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Modified phosphorous 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 Alan;
Assignee: La Jolla Pharmaceutical Company (San Diego, CA)
Primary Examiner: Ambrose; Michael G.
Assistant Examiner:
Attorney, Agent or Firm: Morrison & Foerster LLP
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 compound of the formula ##STR10## where (a) X.
sup.
1 is chlorine and X.
sup.
2 is methyl or RO--, or (b) X.
sup.
2 is RO-- and X.
sup.
1 is NR.
sup.
1 R.
sup.
2 where 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 4-7 carbon atom and 0 to 1 annular chalcogen atoms of atomic number 8 to 16 inclusive (O or S); R is a protecting group; G is a hydrocarbylene group of 2 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 bound to G by one of the sulfur at atoms of the disulfide group, with the proviso that G is of at least 4 carbon atoms when Z is said disulfide group.
2.
A phosphoramidite of the formula ##STR11## 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, 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, inclusive, G is a hydrocarbylene group of 2 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.
3.
The phosphoramidite of claim 2 where Z is ##STR12## where R.
sup.
3 and R.
sup.
4 are individually hydrogen, alkyl of 1 to 20 carbon atoms or monocyclic aryl of 6 to 20 carbon atoms, and Y.
sup.
1 and Y.
sup.
2 are individual hydroxy-protecting groups or are joined by a single-atom bridge to form a five-membered ring protecting group, or --S--S--R.
sup.
5 --O--Y.
sup.
3 where R.
sup.
5 is an alkylene group of 1 to 20 carbon atoms or a monocyclic arylene group of 6 to 20 carbon atoms and Y
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