CN102180924A - L-核糖-lna类似物 - Google Patents
L-核糖-lna类似物 Download PDFInfo
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- CN102180924A CN102180924A CN2011100346082A CN201110034608A CN102180924A CN 102180924 A CN102180924 A CN 102180924A CN 2011100346082 A CN2011100346082 A CN 2011100346082A CN 201110034608 A CN201110034608 A CN 201110034608A CN 102180924 A CN102180924 A CN 102180924A
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- Prior art keywords
- lna
- nucleosides
- ribo
- oligomer
- group
- Prior art date
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Abstract
本发明涉及L-核糖-LNA类似物。核苷类似物,其中,用在C-3’与C-4’转化的立体化学合成2’-4’-桥接锁定核苷构型的核苷类似物,以提供L-核糖-构型LNA核苷。该L-核糖-LNA-核苷合成可应用于所有核碱基,该核碱基包含胸腺嘧啶、腺嘌呤、胞嘧啶、鸟嘌呤和尿嘧啶。这些具有L-核糖-构型的锁定核酸(LNA)已用于2’-O-4’-亚甲基-α-L-核糖呋喃糖基核苷酸以及其中含有L-核糖-LNA核苷酸的寡核苷酸的合成。利用这些L-核糖-LNA改性寡核苷酸,借助它们对于互补核酸的高亲和性,大幅改善靶标互补核酸的方法。
Description
本申请是申请号为00807070.9,申请日为2000年5月4日,发明名称为“L-核糖-LNA类似物”的中国专利申请的分案申请。
技术领域
本发明涉及L-核糖-构型双环状核苷类似物领域,以及用于合成寡核苷酸形成的核苷酸类似物的合成,该合成寡核苷酸可形成具有互补单链与双链核酸的核碱基特定性双显性组合(duplexes)。本发明还涉及可用来作为治疗药物并可结合于寡核苷酸的L-核糖-构型双环状核苷类似物的领域。
背景技术
合成寡核苷酸是在不同领域广泛使用的化合物,例如用于分子生物及以DNA为基础的诊断和治疗。
综合考虑
为了广泛地用于不同的应用范围,寡核苷酸必须满足许多不同的要求。以作为治疗剂为例,有用的寡核苷酸必须能够穿过细胞膜,具有良好的抗细胞外及细胞内核酸酶的性能,优选具有补充如RNAseH的内源酶的能力。在以DNA为基础的治疗及分子生物学中,其它性能,例如寡核苷酸对于作用在天然核酸的大量不同酶成长作为有效基质的能力很重要,该天然核酸如聚合酶、激酶、连接酶和磷酸酶。然而,各种用途的基础是寡核苷酸的基本性能:寡核苷酸可辨识和杂交互补单链核酸的特异性序列,采用Watson-Crick氢键(A-T and G-C)或其它氢键结构如Hoogsteen模式。有两个重要术语即亲和力和特异性,常用于表现寡核苷酸的杂交性能。亲合性为该寡核苷酸对其互补目标序列的键合强度的测量(用该双显性组合的热稳定性(Tm)表示)。该双显性组合中各核碱基对增加热稳定性,因此亲合性随该寡核苷酸尺寸(核碱基)增大而增加。特异性为该寡核苷酸在完全互补和错配目标序列之间的辨别能力的测量。换言之,特异性为目标物中与错配核碱基有关的亲合性损失的测量。
在寡核苷酸尺寸恒定时,特异性随着该寡核苷酸及其目标物之间的错配数目增加而增加(亦即,错配的百分比增加)。反之,在错配数目恒定时,当寡核苷酸尺寸增加时,特异性会减少(即错配的百分比减少)。换言之,寡核苷酸亲合性的增加是以牺牲其特异性为代价的,反之亦然。
一般而言,考虑到天然寡核苷酸的缺点,增强特异性及亲合性的新方法对于以DNA为基础的治疗、诊断及对于分子生物技术极为令人期待。
受构型限制的核苷
已知寡核苷酸在杂交成为目标序列期间会经过构型转化,由单链态的相对任意线圈结构变成双显性组合态的规则结构。
因此,构型限制近年来已应用在寡核苷酸,以寻找较未改性(2’-脱氧)寡核苷酸显示改良的杂交性能。例如具有附加的C-3’、C-5’-桥亚乙基的双环[3.3.0]核苷(M.M.Bolli,B.Schweizer and C.Leumann,Helv.Chem.Acta,1993,76,481;Tarkōy and C.Leumann,Angew.Chem.,Int.Ed.Engl.,1993,32,1432;M.Egli,P.Lubini,M.Dobler and C.Leumann,J.Am.Chem.Soc.,1993115,5855;M.Tarkōy,M.Bolli and C.Leumann,Helv.Chem.Acta,1994,77,716;M.Bolli and C.Leumann,Angew.Chem.,Int.Ed.Engl.,1995,34,694;M.Bolli,P.Lubini and C.Leumann,Helv.Chem.Acta,1995,78,2077;J.C.Litten,C.Epple and C.Leumann,Bioorg.Med.Chem.Lett.,1995,5,1231;J.C.Litten,C.Leumann,Helv.Chem.Acta,1996,79,1129;M.Bolli,J.C.Litten,R.Schültz and C.Leumann,Chem.Biol.,1996,3,197;M.Bolli,H.U.Trafelet and C.Leumann,Nucleic Acids Res.,1996,24,4660)、具有一附加C-1’、C-6’或C-6’、C-4’-桥亚甲基的双碳环[3.1.0]核苷(K.-H.Altmann,R.Kesselring,E.Francotte and G.Rihs,Tetrahedrn Lett.,1994,35,2331;K.-H.Altmann,R.Imwinkelried,R.Kesselring and G.Rihs,Tetrahedron Lett.,1994,35,7635;V.E..Marquez,M.A.Siddiqui,A.Ezzitouni,P.Russ,J.Wang,R.W.Wagner and M.D.Matteucci,J.Med.Chem.,1996,39,3739;A.Ezzitouni and V.E.Marquez,J.Chem.Soc.,Perkin Trans.1,1997,1073)、含有一与一未经改性核苷合成为二聚物的附加C-2’、C-3’-二氧戊环的双环状[3.3.0]-和[4.3.0]核苷,其中该附加环为核苷间键替代天然磷酸二酯键的部份(R.J.Jones,S.Swaminathan,J.F.Millagan,S.Wadwani,B.S.Froehler and M.Matteucci,J.Am.Chem.Soc.,1993,115,9816;J.Wang and