RESUMO
Several quinazoline derivatives have been found to possess a broad spectrum of biological activities. Previously our research group has synthesized and studied the anti-proliferative effects of N-Decyl-N-(2-Methyl-4-Quinazolinyl) Amine (DMQA). The current study evaluated the cytotoxic and apoptotic properties of DMQA in THP-1 cells. The cytotoxic potential of DMQA was assessed using MTT assay on a panel of cancer cell lines which include HeLa, Mia PaCa-2, A 375, B16-F10, A 549,A 431, U937, THP-1, HL-60 and peripheral blood mononuclear cells (PBMC's). Preliminary data revealed that the highest cytotoxic activity was against THP-1 leukemia cell line (IC50=0.66 µg/ml). The apoptotic properties of DMQA on THP-1 cells were characterized by change in nuclear morphology, DNA fragmentation, reduction of pro-caspases-3, 9, Bax/Bcl-2 levels, cleavage of poly (ADP-ribose) polymerase and cytosolic release of cytochrome c. Further investigation revealed a sub-G1 peak, phosphatidyl serine exposure and loss of mitochondrial membrane potential (MMP) in THP-1 cells. The role of caspases was crucial and was demonstrated by the inhibitors Z-VAD-FMK and Z-DEVD-FMK. Moreover DMQA was markedly less effective in inhibiting the growth of normal cells (PBMC's, IC50 =62.17 µg/ml). Based on the results we suggest that DMQA induced apoptosis via intrinsic pathway and could be a promising anticancer agent.
Assuntos
Apoptose/efeitos dos fármacos , Caspases/metabolismo , Quinazolinas/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Caspases/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fragmentação do DNA/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células HL-60 , Células HeLa , Humanos , Leucemia/metabolismo , Leucemia/patologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quinazolinas/química , Proteína X Associada a bcl-2/metabolismoRESUMO
A series of novel alkyltriazole tagged pyrido[2,3-d]pyrimidine derivatives 5 and 6 was prepared starting from 2,3-active functional pyridine 1via cyclization, propargylation followed by reaction with alkyl or perfluoroalkyl azides under Sharpless conditions. All the compounds 5 and 6 were screened for anticancer activity against three cancer cell lines such as U(937), THP-1 and Colo205. The promising compounds 5b and 5e have been identified.
