Articolo in rivista, 2005, ENG, 10.1021/jm049075u

1-methil-3H-pyrazolo[1-2-a]benzo[1-2-3-4]tetrazin-3-ones, design synthesis and biological activity of new antitumoral agents

A.M. Almerico (1); F. Mingoia (2); P. Diana (1); P. Barroja (1); A. Lauria (1); A. Montalbano (1); G. Cirrincione (1); G. Dattolo (1)

(1) Dipartimento Farmacochimico, Tossicologico e Biologico, Università degli studi di Palermo, Via Archirafi 32, 90123 Palermo (Italy) (2) Istituto per lo Studio dei Materiali Nanostrutturati, ISMN-CNR Palermo, Via Ugo LaMalfa 156, 90146 Palermo

1-Methylpyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-ones 4, synthesized in good to excellent yields, were designed as novel alkylating agents because of their peculiar chemical behavior. All derivatives showed antiproliferative activity against more than 50 types of tumor cell lines with GI50 reaching sub-micromolar values. SAR studies revealed that the presence of a chlorine atom is well-tolerated in both positions 8 and 9, whereas in the case of the methyl group, switching from the 8 to the 9 position gives rise to the most active compound of the series, 4g, either for the number of cell lines inhibited and for selectivity against leukaemia and renal cancer subpanels. COMPARE and 3D-MIND computations indicate, for compounds 4, an activity profile analogous to rifamycins and cytidine analogues.

Journal of medicinal chemistry 48 , pp. 2859–2866

Keywords

antiproliferative, pyrazolo[1, 2-a]benzotetrazinone, antitumor agent

CNR authors

Mingoia Francesco Michele

CNR institutes

ISMN – Istituto per lo studio dei materiali nanostrutturati