M.D.Matteucci,Bioorg.Med.Chem.Lett.,1997,7,229)、包含一具有C-2’、C-3’-桥亚甲基作为酰胺及磺酰胺型核苷间键部份的二聚物(C.G.Yannopoulus,W.Q.Zhou,P.Nower,D.Peoch,Y.S.Sanghvi and G.Just,Synlett,1997,378)、双环状[3.3.0]葡萄糖衍生的核苷类似物透过甲醛核苷间键加入三聚物中间(C.G.Yannopoulus,W.Q.Zhou,P.Nower,D.Peoch,Y.S.Sanghvi and G.Just,Synlett,1997,378),具有C-2’、C-3’连接六元环和五元环的双环状[4.3.0]-与[3.3.0]核苷(P.Nielsen,H.M.Pfundheller,J.Wengel,Chem.Commun.,1997,826;P.Nielsen,H.M.Pfundheller,JWengel,XII International Roundtable:Nucleosides,Nucleotides and Their BiologicalApplication;La Jolla,California,September 15-19,1996;Poster PPI 43)已合成并结合到寡脱氧核苷酸中。在所发现的适度改善双显性组合稳定性的情形中,仅涉及DNA或RNA目标物,或关于完全改性而非部分改性的寡核苷酸,反之亦然。
已经报告的大部分类似物的评估,由于缺乏含G、A及C核碱基类似物的数据,以及缺乏指示杂交特异性及杂交模式数据,因而益发复杂。在许多情形中,已经报告单体类似物的合成极为复杂,而在另外一些情况下,完全改性寡核苷酸的合成与广为人使用的标准phosphoramidite化学不兼容。
近来,已报导含锁定核酸(LNA)的寡聚物(Nielsen,P.,Pfundheller,H.M.,Olsen,C.E.and Wengel.J.,J.Chem.Soc.,Perkin Trans.1,1997,3423;Nielsen,P.,Pfundheller,H.M.,Wengel,J.,Chem.Commun.,1997,9,825;Christensen,N.K.,Petersen,M.,Nielsen,P.,Jacobsen,J.P.and Wengel,J.,J.Am.Chem.Soc.,1998,120,5458;Koshkin,A.A.and Wengel,J.,J.Org.Chem.,1998,63,2778;Obika,S.,Morio.K.-I.,Han,Y.and Imanishi,T.,Bioorg.Med.Chem.Lett.,1999,515)。令人感兴趣的是,含有2’-O,4’-C-桥亚甲基LNA单体结合到寡核苷酸序列导致该改性寡核苷酸杂交能力前所未有的改善(Singh,S.K.,Nielsen,P.,Koshkin,A.A.,Olsen,C.E.andWengel,J.,Chem.Commun.,1998,455;Koshkin,A.K.,Singh,S.K.,Nielsen,P.,Rajwanshi,V.K.,Kumar,R.,Meldgaard,M.,Olsen,C.E.,and Wengel,J.,Tetrahedron,1998,54,3607;Koshkin,A.A.Rajwanshi,V.K.,and Wengel,J.,Tetrahedron Lett.,1998,39,4381;Singh,Sanjay K.and Wengel,J.,Chem.Commun.,1998,1247;Kumar,R.,Singh,S.K.,Koshkin,A.A.Rajwanshi,V.K.,Meldgaard,M.,and Wengel,J.,Bioorg.Med.Chem.Lett.,1998,8,2219;Obika,S.et al.Tetrahedron Lett.,1997,38,8735;Obika,S.et al.Tetrahedron Lett.,1998,39,5401;Singh,S.K.,Kumar,R.,andWengel,J.,J.Org.Chem.,1998,63,6078;Koshkin,A.A.,Nielsen,P.,Meldgaard,M.,Rajwanski,V.K.,Singh,S.K.and Wengel,J.,J.Am.Chem.Soc.,1998,120,13252;Singh,S.K.,Kumar,R.,and Wengel,J.,J.Org.Chem.,1998,63,10035)。包含这种LNA单体的寡核苷酸和对应的2’-硫-LNA类似物与互补的DNA和RNA形成具有热稳定性且以前未曾发现的双-或三环状核苷改性寡核苷酸(ΔTm/改性=+3至+11℃)的双显性组合,并表现改善的选择性。
在一系列论文中,Seela等人已研究包括单一或多个2’-脱氧-β-D-木糖呋喃糖基核苷酸单体(Rosemeyer,H.;Seela,F.Helv.Chem.Acta 1991,74,748;Rosemeyer,H.;Krecmerova,M.;Seela,F.Helv.Chem.Acta 1991,74 2054;Seela,F.;Rosemeyer,H.Helv.Chem.Acta 1994,77,883;Seela,F.;Heckel,M.;Rosemeyer,H.Helv.Chem.Acta 1996,79,1451;Rosemeyer,H.;Seela,F.Nucleosides Nucleotides,1995,14,1041;Schoeppe,A.;Hinz,H.-J.;Rosemeyer,H.;Seela,F.Eur.J.Biochem.1996,239,33)的木-DNA(图1,碱基=腺嘌呤-9-基、胞嘧啶-1-基、鸟嘌呤-9-基或胸腺嘧啶-1-基)。与对应的天然2’-脱氧-β-D核糖呋喃糖基相比,一般而言,木-DNA表现出如同镜像的二级结构,此为在熵方面有利的双显性组合结构,对于外切核酸酶有增加的稳定性,对于包含少量2’-脱氧-β-D-木糖呋喃糖基单体的寡核苷酸,对互补DNA有减少的热亲合性(Rosemeyer,H.;Seela,F.Helv.Chem.Acta 1991,74,2054;Seela,F.;Rosemeyer,H.Helv.Chem.Acta 1994,77,883;Seela,F.;Heckel,M.;Rosemeyer,H.Helv.Chem.Acta 1996,79,1451)。
发明内容
基于上述及2’-O,4’-C-亚甲基桥连的LNA单体卓越的性能,决定合成包含单一或多个2’-O,4’-C-亚甲基-α-L-核糖呋喃糖基核苷酸单体。α-L-核糖-LNA计算机模式同样地指出呋喃糖环的S型构型。故而,这项工作的目的在于合成2’-O,4’-C-亚甲基-α-L-核糖呋喃糖基核苷酸单体以及研究含此单体的寡核苷酸的热稳定性。结果显示,改性的L-核糖-LNA有助于互补核酸的高亲合性靶标。当虑及在C-3’和C-4’转化的立体化学性质时,这是一个令人惊讶的事实。
因此,本发明人提供了新型的LNA核苷类似物(L-核糖-LNA)及其中包含具有L-核糖-LNA核苷类似物的寡核苷酸。利用胸腺嘧啶作为核碱基合成该新型L-核糖-LNA核苷类似物,但可以利用其它四个核碱基轻易合成,因此,提供了用于结合寡核苷酸的全组核苷类似物。
本发明涉及包含至少一种如通式I的核苷类似物(后文称为”L-核糖-LNA”)的寡聚物
