Nucleosides having bicyclic sugar moiety

Details Nucleosides having bicyclic sugar moiety Nucleosides having bicyclic sugar moiety

2002-04-30

2004-12-21

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S046000, C514S047000, C514S048000, C514S049000, C514S050000, C514S051000, C536S026700, C536S026800

Reexamination Certificate

active

06833361

ABSTRACT:

FIELD OF THE INVENTION
The field of the invention is nucleoside analogues and methods of their use.
BACKGROUND
Nucleoside and nucleotide analogs have long been used as pharmaceutical ingredients against a variety of viruses and cancers. Currently, a number of nucleoside and nucleotide analogues are in clinical trials for several diseases.
In the cell, nucleosides and nucleotides are phosphorylated or further phosphorylated to the corresponding nucleoside triphosphates. Nucleoside triphosphates serve as inhibitors of DNA or RNA polymerases. Nucleoside triphosphates can also be incorporated into DNA or RNA, which interferes with the elongation of DNA or RNA.
Active nucleoside analogues are generally readily phosphorylated in the target cell. Corresponding nucleoside triphosphates have a high affinity to catalytic sites of the polymerases and compete with the natural nucleoside triphosphates as the substrate of the polymerases.
Certain nucleoside analogues work at the nucleoside or the monophosphate level. One group of promising nucleoside analogues is the nucleosides with conformationally locked sugar moieties. It has been reported that certain conformationally locked carbocyclic nucleoside analogues demonstrated potent activity against HCMV, HSV, and EBV (Siddiqui et al.
Nucleosides Nucleotides
1996, 15, 235-250; Marquez et al.
J. Med. Chem
. 1996, 39, 3739-3747). A conformationally locked, carbocyclic AZT 5′-triphosphate has been reported to be an equipotent inhibitor of HIV reverse transcriptase (Marquez et al.
J. Am. Chem. Soc
. 1998, 120, 2780-2789). Other nucleosides with bicyclic sugar moieties were also prepared even though no activity was found or reported (Chao et al.
Tetrahedron
1997, 53, 1957-1970; Okabe et al.
Tetrahedron lett
. 1989, 30, 2203-2206, Hong, et al.
Tetrahedron Lett
. 1998, 39, 225-228).
Favorable, conformationally locked nucleosides are expected to have a positive impact on antisense oligonucleotides. Oligonucleotides, as potential antisense therapeutics, have been recognized and explored for two decades. Oligonucleotides are capable of forming a double or triple helix with complementary DNA or RNA and have the ability to target the specific sequences in the viral and cancer genome. Specific binding of oligonucleotides to the DNA or RNA targets of interest would inactivate the function associated with the DNA or RNA such as replication, transcription, and translation. Therefore, viral cycles, or cancerous processes can be interrupted while the normal cell cycles are not affected.
Since natural oligonucleotides are labile to the cellular and extracellular nucleases, a great deal of efforts has been made on the study of oligonucleotide modifications, especially those modifications aimed at improving nuclease resistance and binding affinity. Oligonucleotides containing certain bicyclic nucleosides have been shown to demonstrate improved nuclease stability (Leumann et al.
Bioorg. Med. Chem. Letts
. 1995, 5, 1231-4; Altmann et al.
Tetrahedron Lett
. 1994, 35, 2331-2334, 7625-7628). Recently, 2′-O, 4′-C-methylene ribonucleosides, which have a locked 3′-endo sugar pucker, were synthesized and incorporated into oligonucleotides. Hybridization studies show that conformationally locked nucleosides can significantly enhance hybridization of modified oligonucleotides to the complementary RNA and DNA (Obika et al.
Tetrahedron Lett
. 1997, 38, 8735-8738; Koshkin et al.
Tetrahedron
1998, 54, 3607-3630).
There is a need for new, conformationally locked nucleosides with bicyclic sugar moieties. These novel nucleosides should be useful in antiviral, anti-cancer, and other therapies.
SUMMARY OF THE INVENTION
Conformationally locked bicyclic-sugar nucleosides, which have a common geometrical shape, and methods for producing conformationally locked bicyclic-sugar nucleosides are described. Nucleosides are provided having bicyclic sugar moieties and oligonucleotides comprising the following formula:
Wherein X, Y and Z are independently selected from a group of O, S, CH
2
, NR, C═O, C═CH
2
or nothing, where R is selected from a group of hydrogen, alkyl, alkenyl, alkynyl, acyl; R
1
is selected from a group of adenine, cytosine, guanine, hypoxanthine, uracil, thymine, heterocycles, H, OCH
3
, OAc, halogen, sulfonate; R
2
, R
3
are independently selected from a group of H, OH, DMTO, TBDMSO, BnO, THPO, AcO, BzO, OP(NiPr
2
)O(CH
2
)
2
CN, OPO
3
H, PO
3
H, diphosphate, triphosphate; R
2
and R
3
together can be PhCHO
2
, TIPDSO
2
or DTBSO
2
.
The novel nucleosides described herein are anticipated to be useful in antiviral, anti-cancer, and other therapies. Oligonucleotides composed of these modified nucleosides have desired physiological stability and binding affinity that enable them to be useful in therapeutics and diagnostics.


REFERENCES:
patent: 6403566 (2002-06-01), Wang
patent: WO 99/14226 (1999-03-01), None
Altmann, K., et al. 4′,6′-Methano Carbocyclic Thymidine: A Conformationally Constrained Building Block for Oligonucleotides. Tetrahedron Letters (1994), 35(15):2331-2334.
Hong, J.H., et al. Synthesis of Novel D-2′,3′-Dideoxy-2′,3′ endo-methylene Nucleosides. Tetrahedron Letters (1998), 39: 225-228.
Obika, S., et al. Synthesis of 2′-O,4′-C-Methyleneuridine and -cytidine. Novel bicyclic Nucleosides Having a Fixed C3 -endo Sugar Puckering. Tetrahedron Letters (1997), 38(50).

Affiliated with

Also associated with

Rating

Nucleosides having bicyclic sugar moiety does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Nucleosides having bicyclic sugar moiety, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nucleosides having bicyclic sugar moiety will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3335419