title: Synthesis and biological evaluation of indazolo[4,3-bc][1,5]naphthyridines (10-aza-pyrazolo[3,4,5-kl]acridines): a new class of antitumor agents.
abstract: A series of potential DNA-binding antitumor agents, 2-[omega-(alkylamino)alkyl]-9-methoxy-5-nitro-2,6-dihydroindazolo[4,3-bc][1,5]naphthyridines (2a-f), 10-aza derivatives of PZA, has been prepared by condensation of 9-chloro-2-methoxy-6-nitro-5,10-dihydrobenzo[b][1,5]naphthyridin-10-one (6) with the appropriate (omega-aminoalkyl)hydrazine in tetrahydrofuran/methanol. Compound 6 was obtained by heating at 100 degrees C in H(2)SO(4)5, yielded by the condensation of 2,6-dichloro-3-nitrobenzoic acid (4) and 6-methoxy-3-pyridinamine (3). The non-covalent DNA-binding properties of 2 have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives against human hormone-refractory prostate adenocarcinoma cell line (PC-3) are described and compared to that of parent drug PZA. We selected the most cytotoxic target derivatives 2c,d, the in vitro inactive 2f, and reference compound PZA to investigate whether in vitro treatment with these drugs was able to induce necrotic and/or apoptotic cell death. To this purpose, we evaluated the percentage of apoptotic cells in PC-3 treated with the target compounds 2c,d,f and reference compound PZA, by Annexin V staining and Propidium iodide (PI)/Annexin V, biparametric flow cytometric analysis and agarose gel electrophoresis.
authors.affiliation: Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Amelia
authors.initials: A
authors.lastname: Magnano
authors.forename: Silvia
authors.initials: S
authors.lastname: Sparapani
authors.forename: Roberta
authors.initials: R
authors.lastname: Lucciarini
authors.forename: Mosca
authors.initials: M
authors.lastname: Michela
authors.forename: Consuelo
authors.initials: C
authors.lastname: Amantini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Santoni
authors.forename: Ippolito
authors.initials: I
authors.lastname: Antonini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000145:classification* / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000145:classification* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009287:Naphthyridines