Intercalation model for DNA-cross linking in a 1-nitro-9-aminoacridine derivative, an analog of the antitumor agent "ledakrin" (nitracrine)

Journal of Biomolecular Structure & Dynamics
W C StallingsJ J Stezowski

Abstract

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.

References

Sep 6, 1977·Biochimica Et Biophysica Acta·J FilipskiM Chorazy
Jan 1, 1977·Proceedings of the National Academy of Sciences of the United States of America·T D SakoreH M Sobell
Feb 1, 1961·Journal of Molecular Biology·L S LERMAN

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Citations

May 1, 1995·General Pharmacology·M Gniazdowski, L Szmigiero
Aug 9, 2008·Medicinal Research Reviews·Yu Chen, Longqin Hu

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