RESUMO
Some novel 9-anilinothiazolo[5,4-b]quinoline derivatives were synthesized and their cytotoxic activities were examined. The inhibition of some of the most active compounds over human topoisomerase II (Topo II) activity was assessed with the kDNA decatenation assay. The novel compounds differ in the substituents attached to the anilino ring, a dialkylamino alkylamino group, a saturated heterocyclic moiety, a methylthio group at position 2 and a fluorine atom present or absent at 7-position. According to the data, compounds with a diethylaminopropylamino group and a chlorine atom at 4'-position of the anilino ring were the most cytotoxic. The molecular models of all compounds indicated a correlation between hydrophobicity and cytotoxic activity although the direction and magnitude of the dipole moment also had a significant influence on its cytotoxicity. The 2-dialkylaminoalkylamino substituent is flexible and is known to facilitate the crossing of cell membranes; thus, this last barrier may be a limiting step in the mechanisms mediating the cytotoxicity. On the other hand, the activity of 2-methylthio derivatives seems to rely more on the electronic effects brought about by the substitution of the aniline ring. The synthesis, cytotoxicity against cancer cell lines, in vitro inhibition of human topoisomerase II, molecular modeling and the preliminary analysis of structure-activity relationships are presented.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Inibidores da Topoisomerase II , Compostos de Anilina/síntese química , DNA/genética , DNA/metabolismo , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células K562 , Modelos Moleculares , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Quinolinas/síntese química , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologiaRESUMO
A series of novel alkylamino and 9-anilinothiazolo[5,4-b]quinolines were synthesized as potential antitumoral agents. The in vitro cytotoxicity of these compounds was evaluated on several cell lines. The inclusion of electron-withdrawn/acceptor hydrogen-bond groups at position 3' of the anilino ring and the presence of an alkylamino chain on the tricyclic framework (regardless of its position) seem to be structural features relevant to cytotoxic activity.