Methods for the synthesis of functionalized nucleic acids
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/02
C07H-021/04
C07H-021/00
C07H-011/00
C07H-013/12
C07D-265/30
C07D-295/00
C07C-069/96
C07C-315/00
C07C-317/00
C07C-331/00
C07C-381/00
A61K-031/66
A61K-031/70
C07C-309/66
C07D-295/108
C07H-013/04
출원번호
US-0233579
(2012-07-13)
등록번호
US-9605019
(2017-03-28)
국제출원번호
PCT/US2012/046805
(2012-07-13)
§371/§102 date
20140227
(20140227)
국제공개번호
WO2013/012758
(2013-01-24)
발명자
/ 주소
Verdine, Gregory L.
Meena
Iwamoto, Naoki
Butler, David Charles Donnell
출원인 / 주소
WAVE LIFE SCIENCES LTD.
대리인 / 주소
Choate, Hall & Stewart LLP
인용정보
피인용 횟수 :
5인용 특허 :
294
초록▼
The present application, among other things, provides technologies, e.g., reagents, methods, etc. for preparing oligonucleotides comprising phosphorothiotriesters linkages, e.g., oligonucleotides having the structure of IIIa, IIIb or IIIc. In some embodiments, provided methods comprise reacting an H
The present application, among other things, provides technologies, e.g., reagents, methods, etc. for preparing oligonucleotides comprising phosphorothiotriesters linkages, e.g., oligonucleotides having the structure of IIIa, IIIb or IIIc. In some embodiments, provided methods comprise reacting an H-phosphonate of structure Ia or Ib with a silylating reagent to provide a silyloxyphosphonate, and reacting the silyloxyphosphonate with a thiosulfonate reagent of structure IIa or IIb to provide an oligonucleotide of structure IIIa or IIIb. In some embodiments, provided methods comprise reacting an H-phosphonate of structure Ic with a silylating reagent to provide a silyloxyphosphonate, reacting the silyloxyphosphonate with a bis(thiosulfonate) reagent of structure IVc to provide a phosphorothiotriester comprising a thiosulfonate group of structure Vc, and then reacting the phosphorothiotriester comprising a thiosulfonate group of structure Vc with a nucleophile of structure VIc to provide an oligonucleotide of structure IIIc.
대표청구항▼
1. A process for the preparation of an oligonucleotide of structure IIIa comprising the steps of: i) reacting an H-phosphonate of structure Ia with a silylating reagent to provide a silyloxyphosphonate; andii) reacting the silyloxyphosphonate with a thiosulfonate reagent of structure IIa to provide
1. A process for the preparation of an oligonucleotide of structure IIIa comprising the steps of: i) reacting an H-phosphonate of structure Ia with a silylating reagent to provide a silyloxyphosphonate; andii) reacting the silyloxyphosphonate with a thiosulfonate reagent of structure IIa to provide an oligonucleotide of structure IIIa; wherein: the H-phosphonate of structure Ia has the following structure: wherein: W is O;R3 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —ORa or —SRc;Y1 is O, NRd, S, or Se;Ra is a blocking group;Rc is a blocking group;each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or tertiary silyl, or when Rd is attached to a nitrogen atom, —C(O)—O-alkyl, —C(O)—O-alkenyl, —C(O)—O-alkynyl, —C(O)—O-heteroalkyl, —C(O)—O-heteroalkenyl, —C(O)—O-heteroalkynyl, —C(O)—O-aryl, or —C(O)—O-heteroaryl,each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1;Y2 is O, NRd, or S;each instance of R4 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, and Rb is a blocking group;each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase;R5 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid; andn is between 1 and about 200; and the thiosulfonate reagent of structure IIa has the following structure: wherein: X is alkyl, cycloalkyl, or heteroaryl;R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or R1—R2;R1 is —S-alkenylene-, —S-alkylene-, —S-alkylene-aryl-alkylene-, —S—CO-aryl-alkylene-, or —S—CO-alkylene-aryl-alkylene-;R2 is heterocyclo-alkylene-S—, heterocyclo-alkenylene-S—, aminoalkyl-S—, or (alkyl)4N-alkylene-S—; and the oligonucleotide of structure IIIa has the following structure: wherein: W is O;R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or R1—R2;R1 is —S-alkenylene-, —S-alkylene-, —S-alkylene-aryl-alkylene-, —S—CO-aryl-alkylene-, or —S—CO-alkylene-aryl-alkylene-;R2 is heterocyclo-alkylene-S—, heterocyclo-alkenylene-S—, aminoalkyl-S—, or (alkyl)4N-alkylene-S—;R3 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —ORa or —SRc;Y1 is O, NRd, S, or Se;Ra is a blocking group;Rc is a blocking group;each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or tertiary silyl, or when Rd is attached to a nitrogen atom, —C(O)—O-alkyl, —C(O)—O-alkenyl, —C(O)—O-alkynyl, —C(O)—O-heteroalkyl, —C(O)—O-heteroalkenyl, —C(O)—O-heteroalkynyl, —C(O)—O-aryl, or —C(O)—O-heteroaryl;each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1;Y2 is O, NRd, or S;each instance of R4 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, and Rb is a blocking group;each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase;R5 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid; andn is between 1 and about 200; andwherein each heteroaryl group is a mono-, bi-, or poly-cyclic 5-14 membered ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2. A process for the preparation of an oligonucleotide of structure IIIb, comprising the steps of: i) reacting an H-phosphonate of structure Ib with a silylating reagent to provide a silyloxyphosphonate; andii) reacting the silyloxyphosphonate with a thiosulfonate reagent of structure IIb to provide an oligonucleotide of structure IIIb; wherein: the H-phosphonate of structure Ib has the following structure: wherein: at least one H-phosphonate linkage is non-stereorandom;W is independently O, NH, or CH2;R3 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —ORa or —SRc;Y1 is O, NRd, S, or Se;Ra is a blocking group;Rc is a blocking group;each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or tertiary silyl, or when Rd is attached to a nitrogen atom, —C(O)—O-alkyl, —C(O)—O-alkenyl, —C(O)—O-alkynyl, —C(O)—O-heteroalkyl, —C(O)—O-heteroalkenyl, —C(O)—O-heteroalkynyl, —C(O)—O-aryl, or —C(O)—O-heteroaryl,each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1;Y2 is O, NRd, or S;each instance of R4 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, and Rb is a blocking group;each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase;R5 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid; andn is between 1 and about 200; and the thiosulfonate reagent of structure IIb has the following structure: wherein: X is alkyl, cycloalkyl, aryl, or heteroaryl;R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or R1—R2;R1 is —S-alkenylene-, —S-alkylene-, —S-alkylene-aryl-alkylene-, —S—CO-aryl-alkylene-, or —S—CO-alkylene-aryl-alkylene-;R2 is heterocyclo-alkylene-S—, heterocyclo-alkenylene-S—, aminoalkyl-S—, or (alkyl)4N-alkylene-S—;and the oligonucleotide of structure IIIb has the following structure: wherein: at least one phosphorothiotriester linkages is non-stereorandom,W is O;R is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or R1—R2;R1 is —S-alkenylene-, —S-alkylene-, —S-alkylene-aryl-alkylene-, —S—CO-aryl-alkylene-, or —S—CO-alkylene-aryl-alkylene-;R2 is heterocyclo-alkylene-S—, heterocyclo-alkenylene-S—, aminoalkyl-S—, or (alkyl)4N-alkylene-S—;R3 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —ORa or —SRc;Y1 is O, NRd, S, or Se;Ra is a blocking group;Rc is a blocking group;each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or