Structure-activity relationships and mechanism of action of antitumor bis 8-hydroxyquinoline substituted benzylamines.

A series of twenty six 8-hydroxyquinoline substituted amines, structurally related to compounds 2 and 3, were synthesized to evaluate the effects of structural changes on antitumor activity and understand their mechanism of action. The studies were performed on a wide variety of cancer cell lines within glioma and carcinoma models. The results obtained from chemical models and biological techniques such as microarrays suggest the following hypothesis that a quinone methide intermediate which does not react with DNA but which gives covalent protein thiol adducts. Micro-array analysis showed that the drugs induce the expression of a variety of stress related genes responsible for the cytotoxic and cytostatic effects in carcinoma and glioblastoma cells respectively. The described analogues could represent new promising anti-cancer candidates with specific action mechanisms, targeting accessible thiols from specific proteins and inducing potent anti-cancer effects. Copyright 2009 Elsevier Masson SAS. All rights reserved.