Substituted purines and oligonucleotide cross-linking
First Claim
1. A compound having the formula:
- ##STR25## wherein;
G is CR1 ;
R1 is a hydrocarbyl group having from 1 to 6 carbon atoms;
X is halogen, NH2, OH, NHR2 Q1 or OR2 Q1, wherein said R2 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q1 comprises a reactive or non-reactive functionality;
Y is halogen, NH2, H, R3 Q2, or NHR3 Q2, wherein said R3 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q2 comprises a reactive or non-reactive functionality;
W is H, R4 Q3, or NHR4 Q3, wherein said R4 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q3 comprises a reactive or non-reactive functionality;
Z is a ribose sugar analog or a deoxyribose sugar analog which bears at least one substituent at the 3'"'"' or 5'"'"' position of said deoxyribose sugar analog, or at the 2'"'"', 3'"'"', or 5'"'"' position of said ribose sugar analog;
said substituent being selected from the group consisting of O, H, lower alkyl, substituted lower alkyl, aralkyl, heteroaralkyl, heterocycloalkyl, amino-alkylamino, heterocycloalkyl, polyalkylamino, substituted silyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, SOMe, SO2 Me, ONO2, NO2, N3, NH2, NH-alkyl, OCH2 CH═
CH2, OCH═
CH2, OCH2 CCH, OCCH, OCCHO, and an RNA cleaving moiety;
said reactive functionality is selected from the group consisting of halogens, heterocycles, heterocycloalkyls, heterocycloalkylamines, polyalkylamines, aminoalkylamines, ethers, esters, aldehydes, ketones, aryl groups, hydrazines, hydroxylamines, semicarbazides, thiosemicarbazides, hydrazones, hydrazides, alcohols, and thiols; and
said unreactive functionality is selected from the group consisting of alkyl groups, polyamides, intercalators, and ethylene glycols.
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Abstract
This invention is directed to novel purine-based compounds for inclusion into oligonucleotides. The compounds of the invention, when incorporated into oligonucleotides are especially useful as "antisense" agents--agents that are capable of specific hybridization with a nucleotide sequence of an RNA. The compounds of the invention may also be used for cross-linking oligonucleotides. Oligonucleotides are used for a variety of therapeutic and diagnostic purposes, such as treating diseases, regulating gene expression in experimental systems, assaying for RNA and for RNA products through the employment of antisense interactions with such RNA, diagnosing diseases, modulating the production of proteins, and cleaving RNA in site specific fashions. The compounds of the invention include novel heterocyclic bases, nucleosides, and nucleotides. When incorporated into oligonucleotides, the compounds of the invention can be useful for modulating the activity of RNA.
64 Citations
83 Claims
-
1. A compound having the formula:
- ##STR25## wherein;
G is CR1 ;R1 is a hydrocarbyl group having from 1 to 6 carbon atoms; X is halogen, NH2, OH, NHR2 Q1 or OR2 Q1, wherein said R2 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q1 comprises a reactive or non-reactive functionality; Y is halogen, NH2, H, R3 Q2, or NHR3 Q2, wherein said R3 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q2 comprises a reactive or non-reactive functionality; W is H, R4 Q3, or NHR4 Q3, wherein said R4 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q3 comprises a reactive or non-reactive functionality; Z is a ribose sugar analog or a deoxyribose sugar analog which bears at least one substituent at the 3'"'"' or 5'"'"' position of said deoxyribose sugar analog, or at the 2'"'"', 3'"'"', or 5'"'"' position of said ribose sugar analog;
said substituent being selected from the group consisting of O, H, lower alkyl, substituted lower alkyl, aralkyl, heteroaralkyl, heterocycloalkyl, amino-alkylamino, heterocycloalkyl, polyalkylamino, substituted silyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, SOMe, SO2 Me, ONO2, NO2, N3, NH2, NH-alkyl, OCH2 CH═
CH2, OCH═
CH2, OCH2 CCH, OCCH, OCCHO, and an RNA cleaving moiety;said reactive functionality is selected from the group consisting of halogens, heterocycles, heterocycloalkyls, heterocycloalkylamines, polyalkylamines, aminoalkylamines, ethers, esters, aldehydes, ketones, aryl groups, hydrazines, hydroxylamines, semicarbazides, thiosemicarbazides, hydrazones, hydrazides, alcohols, and thiols; and said unreactive functionality is selected from the group consisting of alkyl groups, polyamides, intercalators, and ethylene glycols. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 31, 32, 68, 69)
- ##STR25## wherein;
-
12. A compound having the formula:
- ##STR26## wherein;
