The present invention provides bicyclic cyclohexose nucleoside analogs and oligomeric compounds comprising these nucleoside analogs. These bicyclic nucleoside analogs are useful for enhancing properties of oligomeric compounds including nuclease resistance.
대표청구항▼
1. A bicyclic nucleoside analog of Formula I: wherein: Bx is a heterocyclic base moiety;Z is O;Q is 5′-CR3R4—O-2′, 5′-(CR3R4)2-2′, 5′-CR3═CR4-2′, 5′-CR3R4—O—N(R5)-2′ or 5′-CR3R4—N(R5)—O-2;each R3 and R4 is, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alko
1. A bicyclic nucleoside analog of Formula I: wherein: Bx is a heterocyclic base moiety;Z is O;Q is 5′-CR3R4—O-2′, 5′-(CR3R4)2-2′, 5′-CR3═CR4-2′, 5′-CR3R4—O—N(R5)-2′ or 5′-CR3R4—N(R5)—O-2;each R3 and R4 is, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy or halogen;R5 is H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy or substituted C1-C6 alkoxy;L1 and L2 are each H or one of L1 and L2 is H and the other of L1 and L2 is CH3 or OCH3;one of E1, E2, E3 and E4 is O-T2, two of E1, E2, E3 and E4 are H and the remaining one of E1, E2, E3 and E4 is H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;one of T1 and T2 is H, a hydroxyl protecting group or a phosphorus moiety and the other of T1 and T2 is H, a hydroxyl protecting group or a reactive phosphorus group;each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ5, N(J5)(J6), ═NJ5, SJ5, N3, CN, OC(=L)J5, OC(=L)N(J5)(J6) and C(=L)N(J5)(J6);L is O, S or NJ7; andeach J5, J6 and J7 is, independently, H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C5-C20 aryl or C1-C12 aminoalkyl. 2. The bicyclic nucleoside analog of claim 1 wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine. 3. The bicyclic nucleoside analog of claim 1 wherein three of E1, E2, E3 and E4 are H. 4. The bicyclic nucleoside analog of claim 1 wherein L1 and L2 are each H. 5. The bicyclic nucleoside analog of claim 1 wherein one of L1 and L2 is H and the other of L1 and L2 is CH3. 6. The bicyclic nucleoside analog of claim 1 wherein T1 is 4,4′-dimethoxytrityl and T2 is diisopropylcyanoethoxy phosphoramidite. 7. The bicyclic nucleoside analog of claim 1 wherein Q is 5′-CR3R4—O-2′ or 5′-(CR3R4)2-2′. 8. The bicyclic nucleoside analog of claim 7 wherein each R3 and R4 is H. 9. The bicyclic nucleoside analog of claim 8 wherein Q is 5′-CH2—O-2′. 10. The bicyclic nucleoside analog of claim 1 wherein said reactive phosphorus group is diisopropylcyanoethoxy phosphoramidite or H-phosphonate. 11. The bicyclic nucleoside analog of claim 1 wherein said phosphorus moiety has the formula: wherein: Ra and Rc are each, independently, OH, SH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino or substituted amino; andRb is O or S. 12. The bicyclic nucleoside analog of claim 1 having the configuration of one of formulas Ia, Ib, Ic and Id: 13. An oligomeric compound comprising at least one bicyclic nucleoside analog of Formula II: wherein independently for each bicyclic nucleoside analog of formula II: Bx is a heterocyclic base moiety;Z is O;Q is 5′-CR3R4—O-2′, 5′-(CR3R4)2-2′, 5′-CR3═CR4-2′, 5′-CR3R4—O—N(R5)-2′ or 5′-CR3R4—N(R5)—O-2;each R3 and R4 is, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy or halogen;R5 is H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy or substituted C1-C6 alkoxy;L1 and L2 are each H or one of L1 and L2 is H and the other of L1 and L2 is CH3 or OCH3;one of E4, E5, E6 and E7 is O-T4, two of E4, E5, E6 and E7 are H and the remaining one of E4, E5, E6 and E7 is H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;one of T3 and T4 is an internucleoside linking group linking the bicyclic nucleoside analog to the oligomeric compound and the other of T3 and T4 is H, a protecting group, a phosphorus moiety, a 5′ or 3′-terminal group or an internucleoside linking group linking the bicyclic nucleoside analog to the oligomeric compound;each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ5, N(J5)(J6), ═NJ5, SJ5, N3, CN, OC(=L)J5, OC(=L)N(J5)(J6) and C(=L)N(J5)(J6);L is O, S or NJ7; andeach J5, J6 and J7 is, independently, H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C5-C20 aryl or C1-C12 aminoalkyl. 