其中X选自-O-、-S-、-N(RN*)-、-C(R6R6*)-;
B选自氢、羟基、任选取代的C1-4-烷氧基、任选取代的C1-4-烷基、任选取代的C1-4-酰氧基、核碱基、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体;
P表示核苷间键接到后一单体或5’-端基的自由基位置,这种核苷间键或5’-端基任选地包含取代基R5或相等应用的取代基R5*;
P*表示核苷间键至前一单体,或3’-端基的自由基位置;
R2*与R4*表示由选自-C(RaRb)-、-C(Ra)=C(Rb)-、-C(Ra)=N-、-O-、-Si(R3)2-、-S-、-SO2-、-N(Ra)-和>C=Z的1至4个基团/原子组成的双自由基,
其中Z选自-O-、-S-和-N(Ra)-,且Ra及Rb各分别选自氢、任选取代的C1-12-烷基、任选取代的C2-12-烯基、任选取代的C2-12-炔基、羟基、C1-12-烷氧基、C2-12-烯氧基、羧基、C1-12-烷氧羰基、C1-12-烷羰基、甲酰基、芳基、芳氧基-羰基、芳氧基、芳羰基、杂芳基、杂芳氧基-羰基、杂芳氧基、杂芳羰基、胺基、一和二(C1-6-烷基)胺基、甲酰基、一和二(C1-6-烷基)-胺基-羰基、胺基-C1-6-烷基-胺羰基、一和二(C1-6-烷基)胺基-C1-6-烷基-胺基羰基、C1-6-烷基-羰胺基、甲酰胺基、C1-6-烷酰氧基、磺酰基、C1-6-烷磺酰氧基、硝基、偶氮基、胺磺酰基、C1-6-烷硫基、卤素、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体,其中芳基与杂芳可任选地取代,且成对取代基Ra与Rb皆可为任选取代的亚甲基烯烃(=CH2);
在此取代基R1*、R2、R3*、R5、R5*、R6和R6*各分别选自氢、任选取代的C1-12-烷基、任选取代的C2-12-烯基、任选取代的C2-12-炔基、羟基、C1-12-烷氧基、C2-12-烯氧基、羧基、C1-12-烷氧羰基、C1-12-烷羰基、甲酰基、芳基、芳氧基-羰基、芳氧基、芳羰基、杂芳基、杂芳氧基-羰基、杂芳氧基、杂芳基、胺基、一和二(C1-6-烷基)胺基、甲酰基、一和二(C1-6-烷基)-胺基-羰基、胺基-C1-6-烷基-胺羰基、一和二(C1-6-烷基)胺基-C1-6-烷基-胺基羰基、C1-6-烷基-羰胺基、甲酰胺基、C1-6-烷酰氧基、磺酰基、C1-6-烷磺酰氧基、硝基、叠氮基、胺磺酰基、C1-6-烷硫基、卤素、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体,其中芳基与杂芳基可任选地取代,且成对取代基Ra与Rb都可为氧代基、硫代基、亚酰基或任选取代的亚甲基,或可共同形成由1至5个碳原子亚烷基链所组成的链双自由基,该亚烷基链任选地由单一或多个选自-O-、-S-和-(NRN)-的杂原子/基团中断和/或终断,其中RN选自氢与C1-4-烷基,且两相邻(非成对)取代基可表示形成双键的加成键;且当存在与双自由基无关的RN*时,选自氢与C1-4-烷基;
和其碱性盐类与酸加成盐类。
此外,本发明涉及通式II的核苷类似物(L-核糖-LNA)
其中B选自核碱基、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体;
其中X选自-O-、-S-、-N(RN*)-、-C(R6R6*)-;
各Q及Q*分别选自氢、叠氮基、卤素、氰基、硝基、羟基、Prot-O-、Act-O-、巯基、Prot-S-、Act-S-、C1-6-烷硫基、胺基、Prot-N(RH)-、Act-N(RH)-、一或二(C1-6-烷基)胺基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷基、任选取代的C2-6-烯基、任选取代的C2-6-烯氧基、任选取代的C2-6-炔基、任选取代的C2-6-炔氧基、一磷酸盐、二磷酸盐、三磷酸盐、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基、配体、羧基、磺酰基、羟甲基、Prot-O-CH2-、Act-O-CH2-、胺甲基、Prot-N(RH)-CH2-、Act-N(RH)-CH2-、羧甲基、磺酰甲基,其中Prot分别为-OH、-SH和-NH(RH)的保护基,Act分别为-OH、-SH和-NH(RH)的活化基,且RH选自氢和C1-6-烷基;且R2-与R4-皆表示选自-O-、-(CR*R*)r+s+l-、-(CR*R*)r-O-(CR*R*)s-、-(CR*R*)r-S-(CR*R*)s-、-(CR*R*)r-N(R*)-(CR*R*)s-、-O-(CR*R*)r+s-O-、-S-(CR*R*)r+s-O-、-O-(CR*R*)r+s-S-、-N(R*)-(CR*R*)r+s-O-、-O-(CR*R*)r+s-N(R*)-、-S-(CR*R*)r+s-S-、-N(R*)-(CR*R*)r+s-N(R*)-、-N(R*)-(CR*R*)r+s-S-、和-S-(CR*R*)r+s-N(R*)-;
其中各R*分别选自氢、卤素、叠氮基、氰基、硝基、羟基、巯基、胺基、一或二(C1-6-烷基)胺基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷基、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基、配体,和/或两相邻(非成对)R*可一起表示双键,且各r及s为0至3,条件是r+s总和为1至4;
其中取代基R1*、R2、R3*、R5、R5*、R6和R6*分别选自氢、任选取代的C1-12-烷基、任选取代的C2-12-烯基、任选取代的C2-12-炔基、羟基、C1-12-烷氧基、C2-12-烯氧基、羧基、C1-12-烷氧羰基、C1-12-烷基羰基、甲酰基、芳基、芳氧基-羰基、芳氧基、芳羰基、杂芳基、杂芳氧基-羰基、杂芳氧基、杂芳基羰基、胺基、一和二(C1-6-烷基)胺基、胺甲酰基、一和二(C1-6-烷基)胺基-羰基、胺基-C1-6-烷基-胺基羰基、一和二(C1-6-烷基)胺基-C1-6-烷基-胺基羰基、C1-6-烷基-羰基胺基、胺甲酰胺基、C1-6-烷酰氧基、磺酰基、C1-6-烷基磺酰氧基、硝基、叠氮基、C1-6-烷硫基、卤素、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体,其中芳基与杂芳基可任选地取代,两成对取代基可一起表示氧基、硫基、酰亚胺基、或任选取代的亚甲基,或可共同形成由1至5个碳原子亚烷基链所组成的链双自由基,该亚烷基链任选地由单一或多个选自-O-、-S-和-(NRN)-的杂原子/基团中断和/或终断,其中RN选自氢与C1-4-烷基,且两相邻(非成对)取代基可表示形成双键的加成键;当RN*存在与双自由基无关时选自氢与C1-4-烷基;
以及其碱性盐类与酸加成盐类;
条件为寡核苷酸合成进行的条件下具有反应性的任何化学基(包含任一核碱基)任选地经官能基保护。
本发明还涉及该核苷类似物(L-核糖-LNA)在制备寡聚物中的应用,以及该寡聚物和该核苷类似物在诊断、分子生物学研究和治疗中的应用。
附图说明
