KR920701230A - Exonuclease-resistant oligonucleotides and methods for preparing the same - Google Patents

Exonuclease-resistant oligonucleotides and methods for preparing the same

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Publication number
KR920701230A
KR920701230A KR1019910701767A KR910701767A KR920701230A KR 920701230 A KR920701230 A KR 920701230A KR 1019910701767 A KR1019910701767 A KR 1019910701767A KR 910701767 A KR910701767 A KR 910701767A KR 920701230 A KR920701230 A KR 920701230A
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South Korea
Prior art keywords
oligonucleotide
hydrogen
bonds
formula
substituent
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KR1019910701767A
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Korean (ko)
Inventor
씨. 프륄리 브리안
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원본미기재
길리드 사이언스 인코오퍼레이티드
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Publication of KR920701230A publication Critical patent/KR920701230A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

내용 없음No content

Description

엑소뉴클레아제-내성 올리고뉴클레오티드 및 그 제조방법Exonuclease-resistant oligonucleotides and methods for preparing the same

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음Since this is an open matter, no full text was included.

Claims (16)

3'및/또는 5'말단의 포스포디에스테르 결합이 포스포아미데이트 결합으로 교체되도록 수정되고, 상기 결합의 수가 적어도 1 및 상보적인 올리고뉴클레오티드 가닥에 혼성화하는 것을 방제하는 수 이하, 및/도는 올리고뉴클레오티드가 RNA에 혼성화되었을때 RNAseH 활성을 방해하는 수이하인 것을 특징으로 하는 생리적 상태하에서 분해에 내성을 가지는 올리고뉴클레오티드.Phosphodiester bonds at the 3 'and / or 5' terminus are modified to be replaced by phosphoamidate bonds, wherein the number of bonds is at least 1 and up to the number that prevents hybridization to the complementary oligonucleotide strands, and / or oligos An oligonucleotide resistant to degradation under physiological conditions, wherein the nucleotide is less than or equal to the RNAseH activity when hybridized to RNA. 제1항에 있어서, 포스포아미데이트는 식:The method of claim 1 wherein the phosphoramidate is of the formula: (여기서 R1및 R2는 상보체와의 혼성화를 방지하지 않는 치환체)을 가지는 것을 특징으로 하는 올리고뉴클레오티드.Wherein R 1 and R 2 are substituents that do not prevent hybridization with the complement. 제2항에 있어서, R1및 R2는 양자 모두 수소가 아니라면 수소, 2탄소원자이하의 히드로카르빌 치환체로 이루어진 군에서 독립적으로 선택되는 것을 특징으로 하는 올리고뉴클레오티드.3. The oligonucleotide of claim 2, wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, hydrocarbyl substituents of up to 2 carbon atoms, unless both are hydrogen. 제3항에 있어서, R1및 R2의 하나가 수소이고 다른 하나는 CH3O-(CH2)X-(여기서 X는 1 내지 20범위내의 정수)의 구조식을 가지는 옥시히드로 카르빌 치환체인 것을 특징으로 하는 올리고뉴클레오티드.The oxyhydrocarbyl substituent of claim 3, wherein one of R 1 and R 2 is hydrogen and the other is CH 3 O— (CH 2 ) X — where X is an integer in the range of 1 to 20. Oligonucleotides, characterized in that. 제4항에 있어서, x가 2이고, 옥시히드로카르빌 치환체가 2-메톡시에틸인 것을 특징으로 하는 올리고뉴클레오티드.The oligonucleotide of claim 4 wherein x is 2 and the oxyhydrocarbyl substituent is 2-methoxyethyl. 제3항에 있어서, R1및 R2의 하나는 수소이고 다른 하나는 CH3(CH2)|y-(여기서 y는 0내지 15 범위내의 정수)의 식을 가지는 직쇄사슬 알킬부인 히드로카르빌 치환체인 것을 특징으로 하는 올리고뉴클레오티드.The process of claim 3, wherein one of R 1 and R 2 is hydrogen and the other is CH 3 (CH 2 ) | y - up to a straight chain alkyl denied wherein the hydrocarbyl substituent having the formula (wherein y is an integer in the range 0 to 15) nucleotides. 제6항에 있어서, y가 11이고 상기 히드로카르비 치환체가 도데실인 것을 특징으로 하는 올리고뉴클레오티드.7. The oligonucleotide of claim 6 wherein y is 11 and the hydrocarbyl substituent is dodecyl. 제6항에 있어서, y가 2이고 상기 히드로카르비 치환체가 n-프로필인것을 특징으로 하는 올리고뉴클레오티드.7. The oligonucleotide of claim 6 wherein y is 2 and the hydrocarbyl substituent is n-propyl. 