ACMA (9-amino-6-chloro-2-methoxy acridine) forms three complexes in the presence of DNA

Abstract

The interaction of ACMA (9-amino-6-chloro-2-methoxy acridine) (D) with DNA (P) has been studied by absorbance, fluorescence, circular dichroism, spectrophotometry, viscometry and unwinding electrophoresis. A T-jump kinetic study has also been undertaken. The experimental data show that, totally unlike other drugs, ACMA is able to form with DNA three complexes (PD(I), PD(II), PD(III)) that differ from each other by the characteristics and extent of the binding process. The main features of PD(I) fulfil the classical intercalation pattern and the formation/dissociation kinetics have been elucidated by T-jump techniques. PD(II) and PD(III) are also intercalated species but, in addition to the dye units lodged between base pairs, they also bear dye molecules externally bound, more in PD(III) relative to PD(II). A reaction mechanism is put forward here. Comparison between absorbance, fluorescence and kinetic experiments has enabled us to determine the binding constants of the three complexes, namely (6.5 ± 1.1) × 10(4) M(-1) (PD(I)), (5.5 ± 1.5) × 10(4) M(-1) (PD(II)) and (5.7 ± 0.03) × 10(4) M(-1) (PD(III)). The Comet assay reveals that the ACMA binding to DNA brings about genotoxic properties. The mutagenic potential studied by the Ames test reveals that ACMA can produce frameshift and transversion/transition mutations. ACMA also is able to produce base-pair substitution in the presence of S9 mix. Moreover, the MTT assays have revealed cytotoxicity. The biological effects observed have been rationalized in light of these features.

Synthesis, DNA Binding and Topoisomerase I Inhibition Activity of Thiazacridine and Imidazacridine Derivatives

“…Analysis of DNA binding of the compound 9-amino-6-chloro-2-methoxyacridine (ACMA) showed that fluorescence quenching of ACMA by DNA is informative of intercalation, whereas the absorption spectrum may shed light into possible external binding. It was suggested that the DNA-ACMA interaction is not a simple one and that both the intercalative as external binding can be present [26]. In this way, the kind of interaction of the acridine derivatives produced is consistent both with intercalation as external binding.…”

“…Distinct spectroscopic behaviors stems from the different nature of the substituents located around the main acridine structure that can affect the kinetic and thermodynamic aspects of DNA binding [26]. Absence or presence of an amino moiety at position 3 of the thiazolidin-4-one ring can explain the hypochromic or hyperchromic effect presented by compounds 4 and 5 , respectively.…”

Monomer–Dimer Divergent Behavior toward DNA in a Half-Sandwich Ruthenium(II) Aqua Complex. Antiproliferative Biphasic Activity

“…This feature is often related to unwinding of the double helix, quite a common effect in intercalation. 16 A new, positive, induced CD band appeared at 345 nm, characteristic of the [2c′] + /DNA complex formation, since neither DNA nor [2c′] + displayed any CD signal in that region. The dependence of the molar ellipticity at 275 nm on the C D /C P ratio reveals that the binding isotherm bears out the formation of PD II .…”

The mode of binding ACMA–DNA relies on the base-pair nature

“…[8][9][10] The behaviour of ACMA toward DNA contrasts with that of the acridine proflavine, whose stacking with the DNA bases results in fluorescence enhancement. 11 ACMA has been shown recently to form three different complex species with Calf Thymus (CT)-DNA, 12 which differ from each other by the mode and extent of interaction. CT-DNA is extremely heterogenic both compositionally and structurally; hence, in principle it should not be discarded that the different modes of binding bear relation with the different structural or compositional domains (e.g., ATrich vs. GC-rich), which may display different affinity with the drug.…”