RESUMO
The reactivity of eight purified depsides obtained from six european lichens and that display as 2-oxoalkyl chain in ortho-position of the ester bond was explored. These depsides were found to lead to 1H-Isochromen-1-ones, which exhibit a distinctive blue fluorescence at 365 nm, in the presence of a 10% aqueous solution of KOH. A mechanistic explanation, involving the formation of an enolate intermediate and intramolecular transesterification, was proposed and validated by DFT. By exploiting this fluorescent phenomenon, we conceived a chemical probe (the KUV probe) that is useful for lichen determination, as exemplified on a selection of European Porpidia species.
Assuntos
Ascomicetos , Líquens , Depsídeos/química , Líquens/químicaRESUMO
Strains of enterobacteria that cause urinary tract infections are able to grow in urine with high tonicity. In such conditions bacterias adapt to osmotic forces by incorporation of osmoprotectant compounds including glycine betaine. Accumulation of toxic analogues in bacteria, using inducible betaine transporters, has been previously proposed for development of antibiotics. In this study we report antibacterial effect of two analogues against 82 strains of Escherichia coli isolated form urinary tract infections. Minimal inhibitory concentrations have been measured with and without osmotic stress. The betaine analogues have antibacterial effect against E. coli strains, but only in presence of an osmotic stress.
Assuntos
Antibacterianos/farmacologia , Betaína/análogos & derivados , Betaína/farmacologia , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estresse MecânicoRESUMO
Using solid phase synthesis techniques, we have rapidly obtained a series of eight aryl sulphonamides derived from putrescine. These conjugates with various aryl groups were evaluated for their affinity towards 5-HT6 receptors in man. This evaluation revealed the interest of two compounds which present the same activity level, in the submicromolar range, as two reference derivatives. The most potent will be considered as a new lead for further investigations.
Assuntos
Receptores de Serotonina/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Humanos , Ligantes , Dietilamida do Ácido Lisérgico/metabolismo , Putrescina/análogos & derivados , Putrescina/síntese química , Antagonistas da Serotonina/metabolismoRESUMO
Seven analogues of the bacterial osmoprotectant glycine betaine (GB, trimethylammonioacetate), in which the methyl groups of the Me3N+ moiety are replaced by various substituents, were obtained by SPOS using Wang resin. Their biological activities (osmoprotection vs toxicity), appeared closely related to their uptake efficiency and their catabolism in the betaine-demethylating model bacterium Sinorhizobium meliloti.
Assuntos
Betaína/análogos & derivados , Betaína/farmacologia , Química Orgânica/métodos , Pressão Osmótica/efeitos dos fármacos , Sinorhizobium meliloti/efeitos dos fármacos , Betaína/síntese química , Divisão Celular , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Sinorhizobium meliloti/fisiologia , Succímero/farmacocinética , Succímero/farmacologiaRESUMO
N1-Dansylspermine and related sulfonamides of the natural polyamines are very potent blockers of NMDA-type glutamate receptors. They exhibit pharmacological properties which were not predicted from the constituents of the conjugates. Cytotoxicity and calmodulin antagonism of N1-dansylspermine were especially impressive. Calmodulin antagonism implies that N1-dansylspermine prevents induction of ornithine decarboxylase and inhibits its own active uptake via the polyamine transport system. Structure-activity considerations demonstrated that an aromatic character of the substituent is not required; amide bond formation with an aliphatic sulfonic acid is sufficient to transform spermine into a highly toxic calmodulin antagonist. Cytotoxicity and calmodulin antagonism are properties which are intrinsic to spermine, but they are observed only at very high concentrations. Amide bond formation at N1 with a lipophilic residue appears to 'amplify' these normally latent properties. The use of polyamine conjugates structurally related to the amides described in this work for targeting tumours may be marred by their calmodulin antagonism.
Assuntos
Amina Oxidase (contendo Cobre) , Antineoplásicos/farmacologia , Calmodulina/antagonistas & inibidores , Compostos de Dansil/farmacologia , Poliaminas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Espermina/análogos & derivados , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Transporte Biológico Ativo/efeitos dos fármacos , Calmodulina/metabolismo , Bovinos , Compostos de Dansil/química , Compostos de Dansil/metabolismo , Técnicas In Vitro , Leucemia L1210 , Camundongos , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Poliaminas/química , Poliaminas/metabolismo , Putrescina/metabolismo , Espermina/química , Espermina/metabolismo , Espermina/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologiaRESUMO
A series of N1-monosubstituted putrescine and spermine derivatives was synthesised using a solid phase methodology. We evaluated their cytotoxicity, calmodulin antagonism and polyamine uptake inhibition, pharmacological properties shared by some antitumoral agents.
Assuntos
Amina Oxidase (contendo Cobre) , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Putrescina/análogos & derivados , Espermina/análogos & derivados , Animais , Calmodulina/antagonistas & inibidores , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Desaminação , Leucemia L1210/metabolismo , Leucemia L1210/patologia , Modelos Químicos , Oxirredução , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Putrescina/farmacocinética , Espermina/farmacocinética , Células Tumorais CultivadasRESUMO
Tetracyclic amidines (tetrahydroquino[4.3-b][l]benzazepine: compound 11 and tetrahydrobenzo[k]naphthyridine: compound 12) bearing a putrescine moiety possess significant DNA-binding affinity. We report here that these compounds and their a and b isomers inhibit tumor cell growth and putrescine uptake in 3LL carcinoma cells in vitro. Moreover, compound 11 reduced by 50% the accumulation of putrescine in intestinal brush border membrane vesicles. In CHO-MG, a cell line deficient for the specific polyamine uptake system, the cytotoxicity of these compounds was significantly reduced compared to the CHO wild cell line. The IC50 for CHO-MG was significantly higher than for CHO, demonstrating that the polyamine transport system increased the efficacy of these compounds. The efficacy of compounds 11 and 12 might therefore be related to their ability to interact with DNA as well as their structural analogy with polyamines. Moreover, we clearly show that DFMO enhances the efficacy of these tetracyclic amidines in vivo. Potential mechanisms include: a) lower intracellular polyamine levels reduces polyamine DNA-stabilizing functions, increasing accessibility for DNA-binding drugs; b) DFMO enhances the polyamine uptake system in tumor cells, increasing the entry of tetracyclic amidines bearing a putrescine moiety as well as their accessibility to final DNA-binding sites. The fact that natural polyamine uptake is reduced by the same compounds constitutes an additive mechanism for antitumoral efficiency.