title: Synthesis and biological evaluation of new asymmetrical bisintercalators as potential antitumor drugs.
abstract: The good results obtained in the past decade with various types of potential bisintercalating agents, e.g., LU 79553, DMP 840, BisBFI, MCI3335, WMC-26, BisAC, BisPA, and the asymmetrical derivative WMC-79 (Chart 1), prompted us to investigate a new series of asymmetrical bisintercalators, compounds 1a-t (Chart 2), which can combine the potentiality of bisintercalation with a possible different mechanism of action due to two diverse chromophores. The DNA-binding properties of these compounds have been examined using fluorometric techniques: target compounds are excellent DNA ligands, with a clear preference for binding to AT-rich duplexes. In vitro cytotoxicity of these derivatives toward human hormone-refractory prostate adenocarcinoma cell line (PC-3) is described. Apoptosis assays of four selected compounds are also reported. Very potent cytotoxic compounds, some of them capable of inducing early apoptosis, have been identified.
authors.affiliation: Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, Italy. ippolito.antonini@unicam.it
authors.forename: Ippolito
authors.initials: I
authors.lastname: Antonini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Santoni
authors.forename: Roberta
authors.initials: R
authors.lastname: Lucciarini
authors.forename: Consuelo
authors.initials: C
authors.lastname: Amantini
authors.forename: Silvia
authors.initials: S
authors.lastname: Sparapani
authors.forename: Amelia
authors.initials: A
authors.lastname: Magnano
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D011471:Prostatic Neoplasms; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: C517062:2-(2-(dimethylamino)ethyl)-6-((3-((3-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benzo(de)isoquinolin-2-yl)propyl)methylamino)propyl)amino)-2,3-dihydro-1H,7H-pyrimido(5,6,1-de)acridine-1,3,7-trione; D000166:Acridines; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D007364:Intercalating Agents; C506941:WMC-79; D004247:DNA