图1、2和3所述的方法可同样用来合成胸腺嘧啶之外的其它嘧啶碱基。在图4中所述的步骤可用来制备嘌呤α-L-LNA单体,其中Ad=6-N苯甲酰腺嘌呤-9-基,R=NC(CH2)2OP(NiPr2)。
具体实施方式
当本文提到L-核糖-构型双环状核苷类似物时,使用术语“L-核糖-LNA”(L-ribo-configurated Locked Nucleoside Analogues),该L-核糖-构型双环状核苷类似物可结合到本发明寡聚物中(通式I),或作为分离的化学物质(通式II)。术语“单体的L-核糖-LNA”特别指后一情形。
寡聚物和核苷类似物
如上所述,本发明涉及包含单一或多个L-核糖-构型双环状核苷类似物(后文称为”L-核糖-LNA”)的新型寡聚物(寡核苷酸)。
结合到寡聚物(寡核苷酸)中的各可能的L-核糖-LNA具有通式I
其中X选自-O-(L-核糖呋喃糖改性物)、-S-、-N(RN*)-、-C(R6R6*)-,其中R6、R6*及RN*进一步定义如下。因此,该L-核糖-LNA结合到包含五元环作为该双环结构的主要部分的寡聚物。
在该可能的五元环中间,X位置表示-O-、-S-和-N(RN*)-似乎尤其令人感兴趣,且X位置为-O-时显得特别令人关注。
取代基B表示当该寡聚物与DNA或RNA复合时,能与DNA或RNA(特别是DNA或RNA的核碱基)相互作用(例如通过氢键、共价键或电子相互作用)的基团。或者,取代基B可表示作为标记或信息基团,或取代基B可表示预期与DNA或RNA很少或没有相互作用的基团(例如氢)。因此,该取代基B优选选自氢、羟基、任选取代的C1-4-烷氧基、任选取代的C1-4-烷基、任选取代的C1-4-酰氧基、核碱基、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体。
在本文中,术语“核碱基”涵盖天然核碱基及非天然核碱基。对于本领域的技术人员而言,应明白先前认为是“非天然”的不同核碱基其后已在自然界被发现。因此,“核碱基”不仅包括已知的嘌呤和嘧啶杂环,而且还包括其杂环类似物及互变异构物。核碱基的说明实例为腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶、尿嘧啶、嘌呤、黄嘌呤、二胺基嘌呤、8-氧基-N6-甲基腺嘌呤、7-脱氮黄嘌呤、7-脱氮鸟嘌呤、N4,N4-乙醇胞嘧啶、N6,N6-乙醇-2,6-二胺基嘌呤、5-甲基胞嘧啶、5-(C3-C6)炔基胞嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、拟异-胞嘧啶、2-羟基-5-甲基-4-***吡啶、异胞嘧啶、异鸟嘌呤、肌苷以及如Benner等人于美国专利第5,432,272号所述的“非天然”核碱基。术语“核碱基”意欲涵盖这些实例及其全部类似物和互变异构体。特别令人关注的核碱基为腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶和尿嘧啶,其被视为与在人体中涉及治疗及诊断应用的天然核碱基。
当用于本文时,“DNA嵌体”表示能嵌入DNA或RNA链、双显性组合或三显性组合的基团。DNA嵌体官能部位的实例为吖啶类,蒽类,醌类例如蒽醌、吲哚、喹啉、异喹啉,二氢醌类,蒽环素类(anthracyclines),四环素类(tetracyclines),亚甲基蓝,蒽环素酮,补骨脂内酯类,香豆素类,卤代乙锭,dynemicin,金属配合物例如1,10-菲咯啉-铜,三(4,7-二苯基-1,10-菲咯啉)钌-钴-烯二炔类例如calcheamicin、卟啉类、偏端霉素、纺锤霉素(netropcin)、viologen、道诺霉素。特别令人感兴趣的实例有吖啶类,醌类如蒽醌,亚甲基蓝,补骨脂内酯类,香豆素类以及卤代乙锭。
在本文中,“光化学活性基”涵盖经光照射可以进行化学反应的化合物。其官能基的说明实例为醌类特别是6-甲基-1,4-萘醌、蒽醌、萘醌和1,4-二甲基-蒽醌,diazirines,芳族叠氮类,二苯甲酮类,补骨脂内酯类,重氮化合物类及diazirino化合物。
在本文中,“热化学反应基”定义为可以与其它基团进行由热化学引发的共价键形成的官能基。热化学反应基的官能部分的说明实例为羧酸类,羧酸酯类如活化酯类,羧酸卤素例如酰基氟类、酰基氯类、酰基溴类和酰基碘类,羧酸迭氮类,羧酸酰肼类,磺酸类,磺酸酯类,磺酸卤类,半缩脲类,硫半缩脲类,醛类,酮类,一级醇类,二级醇类,三级醇类,酚类,烷基卤类,硫醇类,二硫化物类,一级胺类,二级胺类,三级胺类,肼类,环氧化物类,马来酰亚胺类以及硼酸衍生物。
在本文中,术语“螯合基”表示包括超过一个键结位置及同时通过超过一个键结位置经常键合至其它分子、原子或离子的分子。螯合基官能部分的实例为亚胺基二乙酸、腈基二乙酸、乙二胺四乙酸(EDTA)、胺基膦酸等。
在本文中,术语“信息基”表示本身可检测或作为检测***一部份的基团。信息基功能部分的实例为生物素、地谷新配基、萤光基(可吸收某种波长电磁辐射例如光线或X光,且经常呈较长波长辐射再度发出吸收能量的基团,例如丹酰(5-二甲基胺基)-1-萘磺酰基)、DOXYL(N-氧基-4,4-二甲基噁唑烷)、PROXYL(N-氧基-2,2,5,5-四甲基吡咯烷)、TEMPO(N-氧基-2,2,6,6-四甲基哌啶)、二硝基苯基、吖啶类、香豆素类、Cy3及Cy5(生物检测***公司商品名)、erytrosine、香豆酸、繖形酮、Texas Red、若丹明、,四甲基若丹明、Rox、7-硝基苯并-2-噁-1-二唑(NBD)、嵌二萘、萤光素、铕、钌、钐及其它稀土金属、放射性同位素标记、化学发光标记(在化学反应中经由发光可被检测的标记)、旋转标记(自由基(例如取代的有机氮氧化物)或其它通过电子旋转共振光谱结合到被测生物分子的顺磁性探针(例如Cu2+、Mg2+))、酶(例如过氧化酶、碱性磷酸酶、β-半乳糖苷酶、和葡萄糖氧化酶)、抗原类、抗体类、半抗原类(可组合抗原但本身无法引发免疫反应的基团,例如肽类和类固醇激素),细胞膜穿透用的载体***例如:脂肪酸残基、类固醇部分(胆固醇基)、维生素A、维生素D、维生素E、特定受体的叶酸肽类、介导胞吞作用的基团、表皮生长因子(EGF)、血管舒缓激肽和血小板衍生生长因子(PDGF)。特别令人感兴趣有例如生物素、萤光基、Texas Red、若丹明、二硝基苯基、地谷新配基、钌、铕、Cy5和Cy3。
在本文中,术语“配体”表示结合的部分。配体可包括例如:芳基(如苯、吡啶、萘、蒽及菲),杂芳基(如噻吩,呋喃,四氢呋喃,吡啶,二噁烷和嘧啶),羧酸类,羧酸酯类,羧酸卤素,羧酸叠氮类,羧酸酰肼类,磺酸类,磺酸酯类,磺酸卤素,半缩脲内,硫半缩脲类,醛类,酮类,一级醇类,二级醇类,三级醇类,酚类,烷基卤素类,硫醇类,二硫化物类,一级胺类,二级胺类,三级胺类,肼类,环氧化物类,顺丁烯二酰亚胺类,C1-C20烷基,其任选地用一或多个杂原子例如氧原子、氮原子和/或硫原子中断或终断,任选地包含芳族或一/多不饱和烃,聚氧乙烯例如聚乙二醇,寡/聚酰胺类例如聚-β-苯胺、聚甘氨酸、聚离胺酸,肽类,寡/多醣类,寡/聚磷酸盐类,毒素,抗生素,细胞毒剂以及类固醇类,也称作“亲和配体”,即对特定蛋白质、抗生素、多醣及寡醣以及其它生物分子的位置具有特异性亲和力的官能基或生物分子。
