Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-10-30
2000-07-18
Wilson, James O
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 221, 536 231, 536 2531, 536 2532, 536 2533, 536 2534, 536 267, 536 268, 536 41, 544263, C07H 2104, C07H 1900, C07D48700
Patent
active
060909323
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to methods of production of modified nucleosides. In particular, this invention includes novel methods for the production of 2'-modified pyrimidines. The preparation of such 2'-modified pyrimidines is accomplished in a novel intramolecular nucleophilic displacement reaction. Also included within the scope of this invention are certain novel 2'-modified pyrimidines prepared according to the method of the invention, and oligonucleotides containing such modified pyrimidine species. 2'-modified purines are also prepared by the method of the invention. The 2'-modified nucleosides are useful as anti-viral and anti-neoplastic agents.
BACKGROUND OF THE INVENTION
Modified nucleotides and oligonucleotides have gained an important role in the development of pharmaceuticals over the last several years. For example, analogs of nucleosides and nucleotides have been employed as antiviral compounds. Oligonucleotides comprised of nucleotide analog building blocks have been used as inhibitors of gene translation. (See, Huryn and Okabe (1992) Chem. Rev. 92:1745-1788).
The recent discovery of oligonucleotide library screening technology has opened up an additional area for the pharmaceutical application of nucleotide analogs in oligonucleotides; as highly specific, high affinity inhibitors of protein function. See, e.g., U.S. Pat. No. 5,270,163 entitled, Nucleic Acid Ligands; and Tuerk and Gold (1990) Science 249:505-510. This technology is called SELEX, an acronym for Systematic Evolution of Ligands by Exponential Enrichment. SELEX can be carried out with libraries comprised of modified oligonucleotides to give ligands incorporating desired chemical functionalities (See, U.S. patent application Ser. No. 08/117,991, filed Sep. 8, 1993 and entitled "High Affinity Nucleic Acid Ligands containing Modified Nucleotides").
Stability against nuclease degradation is a concern in the field of oligonucleotide therapeutics. Oligodeoxynucleotides are often stabilized by the introduction of phosphorothioate internucleotidic linkages. (See, Huryn and Okabe (1992) Chem. Rev. 92:1745-1788; Englisch and Gauss (1991) Angew. Chem. 30:613-722).
Modification of the 2'-position of pyrimidines has also been shown to stabilize oligonucleotides against nuclease degradation. (See, Paolella et al. (1992) EMBO Journal 11:1913-1919; Pieken et al. (1991) Science 253:314-317.) Both 2'-amino and 2'-fluoro nucleotides have been used for this purpose. The 5'-triphosphate derivatives of these modified nucleotides are substrates for T7 RNA polymerase. (Aurup et al. (1992) Biochemistry 31:9636-9641.)
The introduction of modifications to the 2'-position of pyrimidine nucleosides is not a highly efficient process. Furthermore, current technology allows only for the preparation of a few select 2'-modified pyrimidines under harsh reaction conditions with low yield. (Verheyden et al. (1971) J. Org. Chem. 36:250-254.) A general reaction allowing facile preparation of a wide variety of novel and known 2'-modified pyrimidines has to date not been available.
To facilitate incorporation into oligonucleotide libraries, nucleotide analogs have to be prepared as the 5'-triphosphate derivatives. This is the form that is recognized as a substrate for DNA dependent RNA polymerases. Furthermore, analogs also have to be prepared as the phosphoramidites in order to be incorporated into the final oligonucleotide ligand by automated chemical synthesis.
There currently is no reliable method for the stereoselective preparation of ribo-2'-hydroxylaminopyrimidines. Derivatives of such compounds have not been described nor have these compounds been characterized. It has been reported that the BH.sub.3 reduction of the oxime derivative of 2'-ketouridine affords mostly the 2'-hydroxylaminonucleosides of the arabino configuration. (Tronchet et al. (1990) Tetrahedron Lett. 31:531.) 2'-Halomethylpyrimidines are unknown. The 2'-aminopyrimidines are known compounds, however, they have never been prepared by an intramolecular introduction
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McGee Danny P.
Pieken Wolfgang A.
Sebesta David P.
Zhai Yansheng
Proligo LLC
Wilson James O
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