New polyazamacrocyclic 3-hydroxy-4-pyridinone based ligands for iron depletion antitumor activity.

The two polynitrogen heterocyclic based hydroxypyridinone chelators. • Synthesis of new 3-hydroxy-4-pyridinone based ligands. • Excellent iron chelation properties. • Promising ligands with potent antiproliferative activity through iron depletion in vitro. Iron depletion is an efficient strategy for the development of anticancer agents. In an effort to develop efficient chelators, two new 3-hydroxy-4-pyridinone based polyazamacrocycles 1e and 2e were designed and synthesized. A preliminary study of the ligands was carried out to investigate their iron chelating capability and anti-tumor activity. Chelating kinetics revealed that the ligands exhibited excellent iron depletion capacity in neutral and acidic NH 4 OAc buffer solutions. Moreover, MTT assay showed that the new ligands displayed potent inhibitory activity in the proliferation of HepG2 cells. The attachment of hydroxypyridione units on the polyazamacrocycles promoted iron chelating capability and improved the anti-tumor activity by offering additional chelating sites and lipophilicity. These results indicate that two novel compounds may possess the therapeutic potential in the treatment of cancer through depleting cellular iron. [ABSTRACT FROM AUTHOR]