2′-O-amino-containing nucleoside analogs and...

Details 2′-O-amino-containing nucleoside analogs and... 2′-O-amino-containing nucleoside analogs and...

2000-09-19

2003-01-14

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023100, C536S026260, C536S026600, C536S026700, C536S026740, C536S027210, C536S027600, C536S027800, C536S027810, C536S028100, C536S028500, C536S028530, C536S028540

Reexamination Certificate

active

06506888

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel nucleoside or nucleotide analogs, processes for their synthesis and incorporation into polynucleotides.
The following is a brief description of nucleoside analogs. This summary is not meant to be complete but is provided only for an understanding of the invention that follows. This summary is not an admission that all of the work described below is prior art to the claimed invention.
Nucleoside modifications of bases and sugars, have been discovered in a variety of naturally occurring RNA (e.g., tRNA, mRNA, rRNA; reviewed by Hall, 1971 The Modified Nucleosides in Nucleic Acids, Columbia University Press, New York; Limbach et al., 1994
Nucleic Acids Res
. 22, 2183). In an attempt to understand the biological significance, structural and thermodynamic properties, and nuclease resistance of these nucleoside modifications in nucleic acids, several, investigators have chemically synthesized nucleosides, nucleotides and phosphoramidites with various base and sugar modifications and incorporated them into oligonucleotides.
Uhlmann and Peyman, 1990
, Chem. Reviews
90, 543, review the use of certain nucleoside modifications to stabilize antisense oligonucleotides.
Usman et al., International PCT Publication Nos. WO/93/15187; and WO 95/13378; describe the use of sugar, base and backbone modifications to enhance the nuclease stability of enzymatic nucleic acid molecules.
Eckstein et al., International PCT Publication No. WO 92/07065 describe the use of sugar, base and backbone modifications to enhance the nuclease stability of enzymatic nucleic acid molecules.
Grasby et al., 1994
, Proc. Indian Acad. Sci
., 106, 1003, review the “applications of synthetic oligoribonucleotide analogues in studies of RNA structure and function”.
Eaton and Pieken, 1995
, Annu. Rev. Biochem
., 64, 837, review sugar, base and backbone modifications that enhance the nuclease stability of RNA molecules
Mitsunobu, 1981
, Synthesis
, 1, 1-28, described a process for the conversion of alcohol (ROH) to aminooxy alcohol (RONH
2
).
The process described by Mitsunobu (supra) has been applied in the conversion of sugars and disaccharides (Grochowski et al., 1976, 50, C15
; Synthesis
1976, 682
; J. Bull. Pol. Acad. Sci. Chem. Commun
., 1987, 35, 255; Tronchet et al., 1982
, Helv. Shim. Acta
., 65, 1404
; Carbohydr. Res
., 1990, 204).
The process described by Mitsunobu (supra) has also been applied in the synthesis of 3′-O—NH
2
nucleosides and 5′-O—NH
2
nucleosides (Nielsen, 1995
, Annu. Rev. Biomol. Struc
., 24, 167; Burgess et al., 1994
, J. Chem. Soc. Chem. Commun
., 915; Kondo et al., 1985
, Am. Chem. Soc. Symp. Ser
., 16, 93; Vasseur et al., 1992
, J. Am. Chem. Soc
., 114, 4006; Tronchet et al., 1994, 13, 2071; Perbost et al., 1995
, J. Org. Chem
., 60, 5150).
The references cited above are distinct from the presently claimed invention since they do not disclose and/or contemplate the synthesis of the nucleoside analogs, such as the 2′-O-amino nucleosides of the instant invention.
SUMMARY OF THE INVENTION
This invention relates to a nucleoside or a nucleotide comprising a nucleic acid sugar portion, wherein the 2′ position of the sugar has the formula: 2′-O—NHR1, wherein R1 is independently H, aminoacyl group, peptidyl group, biotinyl group, cholesteryl group, lipoic acid residue, retinoic acid residue, folic acid residue, ascorbic acid residue, nicotinic acid residue, 6-aminopenicillanic acid residue, 7-aminocephalosporanic acid residue, alkyl, alkenyl, alkynyl, aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide or ester. The invention also relates to a nucleoside or a nucleotide comprising a nucleic acid sugar portion, wherein the 2′ position of the sugar has the formula: 2′-O—N=R3, wherein R3 is independently pyridoxal residue, pyridoxal-5-phosphate residue, 13-cis-retinal residue, 9-cis-retinal residue, alkyl, alkenyl, alkynyl, alkylaryl, carbocyclic alkylaryl, or heterocyclic alkylaryl.
This invention relates to novel nucleoside analogs having the Formula I:
wherein, R1 is independently H, aminoacyl group, peptidyl group, biotinyl group, cholesteryl group, lipoic acid residue, retinoic acid residue, folic acid residue, ascorbic acid residue, nicotinic acid residue, 6-aminopenicillanic acid residue, 7-aminocephalosporanic acid residue, alkyl, alkenyl, alkynyl, aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide or ester; X is independently a nucleotide base or its analog or hydrogen; Y is independently a phosphorus-containing group; and R2 is independently a blocking group or a phosphorus-containing group.
In a preferred embodiment the invention features novel nucleoside analogs having the Formula II:
wherein, R3 is independently pyridoxal residue, pyridoxal-5-phosphate residue, 13-cis-retinal residue, 9-cis-retinal residue, alkyl, alkenyl, alkynyl, alkylaryl, carbocyclic alkylaryl, or heterocyclic alkylaryl; X is independently a nucleotide base or its analog or hydrogen; Y is independently a phosphorus-containing group; and R2 is independently a blocking group or a phosphorus-containing group.
Specifically, an “alkyl” group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain, and cyclic alkyl groups. Preferably, the alkyl group has 1 to 12 carbons. More preferably it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkyl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxy, cyano, alkoxy, NO
2
or N(CH
3
)
2
, amino, or SH.
The term “alkenyl” group refers to unsaturated hydrocarbon groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkenyl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, NO
2
, halogen, N(CH
3
)
2
, amino, or SH.
The term “alkynyl” refers to an unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkynyl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, ═O, ═S, NO
2
or N(CH
3
)
2
, amino or SH.
An “aryl” group refers to an aromatic group which has at least one ring having a conjugated &pgr; electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. The preferred substituent(s) on aryl groups are halogen, trihalomethyl, hydroxyl, SH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups.
An “alkylaryl” group refers to an alkyl group (as described above) covalently joined to an aryl group (as described above).
“Carbocyclic aryl” groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted.
“Heterocyclic aryl” groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted.
An “amide” refers to an —C(O)—NH—R, where R is either alkyl, aryl, alkylaryl or hydrogen.
An “ester” refers to an —C(O)—OR′, where R is either alkyl, aryl, or alkylaryl.
A “blocking group” is a group which is able to be removed after polynucleotide synthesis and/or which is compatible with solid phase polynucleotide synthesis.
A “phosphorus containing group” can include phosphorus in forms such as dithioates, phosphoramidites and/or as part of an oligonucleotide.
In a prefer

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