tertiary silyl, or when Rd is attached to a nitrogen atom, —C(O)—O-alkyl, —C(O)—O-alkenyl, —C(O)—O-alkynyl, —C(O)—O-heteroalkyl, —C(O)—O-heteroalkenyl, —C(O)—O-heteroalkynyl, —C(O)—O-aryl, or —C(O)—O-heteroaryl;each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1;Y2 is O, NRd, or S;each instance of R4 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, and Rb is a blocking group;each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase;R5 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid; andn is between 1 and about 200; andwherein each heteroaryl group is a mono-, bi-, or poly-cyclic 5-14 membered ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 3. The process of claim 2, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine. 4. The process of claim 2, wherein R1 is: and R2 is: 5. The process of claim 2, wherein the silylating reagent is 1,1,3,3-tetramethyl-1,3-diphenyldisilazane;1,3-dimethyl-1,1,3,3-tetraphenyldisilazane;1-(trimethylsilyl)imidazole;N-trimethylsilyl-N-methyl trifluoroacetamide;bis(dimethylamino)dimethylsilane;bromotrimethylsilane;chlorodimethyl(pentafluorophenyl)silane;chlorotriethylsilane;chlorotriisopropylsilane;chlorotrimethylsilane;dichlorodimethylsilane;hexamethyldisilazane;N,N′-bis(trimethylsilyl)urea;N,N-bis(trimethylsilyl)methylamine;N,N-dimethyltrimethylsilylamine;N,O-bis(trimethylsilyl)acetamide;N,O-bis(trimethylsilyl)carbamate;N,O-bis(trimethylsilyl)trifluoroacetamide;N-methyl-N-(trimethylsilyl)trifluoroacetamide;N-methyl-N-trimethylsilylacetamide;N-methyl-N-trimethylsilylheptafluorobutyramide;N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide;N-methyl-N-trimethylsilylheptafluorobutyramide;trimethylsilyltriflate;triethylsilyltriflate; triisopropylsilyltriflate; ortert-butyldimethylsilyltriflate. 6. The process of claim 2, wherein the silylating reagent is N,O-bis(trimethylsilyl)trifluoroacetamide, trimethylsilyltriflate, chlorotrimethylsilane, or 1-(trimethylsilyl)imidazole. 7. The process of claim 2, wherein the silylating reagent is N,O-bis(trimethylsilyl)trifluoroacetamide. 8. The process of claim 2, wherein the H-phosphonate is covalently linked to a solid phase. 9. A process for the preparation of an oligonucleotide of structure IIIc comprising the steps of: i) reacting an H-phosphonate of structure Ic with a silylating reagent to provide a silyloxyphosphonate;ii) reacting the silyloxyphosphonate with a bis(thiosulfonate) reagent of structure IVc to provide a phosphorothiotriester comprising a thiosulfonate group of structure Vc;iii) reacting the phosphorothiotriester comprising a thiosulfonate group of structure Vc with a nucleophile of structure VIc to provide the oligonucleotide of structure IIIc; wherein: the H-phosphonate of structure Ic has the following structure: wherein: W is O;R3 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —ORa or —SRc;Y1 is O, NRd, S, or Se;Ra is a blocking group;Rc is a blocking group;each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or tertiary silyl, or when Rd is attached to a nitrogen atom, —C(O)—O-alkyl, —C(O)—O-alkenyl, —C(O)—O-alkynyl, —C(O)—O-heteroalkyl, —C(O)—O-heteroalkenyl, —C(O)—O-heteroalkynyl, —C(O)—O-aryl, or —C(O)—O-heteroaryl;each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1;Y2 is O, NRd, or S;each instance of R4 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, and Rb is a blocking group;each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase;R5 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid; andn is between 1 and about 200; and the bis(thiosulfonate) reagent of structure IVc has the following structure: wherein: X is