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Intermediates for providing functional groups on the 5' end of oligonucleotides
| Details |
Inventors: Jones, David S.; Hachmann, John P.; Conrad, Michael J.; Coutts, Stephen; Livingston, Douglas A.;
Assignee: La Jolla Pharmaceutial Company (San Diego, CA)
Primary Examiner: Rollins; John W.
Assistant Examiner: Crane; L. Eric
Attorney, Agent or Firm: Morrison & Foerster
Phosphoramidites of the formula ##STR1## where R is a base-labile protecting group, R.sup.1 and R.sup.2 are individually alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or aryl of 6 to 20 carbon atoms or are joined together to form with the nitrogen atom a cyclic structure of 4-7 carbon atoms and 0 to 1 annular chalcogen atoms of atomic number 8 to 16, G is a hydrocarbylene group of 1 to 20 carbon atoms and Z is a hydroxy-protected vicinal diol group bound to G by one of the vicinal diol carbon atoms or a disulfide group and bound to G by one of the sulfur atoms of the disulfide group, with the proviso that G is of at least 4 carbon atoms when Z is said disulfide group are used in conventional automated oligonucleotide synthesis to introduce a functional aldehyde or thiol group on the 5' end of the oligonucleotide to thereby provide a reactive site on the oligonucleotide that may be used to conjugate the oligonucleotide to molecules that contain a free amino group or an electrophilic center reactive with a thiol group. |
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DETAILED DESCRIPTION We claim: 1.
A partially protected alcohol of the formula: ##STR10## wherein Y.
sup.
1 is selected from dimethoxytrityl, monomethoxytrityl, trityl or pixyl, Y.
sup.
2 is selected from benzoyl, acetyl, isobutyryl, p-bromobenzoyl, t-butyldimethylsilyl, pivaloyl or other base hydrolyzable acyl groups and G is selected from alkyl of 1 to 20 carbon atoms or monocyclic arylene of 6 to 20 carbon atoms.
2.
The alcohol of claim 1, wherein Y.
sup.
1 is dimethoxytrityl, Y.
sup.
2 is benzoyl and G is butylene.
3.
The alcohol of claim 1, wherein G is alkylene of 4 to 20 carbons.
4.
The alcohol of claim 1, wherein G is butylene.
5.
The alcohol of claim 1, wherein Y1 is dimethoxytrityl (DMT).
6.
The alcohol of claim 1, wherein Y2 is benzoyl.
Description:
DESCRIPTION 1.
Technical Field This invention is in the field of organophosphate chemistry and solid state oligonucleotide synthesis.
More particularly, it concerns reactive phosphorous intermediates that may be stably attached to the 5' end of an oligonucleotide and which have an activatable moiety which, when activated, provides a functional aldehyde or sulfhydryl group that may be used to conjugate the oligonucleotide to any molecule having a free amino group.
2.
Background It is necessary to provide oligonucleotides with a free functional group in order to couple the oligonucleotide to labels, ligands, solid surfaces, polymers or other molecules or surfaces.
One technique for providing oligonucleotides with a terminal functional group involves synthesizing the desired oligonucleotide by conventional solid-state automated synthesis procedures and incorporating the functional group at the 5' end of the oligonucleotide via a modified phosphoramidite.
Agrawal, S.
, et al.
, Nucl.
Acids Res.
(1986) 14:6227-6245, describes a modified phosphoramidite that may be introduced on the 5' of an oligonucleotide that has an activatable group that may be activated through deprotection to provide a free amino group on the 5' terminus of the oligonucleotide
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Gene Therapy 
