Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1997-11-04
1999-08-31
Wilson, James O.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 2761, 536 2762, 536 278, 536 2781, 536 285, 536 2851, 536 2852, 536 2853, 536 2854, 536 2855, C07H 1900
Patent
active
059455276
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the field of nucleic acid chemistry, specifically to a process for preparing modified nucleosides. The nucleosides can be pyrimidines or purines. The pyrimidine compounds of the invention can be modified at the 5-, or 6-position of the pyrimidine ring. The purine compounds of the invention can be modified at the 2-, 6- or 8-position of the purine ring. Most preferably, the invention includes a process for preparing 8-position modified purine compounds and 5-position modified pyrimidine compounds. The present invention also includes the modified nucleosides produced by the method. The invention also includes the use of the modified nucleosides as anti-viral, anti-bacterial, anti-fungal or anti-neoplastic agents or as part of an oligonucleotide.
BACKGROUND OF THE INVENTION
Until quite recently, the consideration of oligonucleotides in any function other than strictly informational was not known. Despite the fact that certain oligonucleotides were known to have interesting structural possibilities (e.g., t-RNAs) and other oligonucleotides were bound specifically by polypeptides in nature, very little attention had been focused on the non-informational capacities of oligonucleotides. For this reason, among others, little consideration had been given to using oligonucleotides as pharmaceutical compounds.
There are currently at least three areas of exploration that have led to serious studies regarding the use of oligonucleotides as pharmaceuticals. In the most advanced of the fields, antisense oligonucleotides are utilized to bind to certain regions in an organism to prevent the expression of proteins or to block various cell functions. The discovery of RNA species with catalytic functions--ribozymes--has led to the consideration of RNA species that serve to perform intracellular reactions that will achieve desired effects. And lastly, the discovery of the SELEX process (Systematic Evolution of Ligands by EXponential Enrichment) has shown the research community that oligonucleotides can be identified that will bind to almost any biologically interesting target.
The use of antisense oligonucleotides as a method for controlling gene expression and the potential for using oligonucleotides as pharmaceutical materials has prompted investigations into the introduction of a number of chemical modifications into oligonucleotides to increase their therapeutic activity. Such modifications are designed to increase cell penetration of the oligonucleotides, to stabilize them from nucleases and other enzymes that degrade or interfere with the structure or activity of the oligonucleotide analogs in the body, to enhance their binding to targeted nucleic acids, to provide a mode of disruption (terminating event) once sequence-specifically bound to targeted nucleic acids, and to improve their pharmacokinetic properties. For example, PCT Patent Application Publication WO 91/14696, entitled: Oligonucleotide-Transport Agent Disulfide Conjugates, describes a method for chemically modifying antisense oligonucleotides to enhance entry into a cell.
A variety of methods have been used to render oligonucleotides resistant to degradation by exonucleases. PCT Patent Application Publication WO 90/15065, entitled: Exonuclease-Resistant Oligonucleotides and Methods for Preparing the Same, describes a method for making exonuclease-resistant oligonucleotides by incorporating two or more phosphoramidite and phosphoromonothionate and/or phosphorodithionate linkages at the 5' and/or 3' ends of the oligonucleotide. PCT Patent Application Publication WO 91/06629, entitled: Oligonucleotide Analogs with Novel Linkages, describes oligonucleotide compounds with one or more phosphodiester linkages between adjacent nucleotides replaced by a formacetal/ketal type linkage which are capable of binding RNA or DNA.
A common strategy for stabilization of RNA against endonucleolytic cleavage is to modify the 2'-position of ribonucleotides. Interference with base recognition by enzymes can be used to approach s
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Dewey Torin
Eaton Bruce
Tu Chi
NeXstar Pharmaceuticals, Inc.
Owens Howard
Wilson James O.
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