title: 1-Methyl-3H-pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-ones. Design, synthesis, and biological activity of new antitumor agents.
abstract: 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 GI(50) 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.
authors.affiliation: Dipartimento Farmacochimico, Tossicologico e Biologico, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy. almerico@unipa.it
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Almerico
authors.forename: Francesco
authors.initials: F
authors.lastname: Mingoia
authors.forename: Patrizia
authors.initials: P
authors.lastname: Diana
authors.forename: Paola
authors.initials: P
authors.lastname: Barraja
authors.forename: Antonino
authors.initials: A
authors.lastname: Lauria
authors.forename: Alessandra
authors.initials: A
authors.lastname: Montalbano
authors.forename: Girolamo
authors.initials: G
authors.lastname: Cirrincione
authors.forename: Gaetano
authors.initials: G
authors.lastname: Dattolo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: C500620:1,9-dimethyl-3H-pyrazolo(1,2-a)benzo(1,2,3,4)tetrazin-3-one; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D011720:Pyrazoles