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1.
Chem Biol Drug Des ; 88(4): 519-33, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27198732

RESUMO

Synthesis, in vitro cytotoxic activity, and interaction with tubulin of oxidized, isomeric 1-(5-alkoxybenzo[d][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-ones and 1-(6-alkoxybenzo[d][1,3]oxathiol-5-yl)-3-phenylprop-2-en-1-ones are described. Most of the compounds demonstrated cytotoxic activity at submicromolar concentrations. It was found that oxidation of sulfur atom of the oxathiole-fused chalcones strongly influenced activity of the parent compounds, and that depending on relative position of the sulfur atom in the molecule, the activity was either increased or diminished. For isomers with sulfur atom para to the chalcone carbonyl group, oxidation led to increase in activity, while for isomers with sulfur atom meta to the carbonyl the activity dropped down. It was demonstrated that the compounds interact with tubulin at the colchicine binding site, and the interaction was evaluated using molecular modeling. It was concluded that the observed profound influence of oxidation of the sulfur atom on cytotoxic activity cannot be solely related to interaction of the compounds with tubulin.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Chalconas/síntese química , Chalconas/toxicidade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/toxicidade , Enxofre/química , Linhagem Celular Tumoral , Chalconas/química , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/toxicidade , Avaliação Pré-Clínica de Medicamentos , Células HeLa , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Oxirredução , Compostos de Sulfidrila/química
2.
Eur J Med Chem ; 89: 733-42, 2015 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-25462279

RESUMO

Synthesis, in vitro cytotoxic activity, and interaction with tubulin of (E)-1-(6-alkoxybenzo[d][1,3]oxathiol-5-yl)-3-phenylprop-2-en-1-one derivatives (2) are described. Some of the compounds demonstrated cytotoxic activity at submicromolar concentrations, and the activity could be related to interaction with tubulin at the colchicine binding site. Interaction of selected derivatives with tubulin was evaluated using molecular modeling, and two different modes of the interaction were identified. The proposed models demonstrate how particular structural fragments participate in binding to the tubulin and explain the importance of the fragments for cytotoxic activity. It was demonstrated that concerning binding to tubulin, the 6-alkoxybenzoxathiole ring can be considered as structural equivalent of trimethoxyphenyl motif of colchicine, podophyllotoxin or combretastatin A4. The observation opened new ways of rational modifications of several groups of tubulin binders.


Assuntos
Chalconas/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Tubulina (Proteína)/metabolismo , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Relação Dose-Resposta a Droga , Células HCT116 , Células HeLa , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tubulina (Proteína)/química
3.
Chem Biol Drug Des ; 84(1): 86-91, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24476543

RESUMO

Derivatives of (E)-1-(5-alkoxybenzo[d][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-one demonstrated exceptionally high in vitro cytotoxic activity, with IC50 values of the most active derivatives in the nanomolar range. To identify structural fragments necessary for the activity, several analogs deprived of selected fragments were prepared, and their cytotoxic activity was tested. It was found that the activity depends on combined effects of (i) the heterocyclic ring, (ii) the alkoxy group at position 5 of the benzoxathiole ring, and (iii) the substituents in the phenyl ring B. Replacement of the sulfur atom by oxygen does not influence the activity. None of the listed structural fragments alone assured high cytotoxic activity.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Linhagem Celular Tumoral , Chalconas/química , Chalconas/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade
4.
J Enzyme Inhib Med Chem ; 28(1): 41-51, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22145585

RESUMO

Few series of novel 4-chloro-2-mercaptobenzenesulfonamides have been synthesized by the reactions of N-(benzenesulfonyl)cyanamide potassium salts 7-15 with corresponding hydrazinecarbodithioic acid esters, 1-substituted carbothioic acid hydrazides, methyl 3-aminothiophene-2-carboxylate, methyl 2-aminobenzoate, 2-aminophenol or 2-aminothiophenol. The synthesized compounds (16-49) were screened in vitro for their antibacterial activity. Some of the tested compounds 16, 17, 23, 24, 31, 32 and 48 showed the promising activity against many of anaerobic Gram-positive bacteria strains.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Sulfonamidas/química , Aminofenóis/química , Compostos de Anilina/química , Antibacterianos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Ciclização , Ensaios de Seleção de Medicamentos Antitumorais , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
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