Synthesis and Biological Evaluation of Heteroaryldiamides and Heteroaryldiamines as Cytotoxic Agents, Apoptosis Inducers and Caspase-3 Activators

The work described here involved the synthesis and biological evaluation of new heteroaryldiamides and heteroaryldiamines. A new general model in which the structures can be adjusted has been applied in this study. Three different structural units can be distinguished: a central nucleus and two symmetric terminal units. The central element is either an aliphatic chain of varying length and flexibility, piperazine, or a polyamine nucleus. However, the terminal units are pyridine, quinoline, indole, benzene or pyrido[2,3‐d]pyrimidine with different substituents. The antitumoural activities of the compounds were evaluated in vitro by examining their cytotoxic effects against human breast, colon, and bladder cancer cell lines. Compounds that showed cytotoxic activity were subjected to both apoptosis and caspase‐3 assays. With regard to selectivity, the cytotoxicity was also determined in cell cultures of two nontumoural lines. The most promising compounds are 4c, 5c and 7, which are amino‐pyridinium, quinolyl‐N‐oxide, and pyridyl derivatives, respectively, and these reveal a significant in vitro cytotoxicity in at least two of the three cell lines tested. These compounds induced apoptosis and also produced a rapid dose‐dependent increase in the caspase‐3 level in HT‐29 cells. Other encouraging profiles were found, such as those presented by 1k and 8d, which are cytotoxic and apoptotic but do not provoke an increase in the level of caspase‐3, or those presented by 2f, 3c and 4a, which are slightly cytotoxic but do not show any other significant activity. The different types of behaviour of each compound are not necessarily parallel in the three cell lines tested.