title: Design, synthesis, and biological properties of new bis(acridine-4-carboxamides) as anticancer agents.
abstract: To enhance the outstanding biological response shown by the corresponding monomers 4 and 5, two classes of bis-acridine-4-carboxamides, 9, with a linker between the 4,4' positions, and 13, with a linker between the 1,1' positions, have been prepared as DNA-binding and potential antitumor agents. The noncovalent DNA-binding properties of these compounds have been examined using gel-electrophoresis and fluorometric techniques. The results indicate that (i). target compounds intercalate DNA; (ii). the bis derivatives with the optimal linker are considerably more DNA-affinic than corresponding monomers; (iii). overall affinity is sensitive to the nature of the linker, of the chromophores, and of the substituents at 7,7'; (iv). often, the bis derivatives show a marked AT-preferential binding. In vitro cytotoxic potency of these derivatives toward the human colon adenocarcinoma cell line (HT29) is described and compared to that of reference drugs. Structure-activity relationships are discussed. Some highly DNA-affinic and potent cytotoxic compounds, 9b,f and 13b,c, have been selected for the National Cancer Institute (NCI) screening on 60 human tumor cell lines and identified as new leads in the antitumor strategies.
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: Barbara
authors.initials: B
authors.lastname: Gatto
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Ernesto
authors.initials: E
authors.lastname: Menta
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pescalli
authors.forename: Sante
authors.initials: S
authors.lastname: Martelli
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004587:Electrophoresis, Agar Gel; D005470:Fluorometry; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D004247:DNA