RESUMO
Based on classical colchicine site ligands and a computational model of the colchicine binding site on beta tubulin, two classes of chalcone derivatives were designed, synthesized and evaluated for inhibition of tubulin assembly and toxicity in human cancer cell lines. Docking studies suggested that the chalcone scaffold could fit the colchicine site on tubulin in an orientation similar to that of the natural product. In particular, a 3,4,5-trimethoxyphenyl ring adjacent to the carbonyl group appeared to benefit the ligand-tubulin interaction, occupying the same subcavity as the corresponding moiety in colchicine. Consistent with modeling predictions, several 3,4,5-trimethoxychalcones showed improved cytotoxicity to murine acute lymphoblastic leukemia cells compared with a previously described parent compound, and inhibited tubulin assembly in vitro as potently as colchicine. The most potent chalcones inhibited the growth of human leukemia cell lines at nanomolar concentrations, caused microtubule destabilization and mitotic arrest in human cervical cancer cells, and inhibited human breast cancer cell migration in scratch wound and Boyden chamber assays.
Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Chalconas/síntese química , Chalconas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chalconas/química , Relação Dose-Resposta a Droga , Humanos , Células Jurkat , Camundongos , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Células NIH 3T3 , Polimerização/efeitos dos fármacos , Tubulina (Proteína)/metabolismoRESUMO
The synthesis of several series of imidazo[2,1-a]isoindol-5-ol derivatives and the results of their evaluation against Plasmodium falciparum are presented and discussed. The effects of electron-withdrawing or-donating substituents on different parts of the molecule, as well as those produced by the incorporation of an additional fused ring, were analyzed. Several compounds showed significant antimalarial activity in vitro with IC(50) values as low as 60 nM and a certain efficacy in vivo by reducing parasitemia in Plasmodium berghei mouse models.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Isoindóis/química , Isoindóis/síntese química , Isoindóis/farmacologia , Animais , Antimaláricos/uso terapêutico , Antimaláricos/toxicidade , Benzeno/química , Linhagem Celular , Imidazóis/uso terapêutico , Imidazóis/toxicidade , Concentração Inibidora 50 , Isoindóis/uso terapêutico , Isoindóis/toxicidade , Masculino , Camundongos , Parasitemia/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/patogenicidade , Plasmodium falciparum/efeitos dos fármacosRESUMO
In this study, we investigated the susceptibility to enzymatic and alkaline hydrolysis of diloxanide furoate (DF) and its cyclodextrin inclusion complexes, in aqueous solution. The cyclodextrins (CDs) utilized were beta-cyclodextrin (beta-CD), (2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CD) and (2,3,6-tri-O-methyl)-beta-cyclodextrin (TM-beta-CD). All cyclodextrins studied provided a stabilizing effect to diloxanide furoate hydrolysis. In alkaline hydrolysis (pH 10.75), without the enzyme, beta-CD and TM-beta-CD provided similar effect on the stability of DF, with an inhibition factor in the order of 2.0. The DM-beta-CD, on the other hand, provided more pronounced stabilization effect than the other two CDs, with an inhibition factor around of 8. The maximum activity of the enzyme occured around pH 7.0. In the presence of enzyme, all cyclodextrins produced similar effect, with a DF hydrolysis inhibition factor in the order of 10. However, the plot of rate of hydrolysis versus [CD] fit with a equation based in a model that considers the association of the enzyme with the CDs. Therefore, it is concluded that the stabilization of DF is not only due to its cyclodextrin complex but also due to enzyme inhibition by cyclodextrin complexation.
