Intercalation Model for DNA-Cross Linking in a 1-Nitro-9-aminoacridine Derivative, an Analog of the Antitumor Agent “Ledakrin” (Nitracrine)

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.

The interactions of monomeric acridines and unsymmetrical bisacridines (UAs) with DNA duplexes: an insight provided by NMR and MD studies

“…Albeit numerous references have suggested that Nitracrine (C-283) and—by extent—its analogue, C-1748, are efficient dsDNA intercalators 7 – 10 , 19 – 22 , our examinations have not proven those claims. Nitroacridines are structurally based on acridine, a well-established dsDNA intercalating agent 23 , 24 , thus the assumption on their intercalation mode of action seemed very reasonable.…”

“…Therefore, taking into account the evident broadening of the resonances of the aromatic H5/H6/H8 protons of the D1 – D9 duplexes (with no new DNA resonances arising, which would suggest the presence of a stereochemically defined DNA:ligand adduct, Fig. 2 C,D,I–K) and considering the fact that—at this stage—the TA/TA dinucleotide step should be regarded as a default binding site of acridine-based intercalators, one should conclude that the studied nitroacridines—albeit unspecifically interacting with DNA—are not the most efficient dsDNA intercalators, which contradicts the current paradigm 7 – 10 , 19 , 20 .…”

Tautomerism and steric effects in 1-nitro-9-(alkylamino)acridines (ledakrin or nitracrine analogs): probing structure-activity relationships at the molecular level

“…It seems probable that the conformations of the side chains in the free bases (imino tautomers) and the acid salts (amino tautomers) are more influenced by intermolecular rather than intramolecular interactions, particularly hydrogen-bonding interactions. This is in contrast to unhindered acridines such as C-264, ICR-170-OH, and ICR-191-OH12•13, 16 where, in the absence of a nitro group, there is internal hydrogen bonding in the side chain involving a proton on N(9).…”