alkylene, alkenylene, arylene, or heteroarylene;each R6 is independently alkyl, cycloalkyl, aryl, or heteroaryl; the nucleophile of structure VIc has the following structure: R7—SH,wherein R7 is alkyl, alkenyl, aryl, heterocyclo, aminoalkyl, or (heterocyclo)alkyl; and the oligonucleotide of structure IIIc has the following structure: wherein: W is O;R is R7—S—S—X—;R7 is alkyl, alkenyl, aryl, heterocyclo, aminoalkyl, or (heterocyclo)alkyl;X is alkylene, alkenylene, arylene, or heteroarylene;R3 is —OH, —SH, —NRdRd, —N3, halogen, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —P(O)(Re)2, —ORa or —SRc;Y1 is O, NRd, S, or Se;Ra is a blocking group;Rc is a blocking group;each instance of Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, or tertiary silyl, or when Rd is attached to a nitrogen atom, —C(O)—O-alkyl, —C(O)—O-alkenyl, —C(O)—O-alkynyl, —C(O)—O-heteroalkyl, —C(O)—O-heteroalkenyl, —C(O)—O-heteroalkynyl, —C(O)—O-aryl, or —C(O)—O-heteroaryl;each instance of Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+1, Li+1, or K+1;Y2 is O, NRd, or S;each instance of R4 is independently hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRc, and Rb is a blocking group;each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or modified nucleobase;R5 is hydrogen, a blocking group, a linking moiety connected to a solid support or a linking moiety connected to a nucleic acid;n is between 1 and about 200; andwherein the phosphorous linkages of the H-phosphonate of structure Ic, the phosphorothiotriester comprising a thiosulfonate group of structure Vc, and the oligonucleotide of structure IIIc may optionally comprise non-stereorandom phosphorous linkages; andwherein each heteroaryl group is a mono-, bi-, or poly-cyclic 5-14 membered ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 10. The process of claim 9, wherein the oligonucleotide of structure IIIc comprises non-stereorandom phosphorous linkages and the H-phosphonate of structure Ic comprises non-stereorandom phosphorous linkages. 11. The process of claim 10, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine. 12. The process of claim 9, wherein R6 is methyl. 13. The process of claim 9, wherein the bis(thiosulfonate) reagent of structure IVc is: 14. The process of claim 9, wherein the nucleophile of structure VIc has the following structure: 15. The process of claim 9, wherein the silylating reagent is 1,1,3,3-tetramethyl-1,3-diphenyldisilazane;1,3-dimethyl-1,1,3,3-tetraphenyldisilazane;1-(trimethylsilyl)imidazole;N-trimethylsilyl-N-methyl trifluoroacetamide;bis(dimethylamino)dimethylsilane;bromotrimethylsilane;chlorodimethyl(pentafluorophenyl)silane;chlorotriethylsilane;chlorotriisopropylsilane;chlorotrimethylsilane;dichlorodimethylsilane;hexamethyldisilazane;N,N′-bis(trimethylsilyl)urea;N,N-bis(trimethylsilyl)methylamine;N,N-dimethyltrimethylsilylamine;N,O-bis(trimethylsilyl)acetamide;N,O-bis(trimethylsilyl)carbamate;N,O-bis(trimethylsilyl)trifluoroacetamide;N-methyl-N-(trimethylsilyl)trifluoroacetamide;N-methyl-N-trimethylsilylacetamide;N-methyl-N-trimethylsilylheptafluorobutyramide;N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide;N-methyl-N-trimethylsilylheptafluorobutyramide;trimethylsilyltriflate;triethylsilyltriflate; triisopropylsilyltriflate; ortert-butyldimethylsilyltriflate. 16. The process of claim 9, wherein the silylating reagent is N,O-bis(trimethylsilyl)trifluoroacetamide, trimethylsilyltriflate, chlorotrimethylsilane, or 1-(trimethylsilyl)imidazole. 17. The process of claim 9, wherein the silylating reagent is N,O-bis(trimethylsilyl)trifluoroacetamide. 18. The process of claim 9, wherein the H-phosphonate is covalently linked to a solid phase.