G is N;X is NHR2 Q1 or OR2 Q1, wherein said R2 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q1 comprises a reactive or non-reactive functionality; Y is halogen, NH2, H, R3 Q2, or NHR3 Q2, wherein said R3 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q2 comprises a reactive or non-reactive functionality; W is R4 Q3, or NHR4 Q3, wherein said R4 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q3 comprises a reactive or non-reactive functionality; Z is a ribose sugar analog or a deoxyribose sugar analog which bears at least one substituent at the 3'"'"' or 5'"'"' position of said deoxyribose sugar analog, or at the 2'"'"', 3'"'"', or 5'"'"' position of said ribose sugar analog;
said substituent being selected from the group consisting of O, H, lower alkyl, substituted lower alkyl, aralkyl, heteroaralkyl, heterocycloalkyl, amino-alkylamino, heterocycloalkyl, polyalkylamino, substituted silyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, SOMe, SO2 Me, ONO2, NO2, N3, NH2, NH-alkyl, OCH2 CH═
CH2, OCH═
CH2, OCH2 CCH, OCCH, OCCHO, and an RNA cleaving moiety;said reactive functionality is selected from the group consisting of halogens, heterocycles, heterocycloalkyls, heterocycloalkylamines, polyalkylamines, aminoalkylamines, ethers, esters, aldehydes, ketones, aryl groups, hydrazines, hydroxylamines, semicarbazides, thiosemicarbazides, hydrazones, hydrazides, alcohols, and thiols; and said unreactive functionality is selected from the group consisting of alkyl groups, polyamides, intercalators, and ethylene glycols. - View Dependent Claims (13, 14, 15)
- ##STR26## wherein;
-
16. A compound having the formula:
- ##STR27## wherein;
G is N;X is halogen, NH2, OH, NHR2 Q1 or OR2 Q1, wherein said R2 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q1 comprises a reactive or non-reactive functionality; Y is R3 Q2, or NHR3 Q2, wherein said R3 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q2 comprises a reactive or non-reactive functionality; W is R4 Q3, or NHR4 Q3, wherein said R4 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q3 comprises a reactive or non-reactive functionality; Z is a ribose sugar analog or a deoxyribose sugar analog which bears at least one substituent at the 3'"'"' or 5'"'"' position of said deoxyribose sugar analog, or at the 2'"'"', 3'"'"', or 5'"'"' position of said ribose sugar analog;
said substituent being selected from the group consisting of O, H, lower alkyl, substituted lower alkyl, aralkyl, heteroaralkyl, heterocycloalkyl, amino-alkylamino, heterocycloalkyl, polyalkylamino, substituted silyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, SOMe, SO2 Me, ONO2, NO2, N3, NH2, NH-alkyl, OCH2 CH═
CH2, OCH═
CH2, OCH2 CCH, OCCH, OCCHO, and an RNA cleaving moiety;said reactive functionality is selected from the group consisting of halogens, heterocycles, heterocycloalkyls, heterocycloalkylamines, polyalkylamines, aminoalkylamines, ethers, esters, aldehydes, ketones, aryl groups, hydrazines, hydroxylamines, semicarbazides, thiosemicarbazides, hydrazones, hydrazides, alcohols, and thiols; and said unreactive functionality is selected from the group consisting of alkyl groups, polyamides, intercalators, and ethylene glycols. - View Dependent Claims (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 70)
- ##STR27## wherein;
-
33. An oligonucleotide having at least one nucleotide of the formula:
- ##STR28## wherein;
G is CR1 or N;R1 is H or a hydrocarbyl group having from 1 to 6 carbon atoms; X is halogen, NH2, OH, NHR2 Q1 or OR2 Q1, wherein said R2 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q1 comprises a reactive or non-reactive functionality; Y is halogen, NH2, H, R3 Q2, or NHR3 Q2, wherein said R3 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q2 comprises a reactive or non-reactive functionality; W is H, R4 Q3, or NHR4 Q3, wherein said R4 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q3 comprises a reactive or non-reactive functionality; Z is a ribose sugar analog or a deoxyribose sugar analog which bears at least one substituent at the 3'"'"' or 5'"'"' position of said deoxyribose sugar analog, or at the 2'"'"', 3'"'"', or 5'"'"' position of said ribose sugar analog;
said substituent being selected from the group consisting of O, H, lower alkyl, substituted lower alkyl, aralkyl, heteroaralkyl, heterocycloalkyl, amino-alkylamino, heterocycloalkyl, polyalkylamino, substituted silyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, SOMe, SO2 Me, ONO2, NO2, N3, NH2, NH-alkyl, OCH2 CH═
CH2, OCH═
CH2, OCH2 CCH, OCCH, OCCHO, and an RNA cleaving moiety;said reactive functionality is selected from the group consisting of halogens, heterocycles, heterocycloalkyls, heterocycloalkylamines, polyalkylamines, aminoalkylamines, ethers, esters, aldehydes, ketones, aryl groups, hydrazines, hydroxylamines, semicarbazides, thiosemicarbazides, hydrazones, hydrazides, alcohols, and thiols; said unreactive functionality is selected from the group consisting of alkyl groups, polyamides, intercalators, and ethylene glycols; and wherein at least one of X, Y and W is selected such that X is NHR2 Q1, or OR2 Q1, Y is R3 Q2 or NHR3 Q2, or W is NHR4 Q3. - View Dependent Claims (34, 35, 36, 37, 43)
