Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1994-08-04
1997-06-17
LeGuyader, John L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 231, 536 243, 536 245, 536 2531, 536 2534, 435 6, 435 911, C07H 2100, C07H 2102, C07H 2104, C12Q 168
Patent
active
056398735
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to new chemical compounds as well as their applications. The chemical compounds according to the present invention are oligonucleotide compounds at least partially consisting of an oligo-4'-thioribonucleotide or an oligo-4'-thio-2'-deoxyribonucleotide comprising a concatenation of 4'-thio-nucleotides.
BACKGROUND OF THE INVENTION
In French Patent Applications FR 8,301,223 (2,540,122) and FR 8,411,795 (2,568,254) have been described chemical compounds consisting of an oligonucleotide or an oligodeoxynucleotide comprising a concatentation of natural or modified nucleotides, that is to say beta-nucleotides, onto which is attached by a covalent bond at least one intercalating group, which possess the property of selectively blocking the expression of a gene and which, because of this, are particularly useful in therapy as antiviral, antibiotic, antiparasitic or antitumor substances.
In International Application PCT WO 83/01451, has been described a method for blocking the translation of messenger RNA (mRNA) into protein by hybridization of the mRNA with an oligonucleotide having the sequence complementary to the mRNA, the oligonucleotide being stabilized in phosphotriester form.
In International Application WO 88/04301 have been described oligonucleotides of alpha anomeric configuration having parallel pairings with complementary sequences.
Chemotherapy with antisense oligonucleotides relates to RNA or DNA targets of all living organisms (cells, bacteria, parasites, viruses or oncogenes).
The use of synthetic antisense oligonucleotides having the same structure as the natural nucleic acids is faced, mainly in biological medium, with problems of sensitivity to nucleases and cell penetration.
To overcome these limitations, oligonucleotide analogs capable of being more resistant to nucleases and of penetrating better into the cells across the cyto-plasmic membrane have been synthesized.
There has indeed been described in the prior art derivatives of oligonucleotide compounds resisting enzymatic degradations better, whose phosphate part was modified into thiophosphate or methyl phosphonate especially. However, these derivatives exhibit a chirality at the level of the phosphate capable of generating insoluble diastereoisomers.
SUMMARY OF THE INVENTION
The compounds according to the invention may have the natural anomeric configuration beta or the non-natural anomeric configuration alpha.
Thus, alpha(a) and beta(b) 4'-thionucleotides are represented by the formulae(a) and (b) respectively ##STR1## (a) and (b) represent 4'-thionucleosides, a phosphate should be added in 5' in order to obtain nucleotides.
Under these conditions, many uses for biological and even pharmacological purposes already known for oligonucleotides can be envisaged, and this with greater efficiency.
More precisely, the subject of the present invention is chemical compounds consisting of an oligo-4'-thioribonucleotide or an oligo-4'-thio-2'-deoxyribonucleotide, characterized in that they comprise a concatenation of 4'-thioribonucleotides or 4'-thio-2'-deoxyribonucleotides respectively, it being possible for said concatenation to be optionally linked to an effector, especially a radical corresponding to an intercalating agent or a chemical or photoactivable radical, such as a radical carrying a functional group which reacts directly or indirectly with the nucleotide chains or a radical whose presence permits easy and sensitive detection.
In particular, the subject of the invention is new oligo-4'-thionucleotide derivatives, their preparation and their use especially as probes permitting the detection of a defined sequence of nucleic acids, as artificial nucleases specific for DNA or RNA sequences or alternatively as agents for selectively blocking the expression of a gene, whether endogenous (for example oncogene gene) or exogenous (for example DNA or RNA of viruses, parasites or bacteria).
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 represents the curve for thermal stability of the betadT
REFERENCES:
patent: 4968602 (1990-11-01), Dattagupta
Alderfer et al. "Hydrogen and Carbon NMR Studies on the Conformation of Nucleic Acids Containing 4'-Thio-Furanose", Biophys. J. 25:223a Feb. 1979.
Goodchild "Conjugates of Oligonucleotides and Modified Oligonucleotides . . . " Bioconjugate Chem. 1:165-187. May 1990.
Anisuzzaman, A. et al., "4'-Thioadenosine 3', 5'-Cyclic Phosphate and Derivatives. Chemical Synthesis and Hydrolysis by Phosphodiesterase", Biochemistry 1973, 12(11), 2041-2045.
Hoffman, D. and Whistler, "Synthesis and Properties of Nucleotides Contianing 4-Thio-D-ribofuranose", Biochemistry 1970, 9(11), 2367-2372.
Barascut Jean-Louis
Imbach Jean-Louis
Centre National de la Recherche Scientifique "CNRS"
Larson Thomas G.
LeGuyader John L.
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