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Stec Wojciech J. (Lodz PLX) Uznanski Bogdan (Lodz CA PLX) Bergot B. John (Redwood City CA) Hirschbein Bernard L. (San Francisco CA) Fearon Karen L. (Union City CA), Method of synethesizing sulfurized oligonucleotide analogs.
Stec Wojciech J. (Lodz PLX) Uznanski Bogdan (Lodz CA PLX) Bergot B. John (Redwood City CA) Hirschbein Bernard L. (San Francisco CA) Fearson Karen L. (Union City CA), Method of synthesizing sulfurized oligonucleotide analogs.
Helliwell, Christopher A.; Wesley, Susan V.; Waterhouse, Peter M., Methods and means for producing efficient silencing construct using recombinational cloning.
Helliwell, Christopher A.; Wesley, Susan V.; Waterhouse, Peter M., Methods and means for producing efficient silencing construct using recombinational cloning.
Helliwell, Christopher A.; Wesley, Susan V.; Waterhouse, Peter M., Methods and means for producing efficient silencing construct using recombinational cloning.
Freier, Susan M.; Crooke, Rosanne M.; Graham, Mark J.; Lemonidis, Kristina L.; Bhanot, Sanjay; Tribble, Diane; Watt, Andrew T., Methods for treating hypercholesterolemia.
Chang, Jin Sook; Jo, Jae Hyun; Bae, Hyun Ae; Song, Byeong Cheol; Kim, Sol; Kim, Hye Won, Microorganism producing O-phosphoserine and method of producing L-cysteine or derivatives thereof from O-phosphoserine using the same.
Hung, Gene; Bennett, C. Frank; Freier, Susan M.; Kordasiewicz, Holly; Stanek, Lisa; Cleveland, Don W.; Cheng, Seng H.; Shihabuddin, Lamya, Modulation of huntingtin expression.
Hanecak,Ronnie C.; Anderson,Kevin P.; Bennett,C. Frank; Chiang,Ming Yi; Brown Driver,Vickie L.; Ecker,David J.; Vickers,Timothy A.; Wyatt,Jacqueline R., Modulation of telomere length by oligonucleotides having a G-core sequence.
Garvey,David S.; Letts,L. Gordon; Renfroe,H. Burt; Richardson,Stewart K., Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders.
Domagala John M. (Canton MI) Hagen Susan E. (Ypsilanti MI) Sanchez Joseph P. (Canton MI) Solomon Marjorie S. (Bellevue WA), Novel disubstituted-7-pyrrolidinoquinoline antibacterial agents.
Cook Philip D. (Carlsbad CA) Sanghvi Yogesh S. (San Marcos CA), Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression.
Bennett, C. Frank; Freier, Susan M.; Griffey, Richard H.; Marcusson, Eric G., Oligomeric compounds and compositions for use in modulation of small non-coding RNAs.
Esau, Christine; Lollo, Bridget; Bennett, C. Frank; Freier, Susan M.; Griffey, Richard H.; Baker, Brenda F.; Vickers, Timothy A.; Marcusson, Eric G.; Koller, Erich; Swayze, Eric E.; Jain, Ravi; Bhat, Balkrishen; Peralta, Eigen, Oligomeric compounds and compositions for use in modulation of small non-coding RNAs.
Lollo, Bridget; Bennett, C. Frank; Freier, Susan M.; Griffey, Richard H., Oligomeric compounds and compositions for use in modulation of small non-coding RNAs.
Cook Phillip Dan ; Sanghvi Yogesh S. ; Sprankle Kelly G. ; Ross Bruce S. ; Griffey Rich H., Oligomeric compounds having pyrimidine nucleotide (S) with 2'and 5 substitutions.
