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.

Fused pyrimidine derivatives R 0515Synthesis and Biological Evaluation of 2,4,6-Functionalized Derivatives of Pyrido[2,3-d]pyrimidines as Cytotoxic Agents and Apoptosis Inducers. -A series of title compounds of type (VI) and (X) is prepared and their activities as cytotoxic agents and apoptosis inducers is studied. Some compounds such as (VIa), (VIb), (VId), and (VIf) show significant in-vitro cytotoxicity, induce apoptosis, and also produce a rapid dose-dependent increase in the caspase-3 level in some of the cell lines tested. -(SANMARTIN, C.; DOMINGUEZ, M. V.; CORDEU, L.; CUBEDO, E.; GARCIA-FONCILLAS, J.; FONT, M.; PALOP*, J. A.; Arch.