Synthesis and biological evaluation of 2,4,6-functionalized derivatives of pyrido[2,3-d]pyrimidines as cytotoxic agents and apoptosis inducers
Sanmartín C, Domínguez MV, Cordeu L, Cubedo E, García-Foncillas J, Font M, Palop JA.
Sección de Síntesis, Departamento de Química Orgánica y Farmacéutica, University of Navarra, Pamplona, Spain
Magazine: Archiv der Pharmazie
Date: Jan 1, 2008Medical Oncology
In the search for new derivatives with anticancer activity that are able to induce a selective pro-apoptotic mechanism in cancer cells, we have designed, synthesized, and evaluated a series of new 2-(alkylsulfanyl)-N-alkylpyrido[2,3-d]pyrimidine-4-amine derivatives as cytotoxic and apoptosis inducers. The potential antitumor activity of the compounds was evaluated in vitro by examining their cytotoxic effects against human breast, colon, and bladder cancer-cell lines.
The IC(50)values of the compounds that showed cytotoxic activity were calculated. The cytotoxic compounds were then tested for their ability to induce caspase-3 activation and nuclear-chromatin degradation. Some compounds, such as 6c, 6d, 6e, 6j, 6o, and 6p, show significant in-vitro cytotoxicity in at least two of the three tested cell lines, induced apoptosis, and also produced a rapid dose-dependent increase in the caspase-3 level in some of the cell lines tested. In order to test the selectivity of the compounds, two non-tumoral human cell lines were used. Several compounds of the did not show cytotoxicity in these cell lines.
CITATION Arch Pharm (Weinheim). 2008 Jan;341(1):28-41
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