Claims
- 1. A compound having the formula (III): ##STR45## wherein A is H, O, OH, OR.sup.6, NR.sup.7 R.sup.8, N.sub.3, NHCOR.sup.7, OCOAr, O--CO--OR.sup.9, O--CO--R.sup.9, NCH.sub.2 C.sub.6 H.sub.5, and in which Ar is phenyl or phenyl substituted with 1-3 groups selected from the group consisting of halogen, C.sub.1 -C.sub.12 alkyl or C.sub.1 -C.sub.3 alkoxy;
- "a" is a single bond in the alpha or beta configuration with the proviso that when A.dbd.O, "a" is a double bond;
- R.sup.3 is H, OH or OR.sup.6 ;
- R.sup.4 is H, OH or OR.sup.6 ;
- R.sup.5 is CO.sub.2 R.sup.10, CH.sub.2 OR.sup.9, CONH.sub.2, CONHR.sup.7, CONR.sup.7 R.sup.8, CO--S--R.sup.10, CH.sub.2 S(O).sub.p --S--R.sup.10, CH.sub.2 NH.sub.2, CH.sub.2 NHR.sup.7, CH.sub.2 NR.sup.7 R.sup.8, CH.sub.2 --S(O).sub.p --S--R.sup.10 ;
- R.sup.6 is glycosyl moiety comprising 1-10 monosaccharide units in which the glycosidic linkage at the anomeric carbon atom of each monosaccharide unit is independently alpha or beta;
- R.sup.7 and R.sup.8, independently are H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 alkylcycloalkyl, phenyl, benzyl, or, taken together are (CH.sub.2).sub.f, where f=3-6;
- R.sup.9 is H or C.sub.1 -C.sub.3 alkyl;
- R.sup.10 is H, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkenyl, C.sub.1 -C.sub.10 alkynyl, C.sub.6 H.sub.5 or CH.sub.2 C.sub.6 H.sub.5 ;
- p is 0, 1 or 2;
- n is 0, 1 or 2;
- u is 0, 1, 2, 3, 4 or 5;
- v is 0, 1, 2, 3, 4 or 5, so long as u and v are not both 0;
- Oligo represents an oligonucleotide covalently attached to the group A or R.sup.5 either directly or via a linker group;
- or a salt thereof.
- 2. A process for the preparation of a compound of the formula (I), with "a", A, n, and the R groups as defined previously in claim 1, which comprises: ##STR46## (a) reacting a protected glycoside, where the oxygen atoms at all positions of the sugar except the anomeric position are protected with the same or different groups selected from the group including esters and ethers such as alkyl, silyl, phenyl, or benzyl, with
- (b) an S--R entity under standard conditions where R is C.sub.1 -C.sub.10 alkyl, pyridyl, furyl, thienyl, phenyl substituted with 1-3 groups selected from the group comprising halogen, C.sub.1 -C.sub.3 alkyl, NO.sub.2, C.sub.1 -C.sub.3 alkoxy, to yield a protected thio-glycoside which is further reacted with
- (c) meta-chloroperoxybenzoic acid to yield the corresponding sulfoxide derivative and
- (d) converted to an activated glycosylating agent intermediate with a triflate-containing compound, such as triflic anhydride, methyl triflate, or trimethylsilyltriflate at -78.degree. C. and contacting said activated glycosylating agent with
- (e) a steroid (in which any oxygens which are not to be glycosylated have been protected by standard methods) in the presence of 2,6-di-tert-butyl-4-methylpyridine in toluene, for formation of .alpha.,.alpha. glycoside linkages, or in propionitrile, for the formation of .beta.,.beta. linkages which is then
- (f) deprotected to yield glycosylated steroids of the formula (I).
- 3. The conjugate of claim 1 in which said oligonucleotide is an antisense oligonucleotide.
- 4. The conjugate of claim 1 in which said oligonucleotide has a sequence corresponding to a splice acceptor site or its complement.
- 5. The conjugate of claim 4 in which said oligonucleotide has the sequence 5' ACA CCC AAT TCT GAA AAT GG 3' (SEQ ID NO:1) or its complement.
- 6. The conjugate of claim 1 in which said oligonucleotide has a sequence corresponding to a primer binding site or its complement.
- 7. The conjugate of claim 6 in which said oligonucleotide has the sequence 5' AAG TCC CTG TTC GGG CGC CA 3' (SEQ ID NO:2) or its complement.
Parent Case Info
This application is a continuation-in-part (CIP) of co-pending application Ser. No. 08/230,685, filed Apr. 20, 1994, which is a CIP of co-pending Ser. No. 07/989,667, filed Dec. 14, 1992, which in turn is a CIP of Ser. No. 07/806,985, filed Dec. 13, 1991, now U.S. Pat. no. 5,338,837, the complete disclosures of which are incorporated by reference herein.
Government Interests
This invention was made with Government support under ONR Grant No. N0014-91-J-1230. The Government has certain rights in this invention.
Continuation in Parts (3)
|
Number |
Date |
Country |
Parent |
230685 |
Apr 1994 |
|
Parent |
989667 |
Dec 1992 |
|
Parent |
806985 |
Dec 1991 |
|