4,8-Disubstituted pyrimido[5,4-d]pyrimidines as novel apoptotic independent anticancer agents: synthesis and in vitro activity against HCT116 human colon cancer cells

Colon cancer is amongst the most common types of cancer in both men and women[1,2] and is tightly related with age and unhealthy diets typical of developed countries. Chemotherapy has an important role in fighting this disease but the currently approved drugs are not effective for all patients due to the tumours’ different genetic profiles. Thus, there is a need to create more effective and potent drugs that act in a larger spectrum of the population. In this work we report an efficient synthetic approach to generate novel 4,8-disubstituted pyrimido[5,4-d]pyrimidines and their in vitro anticancer activity in HCT116 human colon cancer cells. The biological results show that most of the compounds tested decreased cell viability with higher potency than that of the reference compound 5-FU, frequently used in chemotherapy. The SAR study suggests that the activity depends on the substituents present in both C4 and C8 of the pyrimido[5,4-d]pyrimidine core. The potential of the most active compounds as inducers of apoptosis was also assessed in HCT116 cells. Compounds showed low induction of apoptosis indicating that their mechanism of action may be apoptosis independent, which can be an advantage in treatment.The author acknowledges the University of Minho, FCT: projects nºF-COMP-01-0124- FEDER-022716 (ref. FCT PEst-/QUI/UI0686/2011) FEDER-COMPETE, National NMR Network (Bruker 400 Avance III), research grant Pest-C/BIA/UI4050/2011, co-funded by the program COMPETE from QREN with co-participation from the European Community fund FEDER and PhD grant awarded to A. Rocha SFRH/BD/85937/2012 for financial support.