RESUMO
Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1·HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1·HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1·HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Tioxantenos/farmacologia , Xantonas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Células MCF-7 , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-Atividade , Tioxantenos/síntese química , Xantonas/síntese químicaRESUMO
Gram-negative marine bacteria are an underexplored source of new chemical entities for a wide range of applications. Even though, some have shown a high antitumor activity. This chapter describes an isolation and screening protocol based on the Dilution-to-Extinction approach coupled with an antiproliferative test oriented to the discovery of new cytotoxic compounds synthesized by marine bacteria. In addition to the discovery of new bioactive secondary metabolites, this protocol provides a high-throughput isolation and screening platform for discarding no bioactive strains during the first steps of the drug discovery process.