Diazapyrene compounds useful for photocleavage of nucleic acids

Details Diazapyrene compounds useful for photocleavage of nucleic acids Diazapyrene compounds useful for photocleavage of nucleic acids

1987-12-15

1990-05-15

Shen, Cecilia

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

546 66, C07D40114, C07D47122, C07H 2100

Patent

active

049259377

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for the photocleavage of nucleic acids by 2,7-diazapyrenium dications, DAP.sup.2+, or their dimeric species, bis-DAP.sup.4+.
It also relates to novel diazapyrene derivatives; these are salts which release dications, DAP.sup.2+, or tetracations, bis-DAP.sup.4+, in solution.
Finally, 2,7-diazapyrenium dications coupled with oligonucleotides can form photoexcision reagents specific for nucleic acids.
Much research has been undertaken in recent years to find artificial reagents capable of cleaving nucleic acids and more particularly deoxyribonucleic acid and ribonucleic acid, commonly called DNA and RNA.
The majority of studies have been carried out with metal complexes which cleave DNA by an oxygen-dependent redox process or by photoactivation. Dyes of the acridine type have also been used to photodamage DNA.
Among the metal complexes which have been used, compounds carrying EDTA-Fe(II) groups and 1,10-phenanthroline-copper complexes may be mentioned in particular.
For example, in FEBS LETTERS, vol. 172, no. 1, Jun. 1984, BOUTORIN et al. describe reagents carrying EDTA-Fe(II) groups which are suitable for the direct cleavage of single-stranded nucleic acids.
Likewise, in SCIENCE, vol. 230, 1985, p. 679-681, TULLIUS et al. use EDTA-Fe(II) to cleave DNA.
HERTZBERG et al. [J. Am. Chem. Soc. 1982, 104, p. 313-315] recommend the use of (methidiumpropyl-EDTA)-Fe(II) as a cofactor in the cleavage of DNA for a number of antitumoral antibiotics.
The use of the 1,10-phenanthroline-copper complex to cleave DNA is described especially by REICH et al. in J. Am. Chem. Soc., Vol. 103, no. 12, 1981 and by R. FAGGIANI et al. in J. Am. Chem. Soc., Vol. 102, p. 5419-5421, 1980.
Moreover, it is known that dyes of the acridine type damage DNA. For example, FREIFELDER et al. [Biophysical Journal, Vol. 1, 1961] showed that DNA irradiated with visible light in the presence of acridine orange depolymerizes and undergoes cleavage.
It will be noted, furthermore, that 4,4'-bipyridinium ions, and in particular methylviologen, have been used in various redox and photoredox processes [AMOUYAL et al., Israel Journal of Chemistry 22, 1982, p. 117-123]. These processes can only take place in the presence of a photosensitizer or under ultraviolet irradiation.
Methylviologen, i.e. 1,1'-dimethyl-4,4'-bipyridinium chloride, commonly called MV.sup.2+, can damage DNA under these conditions.
It has now been found that diazapyrene derivatives, and more particularly 2,7-diazapyrenium cations, can be used for the photocleavage of nucleic acids in visible light without the need for photosensitizers.
Thus, the present invention relates to a process for the photocleavage of nucleic acids which consists in bringing a nucleic acid into contact with a solution of a 2,7-diazapyrene derivative of the type defined below, and in subjecting the resulting reaction mixture to irradiation with visible light.
The diazapyrene derivatives which are suitable for the purposes of the invention correspond to formula (I) below: ##STR1## in which:
R and R', which are identical or different, represent: radical optionally interrupted by one or more heteroatoms such as, for example, oxygen, sulfur or nitrogen, it also being possible for the said hydrocarbon radical optionally to be substituted by hydroxyl, amino or thio groups, by an aryl group or by a heterocyclic group; or
R and R' are identical and represent a group of the formula R.sub.1 Y.sup.-, in which R.sub.1 is the group --(CH.sub.2).sub.3 -- and Y.sup.- is the sulfonato ion, SO.sub.3.sup.- ; or a group of the formula: ##STR2##
X.sup.- is either an anion or nothing if at least one of the substituents R and R' is of the formula R.sub.1 Y.sup.-, in which case the derivatives are internal salts.
In the present description, the expression "aliphatic hydrocarbon radical optionally interrupted by one or more heteroatoms" also denotes aliphatic hydrocarbon groups containing the corresponding onium cations, in particular aliphatic hydrocarbon groups containing one or more quaternized

REFERENCES:
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patent: 3853589 (1974-12-01), Andrews
K. A. Reich et al., Cleavage of DNA by the 1,10-Phenanthroline-Copper Ion Complex, Superoxide Mediates the Reaction Dependent on NADH and Hydrogen Peroxide, Journal of the American Chemical Society, vol. 103, 1981, pp. 3582-3584.
Chemical Abstracts, vol. 75, 1971, Abstract 157073(x), Radiation-Sensitive Materials Containing Nitrogenous Cationic Compounds, Mar. 30, 1971.
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