title: Rational design, synthesis and biological evaluation of thiadiazinoacridines: a new class of antitumor agents.
abstract: A series of potential DNA-binding antitumor agents, 3-[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 12 and 1,3-di[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 13, has been prepared by cyclization with SOCl(2) of 1-[[omega-(alkylamino)alkyl]amino]-9-imino-4-nitro-9,10-dihydroacridines 16 or 1-[[omega-(alkylamino)alkyl]amino]-9-[omega-(alkylamino)alkyl]imino-4-nitro-9,10-dihydroacridines 17, respectively. The non-covalent DNA-binding properties of 12, 13 have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward six tumor cell lines, including human colon adenocarcinoma (HT29) and human ovarian carcinoma (A2780 sensitive, A2780cisR cisplatin-resistant, CH1, CH1cisR cisplatin-resistant, and SKOV-3) cells, are described and compared to that of reference drugs. In vivo antitumor activity of some selected derivatives, endowed with relevant cytotoxic activity against murine leukemia P388 are reported. The 3-[2-(dimethylamino)ethyl]-6-nitro-2,7-dihydro-3H-2 lambda(4)-thiadiazino[3,4,5-kl]acridin-2-one (12d) has been identified as a new lead in the development of anticancer tetracyclic acridine derivatives.
authors.affiliation: Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy. ippolito.antonini@unicam.it
authors.forename: Ippolito
authors.initials: I
authors.lastname: Antonini
authors.forename: Paolo
authors.initials: P
authors.lastname: Polucci
authors.forename: Amelia
authors.initials: A
authors.lastname: Magnano
authors.forename: Diego
authors.initials: D
authors.lastname: Cacciamani
authors.forename: Marek T
authors.initials: MT
authors.lastname: Konieczny
authors.forename: Jolanta
authors.initials: J
authors.lastname: Paradziej-Łukowicz
authors.forename: Sante
authors.initials: S
authors.lastname: Martelli
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D002417:Cattle; D003500:Cyclization; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007941:Leukemia P388; D051379:Mice; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D013829:Thiadiazines; D004247:DNA; C427203:calf thymus DNA