对于本领域的技术人员而言,应明了DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体的上述特定实例对应所讨论基团的“活性/功能”部分。对于本领域的技术人员而言,应可进而明了DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基及配体通常以M-K-形式表示,其中M为所讨论基团的“活性/功能”部分,而K为“活性/官能”部分连接到五元环的间隔基。因此,应可理解在基团B选自DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体的情形中,该基团B具有M-K-形式,其中M分别为DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体的”活性/功能”部分,而K为介于五元环与“活性官能”部分间的包含1-50个原子、优选1-30个原子,特别是1-15个原子的任选间隔基。
在本文中,术语“间隔基”表示热化学和光化学非反应性距离形成基,用以将前述定义的两个或两个以上不同类型部分连接在一起。间隔基基于多种特性选择,该特性包括其疏水性、亲水性、分子挠性及长度(例如,参见Hermanson et.Al.,“Immobilized Affinity Ligand Techniques”,Academic Press,San Diego,California(1992),p.137-ff)。一般而言,间隔基长度小于或大约400在某些应用中,优选小于100该间隔基因而包括一任选地以单一或多个如氧原子、氮原子和/或硫原子的杂原子中断或终止的碳原子链。因此,该间隔基可包括单一或多个酰胺、酯、胺、醚和/或硫醚官能基,通常包括任选的芳族或单/聚不饱和烃类、聚氧乙烯(如聚乙二醇)、寡/聚酰胺(如聚-β-苯胺、聚甘氨酸、聚离胺酸、肽类、寡/多醣类。再者,间隔基可由其化合单元构成。考虑感兴趣基团的“活性官能”部分相对于五元环预定或需要定位及空间方向性,间隔基长度可有变化。特别令人感兴趣的实施方案中,间隔基包括化学可裂解基。化学可裂解基例如包括于还原条件下可裂解的二硫化物基,可由肽酶裂解的肽片段等。
在本发明的一个实施方案中,K表示一可使所讨论基团的“活性/功能”部分直接连接到该五元环的单键。
在优选实施方案中,通式I与II中的取代基B优选选自核碱基,特别是选自腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶和尿嘧啶。
在本发明的寡聚物中(通式I),P表示核苷间键连接到后一单体或5’-端基的自由基位置。当所讨论的L-核糖-LNA并非5’-端基“单体”时,适用前者,反之,当所讨论的L-核糖-LNA为5’-端基“单体”时,适用后者。应可理解(进一步由以下核苷间键和5’-端基的定义将更明了)这种核苷间键或5’-端基可包含取代基R5(或同样可应用:取代基R5*)形成至基团P的双键。(5’-端基指在核苷中对应于核糖部分体的5’-碳原子的位置)
另一方面,P*表示核苷间键接到前一单体,或3’-端基的自由基位置。相似地,当所讨论的L-核糖-LNA并非3’-端基”单体”时,适用前者,反之,当所讨论的L-核糖-LNA为3’-端基”单体”时,适用后者。(3’-端基指在核苷中对应于核糖部分体之3’-碳原子的位置)
在本文中,术语“单体”表示L-核糖-LNA的天然核苷、非天然核苷、PNAs、LNAs等。因此,术语“后一单体”是在5’-端基方向邻近的单体,术语“前一单体”是在3’-端基方向邻近的单体。该后一及前一单体由一L-核糖-LNA单***置观察,可为天然核苷或非天然核苷,或甚至可进而为L-核糖-LNA单体。
因此,在本文中(如上述定义导出),术语“寡聚物”指通过结合单一或多个L-核糖-LNA改性的寡核苷酸。
本发明的关键部分为结合五元环的L-核糖-构型,前提条件为R2*和R4*共同表示在五元环上形成稠合环的双自由基。
在构成双自由基的基团中,Z选自-O-、-S-和-N(Ra)-,且Ra和Rb分别选自氢、任选取代的C1-12-烷基、任选取代的C2-12-烯基、任选取代的C2-12-炔基、羟基、C1-12-烷氧基、C2-12-烯氧基、羧基、C1-12-烷氧羰基、C1-12-烷羰基、甲酰基、芳基、芳氧基-羰基、芳氧基、芳羰基、杂芳基、杂芳氧基-羰基、杂芳氧基、杂芳羰基、胺基、一和二(C1-6-烷基)胺基、甲酰基、一和二(C1-6-烷基)-胺基-羰基、胺基-C1-6-烷基-胺羰基、一和二(C1-6-烷基)胺基-C1-6-烷基-胺基羰基、C1-6-烷基-羰胺基、甲酰胺基、C1-6-烷酰氧基、磺酰基、C1-6-烷磺酰氧基、硝基、偶氮基、胺磺酰基、C1-6-烷硫基、卤素、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体,其中芳基与杂芳基可任选地被取代,且成对取代基Ra与Rb可一起表示任选取代的亚甲基烯烃(=CH2,任选地用如对芳基的任选取代基定义的取代基取代一或两次)。
在本文中,即在本说明书和权利要求书中,该双自由基的方向在使左手侧表示具有最低数目的取代基而右手侧表示具有最高数目的取代基,因此,当R2*及R4*共同表示一双自由基“-O-CH2-”时,可理解该氧原子表示R2*,例如该氧原子连接到R2*的位置,该亚甲基表示R4*。
考虑结合到本发明寡聚物的L-核糖-LNA中双自由基结构令人关注的可能性,可相信该双自由基由成对的非-成对取代基构成,该双自由基优选选自-(CR*R-)r-Y-(CR*R*)s-、-(CR*R*)r-Y-(CR*R*)s-Y-、-Y-(CR*R*)r+s-Y-、-Y-(CR*R*)r-Y-(CR*R*)s-、-(CR*R*)r+s-、-Y-、-Y-Y-所构成的双自由基,其中各Y分别选自-O-、-S-、-Si(R*)2-、-N(R*)-、>C=O、-C(=O)-N(R*)-和-N(R*)-C(=O)-,各R*分别选自氢、卤素、叠氮基、氰基、硝基、羟基、巯基、胺基、一或二(C1-6-烷基)胺基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷基、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体,和/或两个相邻(非成对)R*可一起代表双键,以及各r和s为0至4条件为r+s总和为1至4。特别令人感兴趣的是各双自由基分别选自-Y-、-(CR*R*)r+s-、-(CR*R-)r-Y-(CR*R*)s和-Y-(CR*R*)r+s-Y,其中各r和s为0至3条件为r+s总和为1至4。
特别令人感兴趣的寡聚物为适用于寡聚物的L-核糖-LNA下述标准的寡聚物:R2*及R4*一起表示选自-O-、-S-、-N(R*)-、-(CR*R*)r+s+l-、-(CR*R*)r-O-(CR*R*)s-、-(CR*R*)r-S-(CR*R*)s-、-(CR*R*)r-N(R*)-(CR*R*)s-、-O-(CR*R*)r+s-O-、-S-(CR*R* r+s-O-、-O-(CR*R*)r+s-S-、-N(R*)-(CR*R*)r+s-O-、-O-(CR*R*)r+s-N(R*)-、-S-(CR*R*)r+s-S-、-N(R*)-(CR*R*)r+s-N(R*)-、-N(R*)-(CR*R*)r+s-S-、和-S-(CR*R*)r+s-N(R*)-其中之一的双自由基;其中各r和s为0至3条件为r+s总和为1至4,R*选自氢、羟基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷基、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体,以及任一其余取代基R*为氢。
