Intercalation model for DNA-cross linking in a 1-nitro-9-aminoacridine derivative, an analog of the antitumor agent "ledakrin" (nitracrine).
Ledakrin (nitracrine), C-283, is a 1-nitro-9-aminoacridine derivative that is used in Poland as an antitumor agent. In order to investigate the basis of the activity of this compound the structure of another analog, [9-(3-dimethyl-1-methylpropylimino)-1-nitro-9,10-dihydroacridin e], C-829, that has similar activity, was determined by X-ray crystallographic techniques and was compared with that of ledakrin, already reported in the literature. In both molecules the proximity of the 1-nitro to the substituted 9-aminoacridine group causes extensive distortions. These compounds are believed to act, after metabolic "activation", by cross-linking DNA. Such cross-linking does not occur in the absence of the 1-nitro group or if the nitro group is moved to the 2-, 3- or 4-position. Computer-assisted model-building has been used to test possible intercalative models. It has shown that functional groups on C-829 or C-283 are, when the acridine portion of the molecule is intercalated as in a proflavine dinucleoside phosphate complex, in positions suitable for DNA cross-linking by activated 1-nitro-9-aminoacridine derivatives.
D000609:Aminoacridines; D000970:Antineoplastic Agents; D001665:Binding Sites; D003432:Cross-Linking Reagents; D004247:DNA; D007364:Intercalating Agents; D008958:Models, Molecular; D015394:Molecular Structure; D009564:Nitracrine
D000609:Aminoacridines; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D007364:Intercalating Agents; C025198:C 829; D009564:Nitracrine; D004247:DNA