Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing saccharide radical
Patent
1999-05-18
2000-03-28
Elliott, George C.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing saccharide radical
435 89, 536 221, 536 231, 536 256, C07H 2100, C07H 1910, C07H 1920
Patent
active
060430605
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a novel nucleotide analog, and more particularly, to a nucleotide analog suitable as an antisense molecule.
BACKGROUND ART
In 1978, it was reported for the first time that an antisense molecule inhibited influenza virus infection. Since then, reports have been issued that antisense molecules inhibited the expression of oncogenes and HIV infection. In recent years, antisense oligonucleotides have become one of the most promising pharmaceuticals, because they specifically control the expression of undesirable genes.
The antisense method is based on the idea of controlling a unidirectional flow called the central dogma, i.e., DNA.fwdarw.RNA.fwdarw.protein, by use of an antisense oligonucleotide.
When a naturally occurring oligonucleotide was applied to this method as an antisense molecule, however, it was hydrolyzed with enzymes in vivo, or its permeation through the cell membrane was not high. To solve these problems, numerous nucleic acid derivatives have been synthesized, and studies thereon have been conducted. Examples of synthesized derivatives include a phosphorothioate having a sulfur atom substituting for an oxygen atom on the phosphorus atom, and a methylphosphonate having a substituting methyl group. Recently, molecules in which the phosphorus atom has also been substituted with a carbon atom, or in which the ribose has been converted to an acyclic skeleton have been synthesized (F. Eckstein et al., Biochem., 18, 592 (1979), P. S. Miller et al., Nucleic Acids Res., 11, 5189 (1983), P. Herdewijn et al., J. Chem. Soc. Perkin Trans. 1, 1567 (1993), and P. E. Nielsen et al., Science, 254, 1497 (1991)).
All of the resulting derivatives, however, have been unsatisfactory in terms of in vivo stability or ease of oligonucleotide synthesis.
Under the circumstances, there has been a demand for the provision of a nucleotide analog for an antisense molecule which readily permeates through the cell membrane in vivo, which is minimally hydrolyzed with an enzyme, and the synthesis of which is easy.
DISCLOSURE OF THE INVENTION
The inventors of the present invention have designed a nucleic acid derivative with a modified sugar portion of a nucleic acid, which would be useful in the antisense method. They have synthesized the nucleic acid derivative, and confirmed its usefulness. The present invention will now be described.
A nucleotide analog of the present invention is an oligo- or polynucleotide analog containing one or more monomer units being nucleotide analogs of the following general formula: ##STR2## where B may be identical or different, and is a pyrimidine or purine nucleic acid base, or a derivative thereof.
This monomer unit is a nucleoside analog of the general formula: ##STR3## where B is a pyrimidine or purine nucleic acid base, or a derivative thereof, and Y.sub.1 and Y.sub.2 are identical or different, and is a hydrogen atom or a protective group for a hydroxyl group, provided that the protective group may be a publicly known group, preferably, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, an acyl group, an aralkyl group, or a silyl group, or an amidite derivative thereof.
In the above formula, the alkyl group represents a straight chain or branched chain alkyl group with 1 to 20 carbon atoms. Its examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.
The alkenyl group represents a straight chain or branched chain alkenyl group with 2 to 20 carbon atoms. Its examples include vinyl, allyl, butenyl, pentenyl, geranyl, and farnesyl.
The alkynyl group represents a straight chain or branched chain alkynyl group with 2 to 20 carbon atoms. Its examples include ethynyl, propynyl, and butynyl.
The cycloalkyl group represents a cycloalkyl group with 3 to 8 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Another example is a heterocyclic group in which one or more arbitrary methylene groups
REFERENCES:
Christensen et al. A novel class of Oligonucleotide analogues containing 2'-0,3'0-C-linked [3.2.0]Bicyclioarabinocleoside monomers: Synthesis, Thermal Affinity Studies, and Molecular Modeling, JACS, vol. 120, pp. 5458-5463, 1998.
O-Yang et al. 4'-substituted Nucleosides as Inhibitors of HIV, Tet Lett. vol. 33, No. 1, pp. 41-44, 1992.
Elliott George C.
Epps Janet L.
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