Acridine drugs intercalation

P. Cieplak, S. N. Rao, P. D. J. Grootenhuis, and P. A. Kollman, Free energy calculation on base specificity of drug-DNA interactions Application to daunomycin and acridine intercalation into DNA, Biopol. 29 717 (1990). 

Chemicals, which have planar molecules such as acridine, and the anticancer drugs vincristine and vinblastine can intercalate in the DNA molecule. This distorts the structure and so alters the function of the molecule, possibly leading to mutations via base insertions (see sect. 6.7.7 below). This may also interfere with the excision repair processes during meiosis. 

Publications about oligonucleotides linked to acridine derivatives have been summarized by several authors [246,275-277], The intercalating properties of acridine derivatives have been shown by NMR-studies [278, 279], 9-Amino-6-chloro-2-methoxyacridine is mostly used, which differs only slightly in size from the important intercalator drug, psoralen. Acridine-... 

DNA has also been applied for synkineses of molecular wires. One example applies aligned DNA fibers in which one acridine orange molecule intercalates per 10 base pairs. It shows photocurrents if a voltage is applied to the material placed between comb-form electrodes (Okahata et al., 1998). The dye-DNA complexes are probably not useful as parts of a charge separation system, but they clearly demonstrate extensive electronic communication between bound drug molecules—an influence that serves to raise the efficiency of transition dipole coupling at long distances. 

The nucleotides were then employed to study the behaviour of new alkyl-acridines as these drugs are known to intercalate with DNA. 

Examples of nonnucleoside drugs which inhibit DNA synthesis by binding to the DNA double-helix include the acridines (e.g., proflavine) and various antibiotics (e.g. mitomycin C, adriamycin, daunomycin). The ability of the acridines to bind to DNA and RNA has led to their use as biological stains for these molecules. Binding is achieved by intercalation the planar ring system of proflavine, for example, intercalates (squeezes) between the stacked base pairs of the double-helix. Such a sandwich of DNA with bound molecules would be expected to geometrically distort (i.e., lengthen) the doublehelical structure this has been observed. 

The effect of intercalating drugs on DNA polymerization probably results from an increase in the energy required to separate the two strands. Acting on RNA polymerization, the intercalated proflavine has been shown to decrease the number of binding sites for the enzyme on the DNA template. Thus acridines, in contrast... 

Since acridines are active at low concentrations, it follows that the intercalation process must be biologically very important. This point can be demonstrated when the drug acts in vitro on isolated nucleic adds (as in the preceding Paragraph 8.1.6.2.3, (1), (2) and (4)). In organisms or even in cells, the munber of bound... 

Intercalation is involved in the mechanism of action of two other types of substances some antimalarial drugs and the anthracyoline antibiotics (Fig. 6). The complex they form with double-stranded DNA exhibits many characteristics of the acridine-DNA complex they modify in the same way the hydrodynamic properties of DNA. Chloroquine and quinacrine inhibit the in vitro activity of both DNA primed polymerases, and this is related with the block in nucleic acid synthesis observed when bacteria or plasmodia are treated with these drugs. 

The intercalation of the planar moiety of chloroquine and anthracycline antibiotics can explain the similarity observed between their effects and those of acridines on DNA structure. However, the relative importance of their long side-chain is unknown. The way this chain interacts with DNA is a query, and its rdle in the biological effect of the drugs is not evaluated. 

The ease of intercalation of other chro-monic and potentially chromonic materials. A number of biochemical reagents, such as acridines and ethidium bromide, intercalate readily between the stacked bases in DNA and RNA. Anticancer drugs, such as the square planar platinum complexes, intercalate avidly (Fig. 14) and naturally occurring antibiotics, such as actinomycin, similarly act by intercalation into the stack of bases [67]. They act as tailor-made spanners in the works and prevent the reading and replication of DNA. 

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