Compositions and methods for modulating RNA
AssigneeIsis Pharmaceuticals, Inc.
InventorsPhillip Dan Cook, Thomas Bruice, Charles John Guinosso, Andrew Mamoru Kawasaki, Richard Griffey
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Abstract
Compositions and methods for modulating the activity of RNA are disclosed. In accordance with preferred embodiments, antisense compositions are prepared comprising targeting and reactive portions. The reactive portions preferably comprise one or two imidazole functionalities conjugated to the targeting oligonucleotide via linkers with or without intervening intercalating moieties. Therapeutics, diagnostics and research methods also are disclosed, as are synthetic nucleosides and nucleoside fragments that can be elaborated into oligonucleotides.
Claims60
A compound of the structure:
- G0-G1-G2-G3
- wherein:
- G0 is a nucleoside, a nucleotide or an oligonucleotide;
- G1 is a bivalent linking moiety;
- G2 is an aryl or heteroaryl moiety;
- and
- G3 is an RNA cleaving moiety having at least general acid/base properties.
A compound of the structure:
- 11
- wherein:
- T5 is H, a hydroxyl protecting group, a phosphate group, a nucleotide or an oligonucleotide;
- T3 is H, a hydroxyl protecting group, a nucleotide, an oligonucleotide, a phosphate group, an activated phosphate group or a solid phase support;
- G1′ is a connecting atom;
- G1″ is a bivalent linking moiety;
- G2 is an aryl or heteroaryl moiety;
- G3 is an RNA cleaving moiety;
- and
- Bx is a heterocyclic base moiety.
A compound of the structure:
- 12
- wherein:
- T5 is H, a hydroxyl protecting group, a phosphate group, a nucleotide or an oligonucleotide;
- T3 is H, a hydroxyl protecting group, a nucleotide, an oligonucleotide, a phosphate group, an activated phosphate group or a solid phase support;
- G1′ is a connecting atom;
- G1″ is alkynyl;
- and
- Bx is a heterocyclic base moiety, provided that when Bx is uracil then T3 and T5 are not H or acetyl.
A chemical compound having one of the structures:
- 13
- wherein
- RA is aryl, substituted aryl, or nitrogen heterocyclic;
- RB is Sg-G1′-G1″, Sg-, Bx-, or L-;
- RC is H, O−, COO−, ORG, NH2, C(RG) (RH) (RI), N(RG) (RH) (RI), Cl, Br, F, CF3, SRG, NHC(O)RG, OC(O)RG, NO, nitrogen heterocyclic or another electron donating group;
- RD is (CH2)q;
- RE is H, (CH2)n-RJ, or a chemical functional group comprising RJ;
- RF is C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl, aryl, or cycloalkyl;
- RG, RH, and RI are, independently, H, C1-C10 alkyl, or substituted alkyl;
- RJ is H, nitrogen heterocyclic, a positively charged group, or a phosphoryl hydrogen bond donating group;
- RK is alkyl, acyl or acyl-alkyl;
- Z is NH2 or CH2;
- RL is H or OH;
- Bx is a purine or pyrimidine base or a derivative thereof;
- L is a sugar-linking group;
- Sg is a naturally occurring or non-naturally occurring sugar;
- G1′ is O, S, NH or N-alkyl;
- G1″ is C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl;
- n is from about 1 to about 5;
- and
- q is from about 0 to about 5.
A composition for modulating the activity of RNA, comprising:
- a targeting portion specifically hybridizable with a preselected nucleotide sequence of the RNA;
- and
- a ribofuranosyl nucleotide which bears at its 2′ site a reactive portion capable of intercalating and cleaving RNA.
A process for preparing a compound having structure:
- 15
- wherein:
- T5 and T3 are hydroxyl protecting groups;
- G1′ is O, S, NH or N-alkyl;
- G1″ is alkynyl, alkenyl or alkyl;
- G2 is an aryl or heteroaryl moiety;
- G3 is an RNA cleaving moiety;
- and
- Bx is a heterocyclic base moiety comprising the steps of:
- providing a first reactant having structure:
- 16
- contacting said first reactant with a second reactant having structure T6O-G2-OT6 wherein T6 is a leaving group, said contacting being performed under conditions effective to produce a third reactant wherein having structure:
- 17
- contacting said third reactant with a fourth reactant having structure T7-G3-M-T8 wherein M is Sn, T7 is a blocking group, and T8 is group having one or more alkyl moieties each having 1 to about 5 carbon atoms, said contacting being performed under conditions effective to produce said compound.
Dependencies are inferred from the claim text.