"Targeting DNA and DNA/TopoisomeraseII complex by antiproliferative Pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one derivatives. Insights on their Mechanism of Action."

The development of new strategies aimed to discover new molecules able to act simultaneously upon multiple biotargets in fighting cancer, is an attractive approach to achieve synergistic effects for new therapeutically perspectives. Recently a new series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one derivatives (PBTs), has been explored as potential anticancer candidates because of their promising antiproliferative activity, apoptosis induction in the low ?M range, as well as cell cycle arrest promoters [1,2]. As an hopeful extension of these preliminary findings, we planned to investigate in depth on the mode of action the selected most active derivatives in an effort to get new insights on their anticancer potential. At first, a DNA targeting is approached by means of flow linear dichroism (LD) experiments to evaluate the ability of a molecule to form an intercalative molecular complex. Additionally, we investigated the capacity of compounds to interfere with the catalytic cycle of topoisomerase II. Depending on the choice of functional groups, PBT scaffold exhibit diverse modes of action, including DNA complexation or inhibition of topoisomeraseII activity. Preliminary in silico insights will also be shown on poster session. [1] A.M. Almerico, F. Mingoia, P. Diana, P. Barraia, A. Lauria, A. Montalbano, G. Cirrincione, G. Dattolo, J. Med. Chem., 2005, 48, 2859-2866. [2] F. Mingoia, C. Di Sano, F. Di Blasi, M. Fazzari, A. Martorana, A.M. Almerico, A. Lauria, Eur. J. Med. Chem.,2013, 64, 345-356.