title: Synthesis and biological evaluation of 2,4,6-functionalized derivatives of pyrido[2,3-d]pyrimidines as cytotoxic agents and apoptosis inducers.
abstract: 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.
authors.affiliation: Sección de Síntesis, Departamento de Química Orgánica y Farmacéutica, University of Navarra, Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanmartín
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Domínguez
authors.forename: Lucía
authors.initials: L
authors.lastname: Cordeu
authors.forename: Elena
authors.initials: E
authors.lastname: Cubedo
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Foncillas
authors.forename: María
authors.initials: M
authors.lastname: Font
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Palop
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; D011743:Pyrimidines; D053148:Caspase 3