在一优选实施方案中,至少一个LNA的双自由基中的一基团R*选自DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体(其中后面的基团可包括对取代基B定义的间隔基)。
在另一优选实施方案中,至少一个LNA的双自由基中的一基团R*选自氢、羟基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷基、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体,以及任一其余取代基R*为氢。
关于存在的取代基R1*、R2、R3*、R5、R5*、R6和R6*,分别选自氢、任选取代的C1-12-烷基、任选取代的C2-12-烯基、任选取代的C2-12-炔基、羟基、C1-12-烷氧基、C2-12-烯氧基、羧基、C1-12-烷氧羰基、C1-12-烷羰基、甲醯基、芳基、芳氧基-羰基、芳氧基、芳羰基、杂芳基、杂芳氧基-羰基、杂芳氧基、杂芳羰基、胺基、一和二(C1-6-烷基)胺基、甲酰基、一和二(C1-6-烷基)-胺基-羰基、胺基-C1-6-烷基-胺羰基、一和二(C1-6-烷基)胺基-C1-6-烷基-胺基羰基、C1-6-烷基-羰胺基、甲酰胺基、C1-6-烷酰氧基、磺酰基、C1-6-烷磺酰氧基、硝基、偶氮基、胺磺酰基、C1-6-烷硫基、卤素、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体(其中该后者基团可包含如对取代基B所定义的间隔基),其中芳基与杂芳基可任选地被取代,且成对取代基Ra与Rb皆可为氧代基、硫代基、亚酰基或任选取代的亚甲基,或可共同形成由1至5个碳原子亚烷基链所构成的链双自由基,该亚烷基链任选地由单一或多个选自-O-、-S-和-(NRN)-的杂原子/基团中断和/或终断,其中RN选自氢与C1-4-烷基,且两相邻(非成对)取代基可表示形成双键的加成键;且当存在与双自由基无关的RN*时,选自氢与C1-4-烷基。
该L-核糖LNA存在的各取代基R1*、R2、R3*、R5、R5*、R6和R6*优选选自氢、任选取代的C1-6-烷基、任选取代的C2-6-烯基、羟基、C1-6-烷氧基、C26-烯氧基、羧基、C1-6-烷氧羰基、C1-6-烷羰基、甲酰基、胺基、一和二(C1-6-烷基)胺基、胺甲酰基、一和二(C1-6-烷基)-胺基-羰基、C1-6-烷基-羰胺基、胺甲酰胺基、叠氮基、C1-6-烷酰氧基、磺酰基、胺磺酰基、C1-6-烷硫基、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基及配体及卤素,其中两成对取代基可一起表示氧基,RN*当存在且与双自由基无关时选自氢及C1-4-烷基。
在本发明的一个优选实施方案中,X选自-O-、-S-和-N(RN*)-,特别是-O-,且该L-核糖-LNA存在的各取代基R1*、R2、R3*、R5、R5*、R6和R6*表示氢。
在本发明更优选的实施方案中,X为O,取代基R1*、R2、R3*、R5及R5*表示氢,且结合到寡聚物之L-核糖-LNA的R2*及R4*一起表示选自-O-、-(CH2)0-1-O-(CH2)1-3-、-(CH2)0-1-S-(CH2)1-3-、-(CH2)-N(RN)-(CH2)1-3-和(CH2)2-4-,特别是-O-CH2-、-S-CH2-和-NRH-CH2-的双自由基。一般而言,以目前为止所得结果,构成R2*及R4*的双自由基形成两原子桥,即该双自由基与该呋喃糖环(X=O)形成五元环。
在本发明的一个实施方案中,双自由基为-(CH2)2-4-。
对于这些令人感兴趣的实施方案,优选该L-核糖-LNA具有下列通式Ia的结构
还令人感兴趣的本发明的另一方面为式Ia变化例,其中B处于“α-构型”。
本发明的寡聚物通常包括1至10000个如通式I的L-核糖-LNA(或更复杂的通式Ia)及0至10000个选自天然核苷及核苷类似物的核苷。该核苷数目与L-核糖-LNA数目总和至少为2,优选至少为3,特别至少为5,尤其至少为7,例如在2至15000的范围内,优选在2至100的范围内,例如3至100,特别是在2至50的范围内,例如3至50或5至50或7至50。
已发现部分经L-核糖-LNA改性寡聚物会对DNA或RNA进行强烈杂交(具有增加的亲合性)。现在相信经L-核糖-LNA完全改性的寡聚物及L-核糖-LNA单体与其它L-核糖-构型核苷酸类似物所构成的寡聚物将导致可相媲美的杂交性能。
在本文中,术语“核苷”表示杂环碱基的糖苷。该术语“核苷”广泛用于包含非天然核苷、天然核苷和其它核苷类似物。
核苷的说明实例为包括一核糖部分的核糖核苷和包括一脱氧核糖部分的脱氧核糖核苷。关于这种核糖的碱基,应可理解该碱基可为任一天然碱基,例如:腺嘌呤、鸟嘌呤、胞嘧啶、胸腺嘧啶和尿嘧啶,以及其任一经改性的变体或任一可能的非天然碱基。
当考虑该定义及已知核苷(天然与非天然)和核苷类似物(包括已知双和三环类似物)时,可明了寡聚物可包含单一或多个L-核糖-LNA(关于取代基的选择和双自由基的选择,该L-核糖-LNA可相同或不同)及单一或多个核苷和/或核苷类似物。在本文中,该“寡核苷酸”表示经由核苷间键连接核苷的连续链,然而,应可理解在寡聚物(寡核苷酸)中单一或多个核苷酸单元(单体)的核碱基可利用如上定义的取代基B改性。
该寡聚物可为线型、支链或环状。在支链寡聚物的情形中,支链可位于一核苷中,位于一核苷间键中或在一具体例中位于一L-核糖-LNA。相信在后一情形中,该取代基R2与R3*可表示对前一单体的核苷间键的基团P*,特别是R2表示另外的P*。
如上所述,寡聚物的L-核糖-LNA通过核苷间键连接其它单体。在本文中,术语“核苷间键”表示由2至4个,优选为3个选自-CH2-、-O-、-S-、-NRH-、>C=O、>C=NRH、>C=S、-Si(R”)2-、-SO-、-S(O)2-、-P(O)2-、-P(S)2-、-PO(R”)-、-PO(OCH3)-和-PO(NHRH)-基团/原子组成的键,其中RH选自氢及C1-4-烷基,且R”选自C1-6-烷基及苯基。