Oligonucleolotides having site specific chiral phosphorothioate internucleoside linkages

Inactive Publication Date: 2007-01-09
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0030]In accordance with this theory, the structures 3, 8, 14, 18, 20, and 25 all have geminal disubstituents. Use of this

Problems solved by technology

It is therefore a general object of such therapeutic approaches to interfere with or other-wise modulate gene expression, which would lead to undesired protein formation.
It is unlikely that unmodified, naturally-occurring oligonucleotides will be useful therapeutic agents because they are rapidly degraded by nucleases.
Presently, there is no method to prepare P-chiral oligonucleotides in large scale.
This method suffers from the non-stereospecif

Method used

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  • Oligonucleolotides having site specific chiral phosphorothioate internucleoside linkages
  • Oligonucleolotides having site specific chiral phosphorothioate internucleoside linkages
  • Oligonucleolotides having site specific chiral phosphorothioate internucleoside linkages

Examples

Experimental program
Comparison scheme
Effect test

example 1

Isomerically Pure R and S Isomers of 4-mercapto-4methyl-2-pentanol

[0261]R4-mercapto-4-methyl-2-pentanol and S-4-mercapto-4-methyl-2-pentanol are synthesized according to the procedure of Eliel and Morris-Natschke (Eliel, E. L., Morris-Natschke, S., J.Am.Chem.Soc, 1984, 106, 2937-2942).

example 2

Rp Precursor, Compound 1

[0262]PCl3 (1.3 mL, 15 mmol) is introduced via a syringe into a dry 100-mL round-bottomed flask containing 20 mL of dry THF that has been flushed with argon and sealed with a septum. The flask is cooled to −78° C. in a dry ice / acetone bath, and a solution of (R)-4-mercapto-4-methyl-2-pentanol (15 mmol) in THF (15 mL) containing triethylamine (6.9 mL, 50 mmol) is added via a syringe. The reaction mixture is stirred for 30 min at −78° C. and then warmed to 0° C. for 1 hour. The reaction mixture is partitioned between CH2Cl2 and saturated NaHCO3 and washed with saturated NaCl and dried over anhydrous Na2SO4 to give the title compound.

example 3

Compound 2

[0263]Compound 1 in hexane is treated with morpholine by careful dropwise addition at 0° C. The cold bath is removed, and the mixture is stirred at room temperature for an additional 1 hour. Morpholine hydrochloride is removed by filtration, and Compound 2 is purified by silica gel column chromatography.

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Abstract

Novel chiral compounds that mimic and/or modulate the activity of wild-type nucleic acids are disclosed. In general, the compounds are phosphorothioate oligonucleotides wherein the 5′, and the 3′-terminal internucleoside linkages are chirally Sp and internal internucleoside linkages are chirally Rp.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This patent application is a continuation-in-part of application Ser. No. 09 / 115,027, filed Jul. 14, 1998, now U.S. Pat. No. 6,242,589 entitled “Phosphorothioate Oligonucleotides Having Modified Internucleotide Linkages”, the content of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]This invention relates to the design and synthesis of nuclease resistant phosphorothioate oligonucleotides which are useful for therapeutics, diagnostics and as research reagents. Phosphorothioate oligonucleotides are provided in which all of the internucleoside linkages are chiral. Such compounds are resistant to nuclease degradation and are capable of modulating the activity of DNA and RNA.BACKGROUND OF THE INVENTION[0003]It is well known that most of the bodily states in multi-cellular organisms, including most disease states, are effected by proteins. Such proteins, either acting directly or through their enzymatic or...

Claims

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Application Information

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IPC IPC(8): A61K31/70G01N33/53C07H19/04C07H21/00
CPCC07H19/04C07H21/00
Inventor COOK, PHILLIP DANMANOHARAN, MUTHIAH
Owner IONIS PHARMA INC
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