- ##STR28## wherein;
-
38. An oligonucleotide for affecting RNase H cleavage of RNA comprising:
-
a first oligonucleotide region and a second oligonucleotide region; together said first and said second region having a nucleotide sequence essentially complementary to at least a portion of said RNA; said first region including at least one compound of the formula;
##STR29## wherein;
G is CR1 or N;R1 is H or a hydrocarbyl group having from 1 to 6 carbon atoms; X is halogen, NH2, OH, NHR2 Q1 or OR2 Q1, wherein said R2 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q1 comprises a reactive or non-reactive functionality; Y is halogen, NH2, H, R3 Q2, or NHR3 Q2, wherein said R3 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q2 comprises a reactive or non-reactive functionality; W is H, R4 Q3, or NHR4 Q3, wherein said R4 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q3 comprises a reactive or non-reactive functionality; Z is a ribose sugar analog or a deoxyribose sugar analog which bears at least one substituent at the 3'"'"' or 5'"'"' position of said deoxyribose sugar analog, or at the 2'"'"', 3'"'"', or 5'"'"' position of said ribose sugar analog;
said substituent being selected from the group consisting of O, H, lower alkyl, substituted lower alkyl, aralkyl, heteroaralkyl, heterocycloalkyl, amino-alkylamino, heterocycloalkyl, polyalkylamino, substituted silyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, SOMe, SO2 Me, ONO2, NO2, N3, NH2, NH-alkyl, OCH2 CH═
CH2, OCH═
CH2, OCH2 CCH, OCCH, OCCHO, and an RNA cleaving moiety;said reactive functionality is selected from the group consisting of halogens, heterocycles, heterocycloalkyls, heterocycloalkylamines, polyalkylamines, aminoalkylamines, ethers, esters, aldehydes, ketones, aryl groups, hydrazines, hydroxylamines, semicarbazides, thiosemicarbazides, hydrazones, hydrazides, alcohols, and thiols; said unreactive functionality is selected from the group consisting of alkyl groups, polyamides, intercalators, and ethylene glycols; wherein at least one of X, Y and W is selected such that X is NHR2 Q1 or OR2 Q1, Y is R3 Q2 or NHR3 Q2, or W is NHR4 Q3 ; and said second region including a plurality of consecutive phosphorothioate linked nucleotides having a 2'"'"'-deoxy-erythropentofuranosyl sugar moiety. - View Dependent Claims (39, 40, 41, 42, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67)
-
-
71. A compound having the formula:
- ##STR30## wherein;
G is N;X is OR2 Q1, wherein said R2 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q1 comprises a reactive or non-reactive functionality; Y is halogen, H, R3 Q2, or NHR3 Q2, wherein said R3 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q2 comprises a reactive or non-reactive functionality; W is H; Z is H, a nitrogen protecting group, or Z is a ribose sugar analog or a deoxyribose sugar analog which bears at least one substituent at the 3'"'"' or 5'"'"' position of said deoxyribose sugar analog, or at the 2'"'"', 3'"'"', or 5'"'"' position of said ribose sugar analog;
said substituent being selected from the group consisting of O, H, lower alkyl, substituted lower alkyl, aralkyl, heteroaralkyl, heterocycloalkyl, amino-alkylamino, heterocycloalkyl, polyalkylamino, substituted silyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, SOMe, SO2 Me, ONO2, NO2, N3, NH2, NH-alkyl, OCH2 CH═
CH2, OCH═
CH2, OCH2 CCH, OCCH, OCCHO, and an RNA cleaving moiety;
provided that where Y is NHR3 Q2, said nucleoside sugar moiety is not a 2'"'"'-fluoro arabinofuranosyl sugar moiety;said reactive functionality is selected from the group consisting of halogens, heterocycles, heterocycloalkyls, heterocycloalkylamines, polyalkylamines, aminoalkylamines, ethers, esters, aldehydes, ketones, aryl groups, hydrazines, hydroxylamines, semicarbazides, thiosemicarbazides, hydrazones, hydrazides, alcohols, and thiols; and said unreactive functionality is selected from the group consisting of alkyl groups, polyamides, intercalators, and ethylene glycols. - View Dependent Claims (72, 73)
- ##STR30## wherein;
-
74. The compound of claim 74 wherein said Z bears a substituent selected from the group consisting of F, CF3, OCF3, OCN, O-alkyl, S-alkyl, NH-alkyl, SOMe, SO2 Me, OCH2 CH═
- CH2, OCH═
CH2, OCH2 CCH, OCCH, OCCHO and an RNA cleaving moiety; and
said modified phosphate is a methylphosphonate, phosphorothioate, phosphorodithioate, phosphoramidite, or phosphorotriester.