核苷间键的说明实例为-CH2-CH2-CH2-、-CH2-CO-CH2-、-CH2-CHOH-CH2-、-O-CH2-O-、-O-CH2-CH2-、-O-CH2-CH=、-CH2-CH2-O-、-NRH-CH2-CH2-、-CH2-CH2-NRH-、-CH2-NRH-CH2-、-O-CH2-CH2-NRH-、-NRH-CO-O-、-NRH-CO-NRH-、-NRH-CS-NRH-、-NRH-C(=NRH)-NRH-、-NRH-CO-CH2-NRH-、-O-CO-O-、-O-CO-CH2-O-、-O-CH2-CO-O-、-CH2-CO-NRH-、-O-CO-NRH-、-NRH-CO-CH2-、-O-CH2-CO-NRH-、-O-CH2-CH2-NRH-、-CH=N-O-、-CH2-NRH-O-、-CH2-O-N=(当用作连接后一单体时包括R5)、-CH2-O-NRH-、-CO-NRH-CH2-、-CH2-NRH-O-、-CH2-NRH-CO-、-O-NRH-CH2-、-O-NRH-、-O-CH2-S-、-S-CH2-O-、-CH2-CH2-S-、-O-CH2-CH2-S-、-S-CH2-CH=(当用作连接后一单体时包括R5)、-S-CH2-CH2-、-S-CH2-CH2-O-、-S-CH2-CH2-S-、-CH2-S-CH2-、-CH2-SO-CH2-、-CH2-SO2-CH2-、-O-SO-O-、-O-S(O)2-O-、-O-S(O)2-CH2-、-O-S(O)2-NRH-、-NRH-S(O)2-CH2-、-O-S(O)2-CH2-、-O-P(O)2-O-、-O-P(O,S)-O-、-O-P(S)2-O-、-S-P(O)2-O-、-S-P(O,S)-O-、-S-P(S)2-O-、-O-P(O)2-S-、-O-P(O,S)-S-、-O-P(S)2-S-、-S-P(O)2-S-、-S-P(O,S)-S-、-S-P(S)2-S-、-O-PO(R”)-O-、-O-PO(OCH3)-O-、-O-PO(OCH2CH3)-O-、-O-PO(OCH2CH2S-R)-O-、-O-PO(BH3)-O-、-O-PO(NHRH)-O-、-O-P(O)2-NRH-、-NRH-P(O)2-O-、-O-P(O,NRH)-O-、-CH2-P(O)2-O-、-O-P(O)2-CH2-和-O-Si(R”)2-O-;在-CH2-CO-NRH-、-CH2-NRH-O-、-S-CH2-O-、-O-P(O)2-O-、-O-P(O,S)-O-、-O-P(S)2-O-、-NRH-P(O)2-O-、-O-P(O,NRH)-O-、-O-PO(R”)-O-、-O-PO(CH2)-O-和-O-PO(NHRN)-O-,其中RH选自氢和C1-4-烷基,且R”选自C1-6-烷基和苯基。在Mesmaeker等人所著Current Opinion in Structural Biology 1995,5,343-355中有进一步的说明实例。该核苷间键的左手侧键连接至如P*的五元环如取代基P*,反之右手侧键连接至前一单体的5’-位置。
由上述也可明了,在所讨论的L-核糖-LNA为5’-端基单体的情形中,该基团P也可表示一5’-端基。该5’-端基的实例为氢、羟基、任选取代的C1-6-烷基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷羰氧基、任选取代的芳氧基、一磷酸盐、二磷酸盐、三磷酸盐和-W-A’,其中W选自-O-、-S-和-N(RH)-,其中RH选自氢及C1-6-烷基,A’选自DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体(其中后面的基团可包含如对于该取代基B所定义的间隔基)。
在本说明书和权利要求中,术语“一磷酸盐”、“二磷酸盐”、“三磷酸盐”分别表示式:-O-P(O)2-O*、-O-P(O)2-O-P(O)2-O*及-O-P(O)2-O-P(O)2-O-P(O)2-O*的基团。
在特别令人关注的实施方案中,该基团P表示选自一磷酸盐、二磷酸盐和三磷酸盐的5’-端基。特别是式II的三磷酸盐变体作为如酶(特别是那些在核酸上具有活性的酶)的基质特别令人感兴趣。
同样地,在所讨论的L-核糖-LNA为3’-端基单体的情形中,该基团P*可表示3’-端基。该3’-端基的实例为氢、羟基、任选取代的C1-6-烷基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷羰氧基、任选取代的芳氧基和-W-A’,其中W选自-O-、-S-和-N(RH)-,其中RH选自氢及C1-6-烷基,A’选自DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体(其中后面的基团可包含如对于该取代基B所定义的间隔基)。
在本发明的一个优选实施方案中,该寡聚物具有下式III:
G-[Nu-L]n(0)-{[(L-核糖-LNA)-L]m(q)-[Nu-L]n(q)}q-G* III
其中
q为1至50;
各n(0),...,n(q)分别为0至10000;
各m(1),...,m(q)分别为1至10000;
条件为n(0),...,n(q)和m(1),...,m(q)的总和为2至15000;
G表示5’-端基;
各Nu分别表示选自天然核苷和核苷类似物的核苷;
各L-核糖-LNA分别表示选自Nu和L-核糖-LNA两基团之间的核苷间键,或L与G*表示3’-端基;且各L-核糖-LNA-L分别表示如上定义的通式I,或优选为如上定义的通式Ia的核苷类似物。
在该实施方案中,总的来说,本发明提供了包括L-核糖-LNA与不同核碱基的可能性,特别是选自胸腺嘧啶、胞嘧啶和尿嘧啶的核碱基与选自腺嘌呤和鸟嘌呤的核碱基。在一具体例中,该寡聚物可包括至少一个其中B(在式I或Ia中)选自包括腺嘌呤与鸟嘌呤之基的L-核糖-LNA及至少一个L-核糖-LNA,其中B选自包括胸腺嘧啶、胞嘧啶与尿嘧啶。
除上述定义的寡聚物之外,本发明还提供了用于如制备寡聚物的L-核糖-LNA单体,作为例如核酸聚合酶、聚核酸激酶、端基转化酶的基质,及作为治疗剂,进一步参见如下。单体L-核糖-LNA的整体结构(特别就可能的双自由基而言)对应于定义为寡聚物组成的L-核糖-LNA。但就P和P’基而言,单体L-核糖-LNA与寡聚物的组成略有差异,如后文所述。此外,单体L-核糖-LNA包含官能基保护基,特别在单体L-核糖-LNA欲通过化学合成结合到寡聚物的情形时包含官能基保护基。
此外,本发明涉及通式II的单体L-核糖-LNA核苷(L-核糖-LNA):
其中该取代基B选自核碱基、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体;X选自-O-、-S-、-N(RN*)-和-C(R6R6*)-,优选选自-O-、-S-和-N(RN*)-;
各Q及Q*分别选自氢、叠氮基、卤素、氰基、硝基、羟基、Prot-O-、Act-O-、巯基、Prot-S-、Act-S-、C1-6-烷硫基、胺基、Prot-N(RH)-、Act-N(RH)-、一或二(C1-6-烷基)胺基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷基、任选取代的C2-6-烯基、任选取代的C2-6-烯氧基、任选取代的C2-6-炔基、任选取代的C2-6-炔氧基、一磷酸盐、二磷酸盐、三磷酸盐、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基、配体、羧基、磺酰基、羟甲基、Prot-O-CH2-、Act-O-CH2-、胺甲基、Prot-N(RH)-CH2-、Act-N(RH)-CH2-、羧甲基、磺酰甲基,其中Prot分别为-OH、-SH和-NH(RH)的保护基,Act分别为-OH、-SH和-NH(RH)的活化基,且RH选自氢及C1-6-烷基;和
R2*与R4*一起表示选自-O-、-(CR*R*)r+s+l-、-(CR*R*)r-O-(CR*R*)s-、-(CR*R*)r-S-(CR*R*)s-、-(CR*R*)r-N(R*)-(CR*R*)s-、-O-(CR*R*)r+s-O-、-S-(CR*R*)r+s-O-、-O-(CR*R*)r+s-S-、-N(R*)-(CR*R*)r+s-O-、-O-(CR*R*)r+s-N(R*)-、-S-(CR*R*)r+s-S-、-N(R*)-(CR*R*)r+s-N(R*)-、-N(R*)-(CR*R*)r+s-S-、及-S-(CR*R*)r+s-N(R*)-的双自由基;其中R*如上述对于寡聚物的定义;且与Q或Q*无关的各取代基R1*、R2、R3*、R5和R5*如上述对于寡聚物的定义。
