RESUMO
We synthesized thirty-six novel pyrazole derivatives and studied their antiproliferative activity in human ovarian adenocarcinoma A2780 cells, human lung carcinoma A549 cells, and murine P388 leukemia cells. Four of these substances were selected because of their higher antiproliferative activity and further analyses showed that they were all able to induce apoptosis, although to a different extent. The expression of p53 and p21(waf1), which induce apoptosis and cell cycle arrest, was evaluated by western blot analysis in cells treated with compound 12d. The analysis of the cell cycle showed that all the selected compounds cause a partial G2/M block and the formation of polyploid cells. Furthermore, the four selected compounds were tested for their interaction with the microtubular cytoskeletal system by docking analysis, tubulin polymerization assay and immunofluorescence staining, demonstrating that the compound 12d, unlike the other active derivatives, was able to significantly bind dimers of α- and ß-tubulin, probably causing a molecular distortion resulting in the disassembly of microtubules.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/metabolismo , Camundongos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Modelos Moleculares , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Pirazóis/química , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Five- and six-membered heterocyclic ionone-like derivatives 4-6 have been synthesised in one step and with good yield from the key intermediate 3a and appropriate bifunctional reagents. Four were active as inhibitors of the respiratory burst of human neutrophils without affecting cell viability. The two most active compounds (5a,d) tested in neutrophil migration assays, were also found to be potent inhibitors of neutrophil chemotactic responsiveness. These two molecules could be considered as lead compounds of new drugs which can be an effective tool to treat psoriasis and related neutrophilic dermatoses.