Synthesis and biological evaluation of new asymmetrical bisintercalators as potential antitumor drugs.
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.
Antonini
Ippolito
I
Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, Italy. ippolito.antonini@unicam.it
Santoni
Giorgio
G
Lucciarini
Roberta
R
Amantini
Consuelo
C
Sparapani
Silvia
S
Magnano
Amelia
A
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
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