Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression
First Claim
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1. An oligonucleotide or an oligonucleotide analog comprising at least five covalently bound nucleoside units connected together by phosphate linkages, which nucleoside units individually comprise a ribose or deoxyribose sugar portion covalently bound to a base portion, wherein a plurality of base portions are pyrimidine bases;
- and at least one of said pyrimidine bases is a modified pyrimidine base having the structure;
##STR2## wherein;
X=OH or NH2 ;
B is selected from the group consisting of;
C-lower alkyl, N, C--CF3, C--F, C--Cl, C--Br, C--I, C-halocarbon, C--NO2, C--CF3, C--SH, C--SCH3, C--OH, C--O-lower alkyl, C--CH2 OH, C--CH2 SH, C--CH2 SCH3, C--CH2 OCH3, C--NH2, C--CH2 NH2, C--alkyl-NH2, C-benzyl, C-aryl, C-substituted aryl or benzyl wherein said substituents are selected from the group consisting of methyl, hydroxyl, alkoxy, alcohol, benzyl, phenyl, nitro, thiol, and halogen;
provided that when B is N, then said sugar portion to which said modified pyrimidine base is bound is deoxyribose; and
A is selected from the group consisting of;
C--H, N, C--CF3, C-halocarbon, C--NO2, C--OCF3, C--SH, C--SCH3, C--OH, C--O-lower alkyl, C--CH2 OH, C--CH2 SH, C--CH2 SCH3, C--CH2 OCH3, C--NH2, C--CH2 NH2, C-benzyl, C-aryl, C-substituted aryl or benzyl wherein said substituents are selected from the group consisting of methyl, hydroxyl, alkoxy, alcohol, benzyl, phenyl, nitro, thiol, and halogen.
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Abstract
Oligonucleotide analogs are provided having improved nuclease resistance. Modifications of selected nucleotides through substitutions on the pyrimidine ring are disclosed. Certain preferred embodiments comprise the inclusion of said modified nucleotides at a plurality of sites, especially at the 3'"'"' end of a selected oligonucleotide analog.
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Citations
18 Claims
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1. An oligonucleotide or an oligonucleotide analog comprising at least five covalently bound nucleoside units connected together by phosphate linkages, which nucleoside units individually comprise a ribose or deoxyribose sugar portion covalently bound to a base portion, wherein a plurality of base portions are pyrimidine bases;
- and at least one of said pyrimidine bases is a modified pyrimidine base having the structure;
##STR2## wherein;
X=OH or NH2 ;B is selected from the group consisting of; C-lower alkyl, N, C--CF3, C--F, C--Cl, C--Br, C--I, C-halocarbon, C--NO2, C--CF3, C--SH, C--SCH3, C--OH, C--O-lower alkyl, C--CH2 OH, C--CH2 SH, C--CH2 SCH3, C--CH2 OCH3, C--NH2, C--CH2 NH2, C--alkyl-NH2, C-benzyl, C-aryl, C-substituted aryl or benzyl wherein said substituents are selected from the group consisting of methyl, hydroxyl, alkoxy, alcohol, benzyl, phenyl, nitro, thiol, and halogen;
provided that when B is N, then said sugar portion to which said modified pyrimidine base is bound is deoxyribose; andA is selected from the group consisting of; C--H, N, C--CF3, C-halocarbon, C--NO2, C--OCF3, C--SH, C--SCH3, C--OH, C--O-lower alkyl, C--CH2 OH, C--CH2 SH, C--CH2 SCH3, C--CH2 OCH3, C--NH2, C--CH2 NH2, C-benzyl, C-aryl, C-substituted aryl or benzyl wherein said substituents are selected from the group consisting of methyl, hydroxyl, alkoxy, alcohol, benzyl, phenyl, nitro, thiol, and halogen. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
- and at least one of said pyrimidine bases is a modified pyrimidine base having the structure;
Specification
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Current AssigneeISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
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Original AssigneeISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
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InventorsCook, Philip D., Sanghvi, Yogesh S.
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Primary Examiner(s)Rories, Charles
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Application NumberUS07/971,978Time in Patent Office1,496 DaysField of Search514/44, 514/49, 536/23.1, 536/24.3, 536/24.31, 536/24.32, 536/24.5, 536/26.8, 536/24.33, 536/28.1, 536/28.3, 536/28.54, 536/28.55, 435/6, 935/3, 935/6-8, 935/33-35, 935/38, 935/44-46US Class Current536/23.1CPC Class CodesC07H 19/10 with the saccharide radical...C07H 19/12 Triazine radicalsC07H 21/00 Compounds containing two or...Y10T 436/143333 Saccharide [e.g., DNA, etc.]
