compound 14 is efficiently synthesized by aminolysis of the ester obtained as a single regio-isomer by an one-pot three-component procedure involving metal-assisted cyclization under microwave irradiation conditions.


Assuntos
Antineoplásicos/síntese química , Compostos Aza/síntese química , Indolizidinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indolizidinas/química , Indolizidinas/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
18.
Arch Pharm (Weinheim) ; 340(3): 147-53, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17315260

RESUMO

Novel 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxamide derivatives and the corresponding 7,10-dihydroxy analogues were designed in accordance with Moore's and Pindur's theory and synthesized based on the structural similarity with known antitumour agents such as ellipticine, daunorubicin, mitoxantrone and 9-aminoacridine-4 carboxamide derivatives. These compounds, including structural variations of the amide side chain, were evaluated in the NCI panel of human tumour cell lines, from which 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-(2-dimethylamino-ethyl)-12-carboxamide 11a was found to be the most potent agent within the series. It showed good selectivity towards leukaemia, colon and renal cancer cell lines, with significant GI50 values, from lower than 10 nM to 0.2 microM. Moreover, its cytotoxicity against the adriamicine-resistant breast tumour cell line at a concentration lower than 1 microM turned out to be higher than the values using the clinical anticancer agents, daunorubicin and mitoxantrone.


Assuntos
Antineoplásicos/síntese química , Indolizinas/síntese química , Substâncias Intercalantes/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Indolizinas/farmacologia , Concentração Inibidora 50 , Substâncias Intercalantes/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
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