Diseño, síntesis y evaluación biológica de nuevos derivados de pirido[2,3-d] pirimidina y quinazolina con actividad antitumoral. Valoración de su capacidad antimetastática

Abstract

The disease of cancer has been ranked as a major health burden. Pyrido[2,3-d]pyrimidine and quinazoline derivatives have attracted attention due to their broad range of pharmacological activities: antifungal, antimalarial, anti-inflammatory, anticonvulsant, antibacterial, antihypertensive, and their anticancer activity is one of the most promising aspects as they act through multiple targets. Based on these observations and considering our experience with these heteroaromatic rings, we have synthesized 57 novel 2.4-disubstituted quinazoline and Pyrido[2,3-d]pyrimidine derivatives. These compounds have been screened in vitro against five tumoral cell lines – prostate (PC-3), leukemia (CCRF-CEM), colon (HT-29), lung (HTB-54) and breast (MCF-7) – and two cell lines derived from non-malignant cell lines, one mammary (184B5) and one from bronchial epithelium (BEAS-2B). MCF-7 and HTB-54 have been the most sensitive cell lines with GI50 values below 10 µM for eleven and ten compounds, respectively. To compounds (I.3 and IV.14) evoke a marked cytotoxic effect in all cell lines tested and one compound, IV.7, has been potent and selective against MCF-7. A preliminary study into the mechanism of the potent derivatives I.3, IV.7 andIV.14 indicates that the cytotoxic activities of these compounds might be mediated by inducing cell death without modifications on cell cycle. Moreover, the signalling pathway implicated in the cell death observed upon treatment in MCF-7 cells by compound IV.14 could be AKT/S6 ribosomal/m-TOR. The lead compounds induce inhibition of cell migration in MDA-MB-231 cells and in this inhibition of migration the kinases AKT, S6 ribosomal, FAK and SRC are not implicated.