CNR ExploRA

Contributo in atti di convegno, 2015, ENG

Selective in vitro antileukemic activity (HL-60; K-562; MOLT-4; SR) of new Chloro-propyl-pyrazolo[1,2-a]benzo[1,2,5]triazepin-one

1) F. Mingoia, 2) R. Delisi, 2) A. Martorana, 2) C. Gentile, 2) A. Lauria

1) CNR-ISMN 2) Università di Palermo, STEBICEF

Recently, a new series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives 1, synthesized and submitted to the NCI one dose screening, showed valuable antiproliferative activity reaching in some cases sub-micromolar values. Further investigations, focused on getting new insights on the mechanism of action, provided further support for their proposition as anticancer candidates. Other than the attractive antiproliferative activity, effective apoptosis induction was observed, together with a cell cycle arrest in S phase (HeLa cell). Thus, encouraged by these results, we planned new structural modifications on structure 1 in order to modulate the biological profile. In detail, a ring expansion was approached.The tetrazinecentral moiety was replaced with aseven membered ring [1,2,5]-triazepinoneone(2). Therefore, ten derivatives, variously substituted, were synthesized and submitted to NCI one dose screening. Although literature survey encouraged our research scope because of the wide range of biological properties exhibited by this class of compounds, including anticancer activity, from the NCI screening, only moderate antiproliferative activity was observed. The best value of growth inhibition(GI) was 23% against SNB-75 (CNS cancer), suggesting a central nervous system tropism. Due to the moderate antiproliferative activity showed by the phenyl decorated tricycle (2), we decided to introduce a Chloro-propyl side chain on the expanded ring (3), as shown in Fig.1 with the aim to increase the activity. The biological outcomes provided by the NCI one dose screening evidenced a selective increased antiproliferative activity only towards leukemic tumor cell lines. Detailed results will be shown on poster session.

Tecnologie, Ricerca di base, interdisciplinare traslazionale in ambito biomedico. Simposio IBIM-CNR/STEBICEF, pp. 52–52, Palermo, 17/12/2015, 18/12/2015