제1항에 있어서, 올리고뉴클레오티드가 3' 및 5' 말단 양자에서 수정된 것임을 특징으로 하는 올리고뉴클레오티드.The oligonucleotide of claim 1, wherein the oligonucleotide is modified at both 3 ′ and 5 ′ ends. 제2항에 있어서, R1및 R2의 하나가 수소이고 다른 하나는 중합체인 것을 특징으로 하는 올리고뉴클레오티드.The oligonucleotide of claim 2 wherein one of R 1 and R 2 is hydrogen and the other is a polymer. 제2항에 있어서, R1및 R2의 하나가 수소이고 다른 하나는 슈가부인 것을 특징으로 하는 올리고뉴클레오티드.The oligonucleotide of claim 2 wherein one of R 1 and R 2 is hydrogen and the other is a sugar moiety. 제2항에 있어서, R1및 R2의 하나가 수소이고 다른 하나는 발색단인 것을 특징으로 하는 올리고뉴클레오티드.The oligonucleotide of claim 2, wherein one of R 1 and R 2 is hydrogen and the other is a chromophore. 제2항에 있어서, R1및 R2의 하나가 수소이고 다른 하나는 스테로이드 부인 것을 특징으로 하는 올리고뉴클레오티드.3. The oligonucleotide of claim 2 wherein one of R 1 and R 2 is hydrogen and the other is steroid denier. 제1항에 있어서, 상기 결합의 수가 약 2 내지 10의 범위내인 것을 특징으로 하는 올리고뉴클레오티드.The oligonucleotide of claim 1, wherein the number of bonds is in the range of about 2 to 10. 3. 제1항에 있어서, 3' 말단, 5' 말단 또는 양자에 2내지 10포스포로티오에이트 결합을 더 포함하는 것을 특징으로 하는 올리고뉴클레오티드.The oligonucleotide of claim 1, further comprising 2 to 10 phosphorothioate linkages at the 3 ′ end, 5 ′ end, or both. (a)식(a) (여기서 T는 보호기, P는 보호기 또는 고체상태 캐리어, 및 각 B는 독립적으로 보호 또는 비보호헤테로고리염기 i는 1내지 5로 변하고, 각 Qi는 적어도 하나의 Qi가 수소라면 수소 또는 NR1R2)의 뉴클레오티드를 식NHR1R2(여기서 R1및 R2는 청구범위 1에서 정의한 대로임)의 아민으로 이하의 식의 생산물을 형성하기에 충분한 산화제의 존재하에서 처리하고,(Wherein T is a protecting group, P is a protecting group or a solid carrier, and each B is independently a protected or unprotected heterocyclic base i from 1 to 5, and each Q i is hydrogen or NR 1 if at least one Q i is hydrogen) Nucleotides of R 2 ) are treated with an amine of the formula NHR 1 R 2 , wherein R 1 and R 2 are as defined in claim 1, in the presence of an oxidant sufficient to form a product of the formula (b)패쇄기 T를 제거하고, (c)활성제 존재하에서 캐리어 결합 뉴클레오티드의 5-터미날 수산기로서 5'-패쇄 큐늘레오시드 H-포스포네이트, H-포스포로티오에이트 또는 H-포스포로디티오에이트를 농축하고, (d)5'-터미날 뉴클레오시드의 5'-패쇄기를 제거하고, (e)상기 폴리뉴클레오티드의 요구하는 길이가 얻어질때까지 5'-패쇄 뉴클레오시스H-포스포네이트, H-포스포로티오에이트 및/또는 H-포스포로디티오에이트를 사용하여 (c) 및 (d)단계를 연속적으로 반복하고, (f)산화에 의해 포스포디에스테르, 포스포로티오에이트 및/또는 H-포스포로디티오에이트 인터뉴클레오티드 결합을 형성하고, (g)P로부터 폴리뉴클레오티드를 분리하는 단계로 이루어지는 것을 특징으로 하는 3' 엑소뉴클레아제에 대한 분해에 안정한 폴리뉴클레오티드의 합성방법.(b) removing the scavenger T, and (c) a 5'-blocked culeoleosid H-phosphonate, H-phosphothioate or H-phosphoroditi as a 5-terminal hydroxyl group of the carrier binding nucleotide in the presence of the active agent. Concentrate the oate, (d) remove the 5'-breaker of the 5'-terminal nucleoside, and (e) 5'-blocked nucleosis H-phospho until the desired length of the polynucleotide is obtained. (C) and (d) are successively repeated using Nate, H-phosphorothioate and / or H-phosphorodithioate, and (f) phosphodiester, phosphorothioate and And / or forming H-phosphorodithioate internucleotide bonds and (g) separating the polynucleotides from P. A method of synthesizing polynucleotides stable to degradation of 3 'exonuclease, the method comprising: ※참고사항 : 최초출원 내용에 의하여 공개되는 것임.※ Note: This is to be disclosed by the original application.
KR1019910701767A 1989-06-05 1990-06-05 Exonuclease-resistant oligonucleotides and methods for preparing the same KR920701230A (en)

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US36104589A 1989-06-05 1989-06-05
US361045 1989-06-15
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EP0476071A4 (en) 1992-11-04
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CA2058632A1 (en) 1990-12-06
JPH05500799A (en) 1993-02-18
WO1990015065A1 (en) 1990-12-13

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