14. The oligomeric compound of claim 13 wherein independently for each bicyclic nucleoside analog of formula II, Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine. 15. The oligomeric compound of claim 13 wherein independently for each bicyclic nucleoside analog of formula II, three of E5, E6, E7 and E8 are H. 16. The oligomeric compound of claim 13 wherein independently for each bicyclic nucleoside analog of formula II, L1 and L2 are each H. 17. The oligomeric compound of claim 13 wherein independently for each bicyclic nucleoside analog of formula II, one of L1 and L2 is H and the other of L1 and L2 is CH3. 18. The oligomeric compound of claim 13 wherein each Q is 5′-CR3R4—O-2′ or 5′-(CR3R4)2-2′. 19. The oligomeric compound of claim 18 wherein each R3 and R4 is H. 20. The oligomeric compound of claim 19 wherein each Q is 5′-CH2—O-2′. 21. The oligomeric compound of claim 13 wherein said phosphorus moiety has the formula: wherein: Ra and Rc are each, independently, OH, SH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino or substituted amino; andRb is O or S. 22. The oligomeric compound of claim 13 wherein each bicyclic nucleoside of Formula II has the configuration of one of formulas IIa, IIb, IIc and IId: 23. The oligomeric compound of claim 22 comprising at least one region of from 2 to 5 contiguous bicyclic nucleoside analogs of formula II. 24. The oligomeric compound of claim 23 comprising a gapped oligomeric compound wherein one region of contiguous bicyclic nucleoside analogs of formula II is located at the 5′-end and a second region of contiguous bicyclic nucleoside analogs of formula II is located at the 3′-end, wherein the two regions are separated by an internal region comprising from about 6 to about 18 monomer subunits independently selected from nucleosides and modified nucleosides that are different from the bicyclic nucleoside analogs of formula II. 25. The oligomeric compound of claim 24 wherein said internal region comprises from about 8 to about 14 contiguous β-D-2′-deoxyribofuranosyl nucleosides. 26. The oligomeric compound of claim 13 wherein each internucleoside linking group is a phosphodiester or a phosphorothioate internucleoside linking group. 27. The oligomeric compound of claim 13 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group. 28. The oligomeric compound of claim 13 comprising from about 8 to about 40 monomer subunits in length. 29. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of claim 22.
연구과제 타임라인
LOADING...
LOADING...
LOADING...
LOADING...
LOADING...
이 특허에 인용된 특허 (128)
Tkachuk Zenovy (Kiev SUX) Kvasyuk Eugeny (Kiev SUX) Matsuka Gennady (Kiev SUX) Mikhailopulo Igor (Kiev SUX), (2′-5′) oligoadenylate analogues useful as inhibitors of host-v5.-graft response.
Huynh Dinh Tam (Croissy/Seine FRX) Gouyette Catherine (Vanves FRX) Igolen Jean (Le Mesnil St. Denis FRX), 2,N6-disubstituted and 2,N6-trisubstituted adenosine-3′-phosphoramidites.
Suhadolnik Robert J. (Roslyn PA) Pfleiderer Wolfgang (Constance DEX), 2′,5′-phosphorothioate oligoadenylates and their covalent conjugates with polylysine.
Cook Philip D. (Carlsbad CA) Delecki Daniel J. (Radnor PA) Guinosso Charles (Vista CA), Acyclic nucleoside analogs and oligonucleotide sequences containing them.
Summerton James E. (Corvallis OR) Weller Dwight D. (Corvallis OR) Stirchak Eugene P. (Corvallis OR), Alpha-morpholino ribonucleoside derivatives and polymers thereof.
Sanghvi Yogesh S. (Carlsbad CA) Cook Phillip D. (Carlsbad CA), Backbone modified oligonucleotide analogs and preparation thereof through reductive coupling.
Cook Phillip D. (Carlsbad CA) Sanghvi Yogesh S. (San Marcos CA) Vasseur Jean J. (San Marcos CA) Debart Francoise (Montpellier FRX), Backbone modified oligonucleotide analogues.
Sanghvi Yogesh S. (San Marcos CA) Cook Phillip D. (Vista CA), Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling.
