Acridine dimers: influence of the intercalating ring and of the linking‐chain nature on the equilibrium and kinetic DNA‐binding parameters

Abstract

The rigidity of the linking chain of bifunctional intercalators in the ditercalinium series was shown to be critical for antitumor activity. In order to study the influence of the rigidity of the linking chain on the DNAbinding properties of DNA bifunctional intercalators, fluorescent 9-aminoacridine and 2-methoxy-6-chloro-9-aminoacridine analogues with chains of variable rigidity were synthesized.'H-NMR studies show that the conformation of 9-aminoacridine dimers is almost independent of the nature of the linking chain. A strong self-stacking of the aromatic rings of the 2-methoxy-6-chloro-9-aminoacridine is observed for dimers with flexible chains but not for those with rigid chains.All the dimers having a linking chain long enough to bisintercalate in DNA according to the excluded site model are indeed bisintercalators. The kinetic association constant of all monomers and dimers for poly-. The large increase of DNA binding affinity observed for the dimers is always associated with the expected decrease of the dissociation rate constant.The effect of chain rigidity and pH on the calf thymus DNA binding of 9-aminoacridine and 2-methoxy-6-chloro-9-aminoacridine dimers is quite different. In the series of 9-aminoacridine the pK, of the dimers remains high and therefore no difference of DNA-binding affinity is observed between pH 5 and 7.4. The rigidity of the linking chain does not significantly alter the DNA-binding affinity.In the 2-methoxy-6-chloro-9-aminoacridine series, the pK, of all dimers became smaller than the physiological pH and a dramatic decrease of DNA-binding affinity is observed when the pH is increased from pH 5 to 7.4. This decrease appears significantly smaller for dimers with rigid chains. A similar dramatic decrease of binding affinity at pH 714is not observed for poly[d(A-T)] for the alternating polymer at pH 7.4.Many DNA-intercalating drugs elicit antitumor properties [ 11. Among these are ellipticinium, acridine derivatives, anthracenedione and the antibiotics actinomycin D, daunorubicin and adriamycin. The antitumor properties of these drugs are in part related to their DNA-binding parameters [2 -71. In order to obtain new anticancer agents, it was logical to design molecules which bind to DNA with higher affinity. Such molecules might be able to compete in vivo with the DNA-binding proteins like repressors or polymerases. Several polyfunctional intercalators were synthesized or isolated and their DNA-binding properties studied [8 -211. As expected these compounds exhibited DNA-binding affinities much greater than their corresponding monomers [22 -241.Moreover, in the series of 7H-pyridocarbazole dimers, several molecules elicited strong antitumor activity [25, 261. These antitumor properties were strictly restricted to dimers connected by rigid chains like bis(ethy1piperidine) 127, 281. These observations led us to study the influence of the linking chain nature on the conformational properties of such dimersCorrespondence to J

Bisimidazoacridones: 2. Steady-state and Time-resolved Fluorescence Studies of Their Diverse Interactions with DNA¶§

“…Evidence of various deviations from the classical intercalation mode was reported, such as ligand tilting with respect to the DNA axis (18) or half‐intercalation of a ligand (12). In some cases, monointercalation is affected by drug dimerization (24,38). Because intercalation results in partial unwinding and bending of the DNA duplex, whereas minor groove binding does not perturb the overall topology of B‐form DNA (39), the degree of intercalation may have a profound effect on the sequelae of binding, including recognition by DNA repair proteins and assembly of transcriptional machinery.…”

“…The increase of the fluorescence signal upon binding to DNA was observed for ethidium (9,10), some imidazoacridinones (11) and cyanine dyes (12), whereas the fluorescence quenching by DNA binding was found for some polycyclic acridines (13), safranin T (14) and anthracyclines (15). It is worth mentioning that the kind and strength of the fluorescence signal upon binding depends not only on the drug type but also on the side chain substituents and linker structure and, to a very great extent, are DNA sequence dependent (13,(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

A Role of the 9-Aminoacridines and their Conjugates in a Life Science

“…However, only rigid chain derivatives of 9-amino-6-chloro-2-methoxyacridine are active at that pH. Furthermore, the conformation of the former dimers is almost independent of the nature of linking chain, whereas the strong self-stacking of the aromatic rings of the latter is observed for dimers with flexible chains but not for those with rigid chains [136].…”

“…The influence of flexibility of two-acridine linking chains and the differences in activity of 9-aminoacridine and 9-amino-6-chloro-2-methoxyacridine were investigated [136]. Due to difference in pK a of both the mentioned 9-aminoacridines, the biological activity of their derivatives is dependent on pH.…”

3,6-Bis(dimethylamino)-10-(10-iododecyl)acridinium iodide

“…These dyes self-associate in aqueous solution through interactions of their %-electron systems, forming pairs or larger aggregates (Vitagliano, 1983;Costantino et al, 1984;Markovits et al, 1989). Crystallographic studies of these compounds are able to give a detailed description of the molecular arrangements in the solid state and provide valuable information on the ®ne geometry of self-association processes, such as the scheme and extent of overlap (Mattia et al, 1984;Sivaraman et al, 1996;Copp et al, 2000;Puliti & Mattia, 2001).…”