", New pyrazolo[1,2-a]benzo[1,2,5]triazepine-3,6(7H)dione derivatives: The influence of the side chains in the tuning of antiproliferative activity"

Recently, a novel series of derivatives 2a-d, incorporating the new ring system pyrazolo[1,2-a][1,2,5]benzotriazepin-3,6(7H)-dione, has been synthesized and evaluated as anticancer agents. Several derivatives, screened against more than 50 types of human tumor cell lines (NCI), showed moderate antiproliferative activity coupled with a promising selective CNS tumor cell tropism. These derivatives, were designed as evolution of the previously proposed first series of pyrazolo[1,2-a]benzo-[1,2,3,4]tetrazin-3-one derivatives 1 [1] endowed with antiproliferative activity in low micromolar range. A further second series highlighted these derivatives as effective on apoptosis induction, cell cycle arrest on S phase (HeLa). [2] Thus, to investigate the effect of a ring expansion, moving from a tetrazine central moiety to a triazepinone one, we planned to introduce a series of side chains in order to modulate their biological profile. Exploiting the synthetic pathway, an easy access in the functionalization on ring Z was reached obtaining a small library of 20 compounds. Several 6/7-(3-R4 -propyl)-1-methyl-9-R1 -3H,5H-pyrazolo[1,2-a]benzo[1,2,5]triazepin-3-one (3a-d)(1'-5') derivatives were submitted to the MTT assay to assess their grown inhibition activity against HeLa cells. Among them, the most part resulted not active or showed low antiproliferative activity, while the 3c2' derivative revealed as the most effective showing IG50 value of about 27mM. Interestingly, none of the screened derivatives, tested in the concentration range 50-1 ?M, affected the cell membrane integrity, as determined preliminary by the Trypan Blu exclusion method. References 1. A.M. Almerico, F. Mingoia, P. Diana, P. Barraja, A. Lauria, A. Montalbano, G. Dattolo, G. Cirrincione, 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.