Spielvogel Bernard F. (Raleigh NC) Sood Anup (Durham NC) Hall Iris H. (Chapel Hill NC) Ramsay Shaw Barbara (Durham NC), Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same.
Altmann Karl-Heinz (Basel CHX) Imwinkelried Rene (Brig-Glis CHX) Eschenmoser Albert (Kusnacht CHX), Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use.
Altmann Karl-Heinz (Basel CHX) Imwinkelried Rene (Brig-Glis CHX) Eschenmoser Albert (Kusnacht CHX), Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use.
Ohtsuka Eiko (Sappro JPX) Inoue Hideo (Sappro JPX) Morisawa Hirokazu (Kawasaki JPX) Shibahara Susumu (Kawasaki JPX) Mukai Sachiko (Kawasaki JPX) Nishihara Tohru (Kurashiki JPX), Compounds for the cleavage at a specific position of RNA, oligomers employed for the formation of said compounds, and st.
Baxter Anthony D. (Northwich GB2) Baylis Eric K. (Stockport GB2) Collingwood Stephen P. (Westhoughton GB2) Taylor Roger J. (Stretford GB2) De Mesmaeker Alain (Kanerkinden CHX) Schmit Chantal (Basel C, Dinucleoside phosphinates and their pharmaceutical compositions.
Froehler Brian (Belmont CA) Matteucci Mark (Burlingame CA), Enhanced triple-helix and double-helix formation with oligomers containing modified purines.
Froehler Brian (Belmont CA) Wagner Rick (Belmont CA) Matteucci Mark (Burlingame CA) Jones Robert J. (Millbrae CA) Gutierrez Arnold J. (Sandy Lane CA) Pudlo Jeff (Burlingame CA), Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines.
Rogers Thomas E. (Manchester MO) Gray Steven H. (Ellisville MO) Devadas Balekudru (Chesterfield MO) Adams Steven P. (St. Charles MO), Improved probes using nucleosides containing 3-dezauracil analogs.
Cohen Jack S. (Bethesda MD) Neckers Len (Bethesda MD) Stein Cy (Gaithersburg MD) Loke She L. (Wheaton MD) Shinozuka Kazuo (Kazo JPX), Inhibitors for replication of retroviruses and for the expression of oncogene products.
Cohen Jack S. (Bethesda MD) Neckers Len (Bethesda MD) Stein Cy (Gaithersburg MD) Loke She L. (Wheaton MD) Shinozuka Kazuo (Kazo JPX), Inhibitors for replication of retroviruses and for the expression of oncogene products.
Cohen Jack S. (Bethesda MD) Neckers Len (Bethesda MD) Stein Cy (Gaithersburg MD) Loke Shee L. (Wheaton MD) Shinozuka Kazuo (Kazo JPX), Inhibitors for replication of retroviruses and for the expression of oncogene products.
Benner Steven A. (Hadlaubstrasse 151 CH-8006 Zurich CHX), Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Walder Joseph A. (Iowa City IA) Walder Roxanne Y. (Iowa City IA) Eder Paul S. (Iowa City IA) Dagle John M. (Iowa City IA), Methods for blocking the expression of specifically targeted genes.
Froehler Brian ; Wagner Rick ; Matteucci Mark ; Jones Robert J. ; Gutierrez Arnold J. ; Pudlo Jeff, Methods of using oligomers containing modified pyrimidines.
Matteucci Mark (Burlingame CA) Jones Robert J. (Daly City CA) Munger John (San Francisco CA), Modified internucleoside linkages having one nitrogen and two carbon atoms.
Ts\o Paul O. P. (2117 Folkstone Rd. Lutherville MD 21093) Miller Paul S. (225 Hopkins Rd. Baltimore MD 21212), Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof.
Cook Philip D. (Carlsbad CA) Sanghvi Yogesh S. (San Marcos CA), Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression.
Swaminathan Sundaramoorthi ; Matteucci Mark ; Jones Robert J. ; Pudlo Jeff ; Munger John, Nuclease stable and binding competent oligomers and methods for their use.
Walder Joseph A. (Iowa City IA) Walder Roxanne Y. (Iowa City IA), Nucleic acid hybridization and amplification method for detection of specific sequences in which a complementary labeled.
Buhr Chris (Daly City CA) Matteucci Mark (Burlingame CA) Bischofberger Norbert W. (San Carlos CA) Froehler Brian (Belmont CA), Nucleoside 5′-methylene phosphonates.
