Isis Pharmaceuticals, Inc.

Allister S Fraser

Muthiah Manoharan

Phillip Dan Cook

Andrew Mamoru Kawasaki

Thazha P Prakash

Charles John Guinosso

P Dan Cook

Pei-Pei Kung

Michael E Jung

Haoyun An

Methods for the regioselective alkylation at the 2&prime;-hydroxy position over the 3&prime;-hydroxy position of nucleosides and nucleoside analogs, forming 2&prime;-O-ester modified compounds, are disclosed. Reduction and derivatization of the 2&prime;-O-ester provides 2&prime;-O-modified nucleosides and nucleoside analogs useful for the synthesis of oligomeric compounds having improved hybridization affinity and nuclease resistance.

Regioselective synthesis of 2&prime;-O-modified nucleosides

Methods for the alkylation of alcohols, amines and thiols by the use of cyclic sulfates are disclosed. The alkylated sulfates formed are versatile intermediates which may be further elaborated by methods of the invention. In particular, methods for the alkylation of the 2&prime;, 3&prime; or 5&prime;-hydroxy position of nucleosides and nucleoside analogs with cyclic sulfates to form the 2&prime;, 3&prime; or 5&prime;-O-alkyl sulfate modified compounds are disclosed. Displacement of the 2&prime;,3&prime; or 5&prime;-O-sulfate with a nucleophile provides 2&prime;, 3&prime; or 5&prime;-O-modified nucleosides and nucleoside analogs useful for the synthesis of oligomeric compounds having improved hybridization affinity and nuclease resistance.

Alkylation of alcohols, amines, thiols and their derivatives by cyclic sulfate intermediates

Novel macrocyclic compounds are constructed to include a ring or ring system having two bridgehead atoms with a bridge extending between the bridgehead atoms. Located in at least the bridge are two or more nitrogenous moieties that are derivatized with chemical functional groups. The ring or ring systems can include further nitrogenous moieties, either as ring atoms or on pendant groups attached to the ring. These can also be derivatized with chemical functional groups. The totality of the chemical functional groups imparts certain conformational and other properties to the compounds. In accordance with certain embodiments of the invention, libraries of such compounds are prepared utilizing permutations and combinations of the chemical functional groups and the nitrogenous moieties to build complexity into the library.

Macrocyclic compounds having nitrogen-containing linkages

Nucleosidic monomers and oligomeric compounds prepared therefrom are provided. Also provided is a novel method of deprotection of oligomeric compounds. Oligomeric compounds having at least one 2'-O-acetamido modified nucleosidic monomer are expected to have increased nuclease resistance and binding affinity to a complementary strand of nucleic acid. Such oligomeric compounds are useful for diagnostics and other research purposes, for modulating the expression of a protein in organisms, and for the diagnosis, detection and treatment of other conditions responsive to oligonucleotide therapeutics.

2'-O-acetamido modified monomers and oligomers

Nitrogenous macrocyclic compounds

Growing community of inventors

Carlsbad, CA, United States of America

Allister S Fraser