- CH2, OCH═
-
75. A compound having the formula:
- ##STR31## wherein;
G is N;X is NHR2 Q1 wherein said R2 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q1 comprises a reactive or non-reactive functionality; Y is R3 Q2, or NHR3 Q2, wherein said R3 is a hydrocarbyl group having from 1 to about 20 carbon atoms, and Q2 comprises a reactive or non-reactive functionality; W is H; Z is H, a nitrogen protecting group, or Z is a ribose sugar analog or a deoxyribose sugar analog which bears at least one substituent at the 3'"'"' or 5'"'"'3 position of said deoxyribose sugar analog, or at the 2'"'"', 3'"'"', or 5'"'"' position of said ribose sugar analog;
said substituent being selected from the group consisting of O, H, lower alkyl, substituted lower alkyl, aralkyl, heteroaralkyl, heterocycloalkyl, amino-alkylamino, heterocycloalkyl, polyalkylamino, substituted silyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, SOMe, SO2 Me, ONO2, NO2, N3, NH2, NH-alkyl, OCH2 CH═
CH2, OCH═
CH2, OCH2 CCH, OCCH, OCCHO, and an RNA cleaving moiety;
provided that where X is NHR2 Q1 and Y is NHR3 Q2, said nucleoside sugar moiety is not a 2'"'"'-fluoro arabinofuranosyl sugar moiety;said reactive functionality is selected from the group consisting of halogens, heterocycles, heterocycloalkyls, heterocycloalkylamines, polyalkylamines, aminoalkylamines, ethers, esters, aldehydes, ketones, hydrazines, hydroxylamines, semicarbazides, thiosemicarbazides, hydrazones, hydrazides, alcohols, and thiols; and said unreactive functionality is selected from the group consisting of alkyl groups, polyamides, intercalators, and ethylene glycols. - View Dependent Claims (76, 77, 78)
- ##STR31## wherein;
-
79. A cross-linked nucleic acid comprising:
-
a first oligonucleotide region and a second oligonucleotide region, wherein said first region includes at least one nucleotide of the formula;
##STR32## wherein;
G is CR5 or N;R5 is H or a hydrocarbyl group having from 1 to 6 carbon atoms; X is halogen NH2, OH, NHR6 Q1, OR6 Q1, NHJ, OJ or SJ wherein said R6 is H or a hydrocarbyl group having from 2 to about 20 carbon atoms; Q1 comprises at least one reactive or non-reactive functionality; J comprises a space spanning group R7 and an active functional group Q4 ; Y is halogen, NH2, H, SH, OH, NHJ, OJ or SJ where J comprises a space spanning group R7 and an active functional group Q4 ; W is H, NHK, OK or SK where K comprises a space spanning group R7 and an active non-psoralen functional group Q5 ; Z is a ribose sugar analog or a deoxyribose sugar analog which bears at least one substituent at the 3'"'"' or 5'"'"' position of said deoxyribose sugar analog, or at the 2'"'"', 3'"'"', or 5'"'"' position of said ribose sugar analog;
said substituent being selected from the group consisting of O, H, lower alkyl, substituted lower alkyl, aralkyl, heteroaralkyl, heterocycloalkyl, amino-alkylamino, heterocycloalkyl, polyalkylamino, substituted silyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, SOMe, SO2 Me, ONO2, NO2, N3, NH2, NH-alkyl, OCH2 CH═
CH2, OCH═
CH2, OCH2 CCH, OCCH, OCCHO, and an RNA cleaving moiety;said space spanning group R7 is a hydrocarbyl group having from 2 to about 20 carbon atoms; at least one of said X or Y groups is NHJ, OJ or SJ, or at least one of said W groups is NHK, OK or SK; and said second region includes a second nucleotide of said formula capable of covalently bonding with said J group or said W group of said nucleotide of said formula in said first oligonucleotide region thereby forming a covalent cross-linkage between said first and said second oligonucleotide regions. - View Dependent Claims (80, 81, 82, 83)
-
Specification