Thiol-derivatized nucleosides
AssigneeIsis Pharmaceuticals, Inc.
InventorsPhillip D. Cook, Muthiah Manoharan
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Abstract
Nucleosides and linked nucleosides functionalized to include alkylthiol chemical functionality at ribofuranosyl positions, nucleosidic base positions, or on internucleoside linkages. In certain embodiments, the compounds of the invention further include steroids, reporter molecules, reporter enzymes, lipophilic molecules, peptides or proteins attached to the nucleosides through the alkylthio group.
Claims25
A nucleoside comprising a ribofuranosyl sugar portion and a base portion, wherein said nucleoside bears at a 2'-O-position, a 3'-O-position, or a 5'O-position a substituent having formula:
- --R.sub.s --S--R.sub.1
- where:
- R.sub.S has formula R.sub.A, R.sub.A --C(O)--Q--R.sub.A RA--Q--R.sub.A --Q--R.sub.A ;
- each R.sub.A is independently selected from alkyl having from 1 to about 10 carbon atoms;
- each Q is independently selected from NH, O, and S;
- R.sub.1 is H or a thiol protecting group or has formula S--R.sub.2, CH.sub.2 C(O)--NH--R.sub.2, --CH.sub.2 --CH.dbd.CH--C(O)--R.sub.2, --CH.sub.2 --CH.sub.2 --NH--S(O).sub.2 R.sub.2 ;
- or (maleimido)--R.sub.2;
- and
- R.sub.2 is a steroid molecule, a reporter molecule, a lipophilic molecule, a peptide, a protein, an alkylator, an intercalator, a crown ether, a crown amine, a porphyrin, a peptide nucleic acid, or a thiol attached to a poly(ethylene glycol).
The compound of claim 9 wherein R.sub.1 is CH.sub.2 C(O)--NH--R.sub.2 and R.sub.2 is o-phenanthroline.
A nucleoside comprising a ribofuranosyl sugar portion and a base portion, wherein said nucleoside bears at a 2'-O-position, a 3'-O-position, or a 5'-O-position a substituent having formula:
- --R.sub.S --S--R.sub.1
- where:
- R.sub.S has formula R.sub.A, R.sub.A --C(O)--Q--R.sub.A, R.sub.A --Q --R.sub.A --R.sub.A ;
- each R.sub.A is independently selected from alkyl having from 1 to about 10 carbon atoms;
- each Q is independently selected from NH, O, and S;
- R.sub.1 is H or a thiol protecting group or has formula S--R.sub.2, CH.sub.2 C(O)--NH--R.sub.2, CH.sub.2 --CH.dbd.CH--C(O)--R.sub.2, --CH.sub.2 --CH2--NH--S(O).sub.2 --R.sub.2, or (maleimido)--R.sub.2 ;
- and
- R.sub.2 is a crosslinking agent.
A nucleoside comprising a ribofuranosyl sugar portion and a base portion, wherein said nucleoside bears at a 5pyrimidine position or at a 2-, 6-, or 8-purine position a substituent having formula:
- --Q --R.sub.A --S--R.sub.1 ;
- or
- --C.tbd.C--R.sub.A --Q--C(0)--R.sub.A --S--R.sub.1 ;
- --CH.dbd.CH--C(O)--Q --R.sub.A --S--R.sub.1 ;
- or
- --CH.dbd.CH--R.sub.A --Q--C(O)--Q--R.sub.A --S--R.sub.1 ;
- where:
- each R.sub.A is independently alkyl having from 1 to about 10 carbon atoms;
- Q is NH, O, or S;
- R.sub.1 is H or a thiol protecting group or has formula
- S--R.sub.2, CH.sub.2 C(O)--NH--R.sub.2, CH.sub.2 --CH.dbd.CH--C(O)--R.sub.2, --CH.sub.2 --CH.sub.2 --NH --S(O).sub.2 R.sub.2, or (maleimido)--R.sub.2 ;
- and
- R.sub.2 is a steroid molecule, a reporter molecule, a lipophilic molecule, a peptide, a protein, an alkylator, an intercalator, a crown ether, a crown amine, a porphyrin, a peptide mucleic acid, or a thiol attached to a poly(ethylene glycol);
- provided that a 6-purine substituent does not have formula --NH--R.sub.A --S--R.sub.1 when R.sub.1 is H or a thiol protecting group.
A nucleoside comprising a ribofuranosyl sugar portion and a base portion, wherein said nuceloside bears at a 5-pyrimidine positon or at a 2-, 6-, or 8-purine position a substitutent having formula:
- --Q--R.sub.A --S--R.sub.1 ;
- or
- --C.tbd.C--R.sub.A --Q--C(O)--R.sub.A --S--R.sub.1 ;
- --CH.dbd.Ch--C(O)--Q--R.sub.A --S--R.sub.1 ;
- or
- --CH.dbd.CH--R.sub.A --Q--C(O)--Q--R.sub.A --S--R.sub.1 ;
- wherein:
- each R.sub.A is independently alkyl having from 1 to about 10 carbon atoms;
- Q is NH, O, or S;
- R.sub.1 is H or a thiol protecting group or has formula S--R.sub.2, CH.sub.2 C(O)--NH--R.sub.2, CH.sub.2 --CH.dbd.CH--C(O)--R.sub.2, --CH.sub.2 --CH.sub.2 --NH--S(O)--.sub.2 --R.sub.2, or (maleimido)--R.sub.2 ;
- and
- R.sub.2 is a crosslinking agent;
- provided that a 6-purine substituent does not have formula --NH--R.sub.A --S--R.sub.1 when R.sup.1 is H or a thiol protecting group.
A process for derivatizing a nucleoside bearing a 2'-hydroxy group, a 3'-hydroxy group, or a 5'-hydroxy group, comprising contacting said nucleoside with a compound having formula L.sub.1 --R.sub.A --S--R.sub.1a for a time and under conditions effective to form a linkage having formula --O--R.sub.A --S--R.sub.1a, wherein L.sub.1 is a leaving group and R.sub.1a is an acid labile thiol protecting group.
Dependencies are inferred from the claim text.