- Synthesis and biological evaluation of 2,4,6-functionalized derivatives of pyrido[2,3-d]pyrimidines as cytotoxic agents and apoptosis inducers
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In the search for new derivatives with anticancer activity that are able to induce a selective proapoptotic 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 IC50 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.
- Sanmartin, Carmen,Dominguez, Maria Victoria,Cordeu, Lucia,Cubedo, Elena,Garcia-Foncillas, Jesus,Font, Maria,Palop, Juan Antonio
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- New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidin-5-one derivatives as diuretics
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A series of new 5H-[1,3]thiazolo[3,2-α]pyrido[3,2-e]pyrimidin-5-ones 3-substituted and/or 8,9-hydrogenated was prepared and tested for their diuretic, natriuretic and kaliuretic activities on male Wistar rats at a dosage of 25 mg/kg or less. Diuretic and saliuretic activities were strongly influenced by substituents in 3-position. Quantitative structure-activity relationships show that electron withdrawn substituents in 3-position enhance both diuretic and saliuretic activities at 25 mg/kg. Global analysis of the variations introduced on pyridine, pyrimidine and thiazole rings of this tricyclic system showed an increase of diuretic and natriuretic activities when the formal charge on N(9a) and C(9b) increases. Potassium ion excretion also increases, although not as drastically as in the earlier cases. Regression equations were calculated by partial least squares method (PLS) and validated by the cross-validation (leave-one-out) technique.
- Monge,Martinez-Merino,Simon,Sanmartin
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p. 306 - 310
(2007/10/02)
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- NEW 5-SUBSTITUTED DERIVATIVES OF ETHYL 2,3-DIHYDRO-3-OXOISOTHIAZOLOPYRIDINE-2-ACETATE
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New series of ethyl 5-substituted 2,3-dihydro-3-oxoisothiazolopyridine-2-acetate was prepared either a) directly by reaction of 5-substituted 2-chlorothio-3-pyridinecarbonyl chlorides with ethyl glycinate or b) by oxidation of the correspondent 2-mercapto-3-pyridinecarboxamides.New 5-substituted 1,2-dihydro-2-thio-3-pyridinecarboxylic acids as starting materials are described.
- Martinez-Merino, Victor,Gil, Maria J.,Gonzalez, Alberto,Zabalza, Jose M.,Navarro, Javier,Manu, Maria A.
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p. 333 - 344
(2007/10/02)
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