Froehler Brian C. (Belmont CA) Buhr Chris A. (Daly City CA), Nucleoside hydrogen phosphonodithioate diesters and activated phosphonodithioate analogues.
Meyer ; Jr. Rich B. (Woodinville WA) Adams A. David (Snohomish WA) Petrie Charles R. (Woodinville WA), Oligo (aa
상세보기
Letsinger Robert L. (Wilmette IL) Gryaznov Sergei M. (San Mateo CA), Oligodeoxyribonucleotides including 3′-aminonucleoside-phosphoramidate linkages and terminal 3′-amino groups.
Bischofberger Norbert (San Carlos CA) Kent Ken (Mountain View CA) Wagner Rick (Burlingame CA) Buhr Chris (Daly City CA) Lin Kuei-Ying (Fremont CA), Oligonucleotide analogs capable of passive cell membrane permeation.
Weis Alexander Ludvik (Berwyn PA) Hausheer Frederick Herman (San Antonio TX) Chaturvedula Prasad Venkata Chala (Exton PA) Delecki Daniel Joseph (Radnor PA) Cavanaugh ; Jr. Paul Francis (West Chester , Oligonucleotide analogues containing phosphate diester linkage substitutes, compositions thereof, and precursor dinucleo.
Smith Lloyd M. (South Pasadena CA) Fung Steven (Palo Alto CA) Kaiser ; Jr. Robert J. (Glendale CA), Oligonucleotides possessing a primary amino group in the terminal nucleotide.
Lebleu Bernard (Montpellier FRX) Bayard Bernard (Castelnau Le Lez FRX), Oligonucleotides with modified phosphate and modified carbohydrate moieties at the respective chain termini.
Imbach Jean-Louis (Montpellier FRX) Gosselin Gilles J. M. (Montpellier FRX), Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon.
Spielvogel Bernard F. (Raleigh NC) Sood Anup (Durham NC) Hall Iris H. (Chapel Hill NC) Shaw Barbara R. (Durham NC), Oligoribonucleoside and oligodeoxyribonucleoside boranophosphates.
Misiura Konrad (Lodz PLX) Gait Michael (Cambridge GB3), Phosphoramidite derivatives, their preparation and the use thereof in the incorporation of reporter groups on synthetic.
Maddry Joseph A. (Birmingham AL) Reynolds Robert C. (Birmingham AL) Secrist John A. (Birmingham AL) Montgomery John A. (Birmingham AL) Crooks Peter A. (Lexington KY), Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages.
Caruthers Marvin H. (Boulder CO) Marshall William S. (Boulder CO) Brill Wolfgang (Freiburg DEX) Nielsen John (Horsholm DKX), Polynucleotide phosphorodithioate.
Urdea Michael S. (Alamo CA) Horn Thomas (Berkeley CA), Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use.
Spielvogel Bernard F. (Raleigh NC) Sood Anup (Durham NC) Hall Iris H. (Chapel Hill NC) Ramsay Shaw Barbara (Durham NC), Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates.
Hawkins Mary E. (Potomac MD) Pfleiderer Wolfgang (Konstanz MD DEX) Davis Michael D. (Rockville MD) Balis Frank (Bethesda MD), Pteridine nucleotide analogs as fluorescent DNA probes.
Van Ness Jeffrey (Bothell WA) Petrie Charles R. (Woodinville WA) Tabone John C. (Bothell WA) Vermeulen Nicolaas M. J. (Woodinville WA), Solid supports for nucleic acid hybridization assays.
Cook Phillip Dan (Carlsbad CA) Manoharan Muthiah (Carlsbad CA) Ramasamy Kanda S. (Laguna Hills CA), Substituted purines and oligonucleotide cross-linking.
Summerton James E. (Corvallis OR) Weller Dwight D. (Corvallis OR), Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages.
Bennett, C. Frank; Freier, Susan M.; Rigo, Frank; Cleveland, Don W.; Lagier-Tourenne, Clotilde; Ravits, John M.; Baughn, Michael W., Methods for modulating C9ORF72 expression.
Bennett, C. Frank; Freier, Susan M.; MacLeod, Robert A.; Pandey, Sanjay K.; Thornton, Charles A.; Wheeler, Thurman; Cheng, Seng H.; Leger, Andrew; Wentworth, Bruce M., Modulation of dystrophia myotonica-protein kinase (DMPK) expression.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.