Amidite derivatives and oligonucleotide derivatives

Details Amidite derivatives and oligonucleotide derivatives Amidite derivatives and oligonucleotide derivatives

1997-12-22

2000-05-02

Riley, Jezia

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 111, 536 41, 536 221, 536 253, 536 2533, 536 2534, 435 6, 435 911, 435 912, C07H 2102, C07H 1900, C07H 2100, C07H 100

Patent

active

060574313

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention relates to amidite derivatives having a monosaccharide or a derivative thereof at their terminals. In particular, the present invention relates to oligonucleotide derivatives in which oligonucleotides are introduced into said amidite derivatives.
2. Description of the Related Art
In recent years, attempts have been made to suppress the expression of targeted genes using oligonucleotides, specifically antisense oligonucleotides. However, it was found that when administered directly into the body, the oligonucleotides were readily decomposed in the blood, or the greater portion was readily excreted in the urine. Moreover, the nucleotides were decomposed or excreted without being incorporated into the targeted cells of lesioned organs.
To resolve these problems, it has been reported that the formation of a conjugate of asialoorosomucoid with poly-L-lysine yields a complex which ionically interacts with the antisense oligonucleotide of human hepatitis B virus and the ionic complex enhanced the inhibitory effect of the antisence oligodeoxynucleotide on the biosynthesis of viral protein significantly (G. Y. Wu and C. H. Wu (1992) J. Biol. Chem. 267, 12436) and that the chloramphenicol acetyltransferase gene can be transferred into and expressed in the liver using a similar complex (G. Y. Wu and C. H. Wu (1991) Biotherapy 3, 879). Techniques used in these reports are described in WO 93/04701 and 92/20316. Furthermore, it is reported in WO 93/19768 that a complex formed between DNA and a saccharide derivative, which was covalently coupled with a molecule to intercalate into DNA by inserting in the double helix structure (i.e. intercalator) was incorporated into a cell which specifically recognized the saccharide such that it was useful for the efficient expression of genetic information. Nakai et al intravenously injected an antisense nucleic acid complex, and a simulation of the amount delivered into the liver showed that this type of non-covalently bonded complex easily dissociates in the blood to preclude any significant transfer into the liver (D. Nakai, T. Seita and Y. Sugiyama (1995) Pharm. Tech. Japan, 11, 27).
On the other hand, it is known that a compound in which galactose is introduced into carboxymethylated dextran (M. Nishikawa et al. (1993) Pharmaceutical Research 10, 1253), and a compound in which galactose is introduced into poly-L-glutamic acid are selectively distributed in hepatocytes (H. Hirabayashi et al (1994) Proceedings of the General Presentation of the 144th Annual Meeting of Japan Pharmacological Association 30(6) 15-4).


SUMMARY OF THE INVENTION

The present inventors have found that a complex of an oligonucleotide with an amidite derivative having a monosaccharide residue at its terminal is delivered to a specific organ and suppresses expression of a specific gene in cells of the organ. The present invention is based on these findings.
Accordingly, an objective of the present invention is to provide compounds which can incorporate oligonucleotides into organ cells, particularly into hepatocytes.
Another objective of the present invention is to provide amidite derivatives which are useful for synthesis of the compounds.
A compound of the present invention can be represented by general formula (I): ##STR3## in which X is group (II): ##STR4## (in which Y is a leaving group) or group (III): ##STR5## (in which Z is an oligonucleotide or its derivative), T.sup.1 is --(CH.sub.2)s-- (in which s represents an integer between 2 and 10), or (CH.sub.2 CH.sub.2 O)t--(CH.sub.2).sub.2 -- (in which t represents an integer between 1 and 3), 10), --(CH.sub.2 CH.sub.2 O)v--(CH.sub.2).sub.2 -- (in which v represents an integer between 1 and 3), or group (IV): ##STR6## in which T.sup.1 * and T.sup.1 ** are each as defined above for T.sup.1, and n*, p*, q*, T.sup.3 *, T.sup.4 * and F.sup.3 are each as defined below for n, p, q, T.sup.3, T.sup.4 and F.sup.1, where each group and its asterisk-labeled counterpart can be the same or d

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