Lin, Hui-Ling; Liang, Teh-Ming; Chang, Tsung Chain; Cheng, Sheng-Shung, Oligonucleotide sequences and DNA chip for identifying filamentous microorganisms and the identification method thereof.
Cook Phillip Dan (San Marcos CA) Hoke Glenn (Mt. Airy MD), Oligonucleotides for modulating Ha-ras or Ki-ras having phosphorothioate linkages of high chiral purity.
Cook Phillip Dan (San Marcos CA) Hoke Glenn (Mt. Airy MD), Oligonucleotides for modulating RAF kinase having phosphorothioate linkages of high chiral purity.
Cook Phillip D. (San Marcos CA) Hoke Glenn (Mt. Airy MD), Oligonucleotides for modulating cytomegalovirus having phosphorothioate linkages of high chiral purity.
Cook Phillip D. (San Marcos CA) Hoke Glenn (Mt. Airy MD), Oligonucleotides for modulating hepatitis C virus having phosphorothioate linkages of high chiral purity.
Cook Phillip D. (San Marcos CA) Hoke Glenn (Mt. Airy MD), Oligonucleotides for modulating protein kinase C having phosphorothioate linkages of high chiral purity.
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.
Manolova, Vania; Bachmann, Martin F.; Cornelius, Andreas; Maurer, Patrik; Meijerink, Edwin; Proba, Karl G.; Schwarz, Katrin, Packaging of immunostimulatory oligonucleotides into virus-like particles: method of preparation and use.
Allerson, Charles; Bhat, Balkrishen; Swayze, Eric E.; Prakash, Thazha P., Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation.
Allerson, Charles; Bhat, Balkrishen; Swayze, Eric E.; Prakash, Thazha P., Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation.
Just George,CAX ; Xin Zhili ; Marsault Eric,CAX ; Jin Yi,CAX ; Wang Jianchao,CAX ; Manoharan Muthiah, Preparation of phosphorothioate and boranophosphate oligomers.
Cook Phillip Dan ; Sanghvi Yogesh S. ; Sprankle Kelly G. ; Ross Bruce S. ; Griffey Rich H. ; Springer Robert H., Process for the synthesis of 2'-O-substituted pyrimidines and oligomeric compounds therefrom.
Wojciech J. Stec PL; Lucyna A. Wozniak PL; Arkadiusz Chworos PL; Jaroslaw Pyzowski PL, Process for the synthesis of modified P-chiral nucleotide analogues.
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.
Torrence Paul F. ; Silverman Robert Hugh ; Cirino Nick Mario ; Li Guiying ; Xiao Wei, RNase L activators and antisense oligonucleotides effective to treat RSV infections.
Torrence Paul F. ; Silverman Robert Hugh ; Cirino Nick Mario ; Li Guiying ; Xiao Wei ; Player Mark R., RNase L activators and antisense oligonucleotides effective to treat RSV infections.
Robert H. Silverman ; Seiji Kondo ; John K. Cowell ; Guiying Li ; Paul F. Torrence, RNase L activators and antisense oligonucleotides effective to treat telomerase-expressing malignancies.
Benson, Scott C.; Zou, Ruiming N.; Upadhya, Krishna G.; Kenney, Paul M.; Cassel, Jonathan M., Reagents useful for synthesizing rhodamine-labeled oligonucleotides.
Bennett, C. Frank; Hayden, Michael; Freier, Susan M.; Greenlee, Sarah; Carroll, Jeffrey; Warby, Simon; Swayze, Eric E., Selective reduction of allelic variants.
Stec Wojciech J. (Lodz PLX) Grajkowski Andrzej (Lodz PLX) Uznanski Bogdan (Lodz PLX), Solid phase oligonucleotide synthesis using phospholane intermediates.
Cook Phillip Dan (Carlsbad CA) Manoharan Muthiah (Carlsbad CA) Ramasamy Kanda S. (Laguna Hills CA), Substituted purines and oligonucleotide cross-linking.
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