该单体L-核糖-LNA还包括其碱性盐类与酸加成盐类。
此外,应理解,在寡核苷酸合成进行的条件下具有反应性的任一化学基(包含任一核碱基)任选地被官能基保护,如本领域中所公知的。这表示如羟基、胺基、羧基、磺酰基及巯基和核碱基的单体L-核糖-LNA基团任选地被官能基保护。保护(与脱保护)通过本领域的技术人员公知的方法进行(参见,例如:Greene,T.W.andWuts,P.G.M.,“Protective Groups in Organic Synthesis”2nd ed.,John Wiley,N.Y.(1991),and M.J.Gait,Oligonucleotide Syntheis,IRL Press,1984)。
羟基保护基的说明实例为任选取代的三苯甲基(Tr)如4,4’-二甲氧三苯甲基(DMT)、4-单甲氧三苯甲基(MMT)及三苯甲基,任选取代的9-(9苯基)呫吨基(pixyl),任选取代的乙氧羰氧基,对-苯基偶氮苯氧羰氧基,四羟基哌喃基(thp),9-芴基甲氧羰基(Fmoc),甲氧四羟基哌喃基(mthp),硅烷氧基如三甲硅烷基(TMS)、三异丙硅烷基(TIPS)、叔丁基二甲基硅烷基(TBDMS)、三乙硅烷基(TES)及苯基-二甲硅烷基,苯氧基羰基或经取代的苯氧基羰基醚如2-溴苯氧基羰基,叔丁基醚,烷基醚如甲醚,乙缩醛(包含两个羟基),酰氧基如乙酰基或卤代乙酰基如氯代乙酰基或氟代乙酰基、异丁酰基、三甲基乙酰基、苯甲酰基和取代苯甲酰基、甲氧甲基(MOM),苄醚或经取代的苄醚如2,6-二氯苄基(2,6-Cl2Bzl)。或者,该羟基可任选地经连接基连到固体载体而被保护。
胺基保护基的说明实例为Fmoc(芴基甲氧羰基)、BOC(叔丁氧基羰基)、三氟乙酰基、烯丙氧基羰基(alloc,AOC)、苄基-氧基羰基(Z,Cbz)、取代苄氧基羰基,例如:2-氯苄氧基羰基(2-ClZ)、单甲氧三苯甲基(MMT)、二甲氧三苯甲基(DMT)、苯二甲酰基和9-(9-苯基)呫吨基(pixyl)。
羧基保护基的说明实例为烯丙基酯类,甲基酯类,乙基酯类,2-氰基乙基酯类,三甲基硅烷基乙基酯类,苄基酯类(Obzl),2-金刚烷基酯类(O-2-Ada),环己基酯类(OcHex),1,3-噁唑啉类,噁唑类,1,3-噁唑啶类,酰胺类或酰肼类。
巯基保护基的说明实例为三苯甲基(T、乙酰胺基甲基(acm)、三甲基乙酰胺基甲基(Tacm)、2,4,6-三甲氧苄基(Tmob)、叔丁基烃磺基(StBu)、9-芴基甲基(Fm)、3-硝基-2-吡啶基烃硫基(Nprs)和4-甲基苄基(Meb)。
此外,或许需要或希望保护任何单体L-核糖-LNA中所含的核碱基,特别是当依据本发明将单体L-核糖-LNA结合到寡聚物时。在本文中,术语“受保护的核碱基”表示所讨论的核碱基带有本领域技术人员公知的保护基(参见例如:Protocolsfor Oligonucleotides and Analogs,vol 20,(Sudhir Agrawai,ed.),Humana Press,1993,`Totowa,NJ:S.L.Beaucage and R.P.lyer,Tetrahedron,1993,49,6123;S.L.Beaucage and R.P.lyer,Tetrahedron,1992,48,2223;and E.Uhlmann and A.Peyman,Chem.Rev.,90,543.)。说明实例为苯甲酰基、异丁酰基、叔丁基、叔丁氧羰基、4-氯-苄氧羰基、9-芴基甲基、9-芴基甲氧羰基、4-甲氧苯甲酰基、4-甲氧三苯甲基、任选取代的***基、对甲苯磺酰基、任选取代的磺酰基、异丙基、任选取代的脒类、任选取代的三苯甲基、苯氧乙酰基、任选取代的酰基、pixyl、四氢哌喃基、任选取代的硅烷基醚类和4-甲氧苄氧羰基。在“Protocols for oligonucleotideconjugates”中第一章,Methods in Molecular Biology,vol 26,(sudhir Agrawal,ed.),Humana Press,1993,Totowa,NJ.and S.L.Beaucage and R.P.lyer,Tetrahedron,1993,48,2223公开了另外合适的实例。
在一优选实施方案中,在单体L-核糖-LNA中的B基优选选自核碱基和受保护的核碱基。
在本发明的单体L-核糖-LNA的具体例中,Q及Q*其中之一,优选为Q*,表示选自Act-O-、Act-S-、Act-N(RH)-、Act-O-CH2-、Act-S-CH2-、Act-N(RH)-CH2-,Q及Q*其中另一个,优选为Q,表示选自氢、叠氮基、卤素、氰基、硝基、羟基、Prot-O-、巯基、Prot-S-、C1-6-烷硫基、胺基、Prot-N(RH)-、一或二(C1-6-烷基)胺基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷基、任选取代的C2-6-烯基、任选取代的C2-6-烯氧基、任选取代的C2-6-炔基、任选取代的C2-6-炔氧基、一磷酸盐、二磷酸盐、三磷酸盐、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基、配体、羧基、磺酰基、羟甲基、Prot-O-CH2-、胺甲基、Prot-N(RH)-CH2-、羧甲基、磺酰甲基,且RH选自氢及C1-6-烷基。
上述情形中,Prot基团分别表示-OH、-SH和-NH(RH)的保护基。但考虑到需要有稳定且可逆的保护基,然而,考虑到对稳定的和可逆的保护基的需要,这种保护基选自如上定义的羟基保护基、巯基保护基以及胺基保护基。然而,-OH的任何保护基优选选自任选取代的三苯甲基如二甲氧三苯甲基(DMT)、一甲氧三苯甲基(MMT)和三苯甲基,以及9-(9-苯基)呫吨基(pixyl)、任选取代的四羟基哌喃基(thp)(对于phosphoramidite寡核苷酸合成更适合的羟基保护基记载于Agrawal,ed.”Protocols for Oligonucleotide Conjugates”;Methods in Molecular Biology,vol.26,Humana Press,Totowa,NJ(1994)and Protocols for Oligonucleotides and Analogs,vol20,(Sudhir Agrawal,ed),Humana Press,1993,Totowa,NJ中),或经保护的乙缩醛;-SH的任一保护基选自三苯甲基,例如:二甲氧三苯甲基(DMT)、单甲氧三苯甲基(MMT)及三苯甲基,及任选取代的9-(9苯基)呫吨基(pixyl)、任选取代的四羟基哌喃基(thp)(对于phosphoramidite寡核苷酸合成更适合的巯基保护基记载于Agrawal(参见上述));-NH(RH)的任一保护基选自三苯甲基,例如:二甲氧三苯甲基(DMT)、单甲氧三苯甲基(MMT)及三苯甲基,及任选取代的9-(9苯基)呫吨基(pixyl)、任选取代的四羟基哌喃基(thp)(对于phosphoramidite寡核苷酸合成更适合的胺基保护基也记载于Agrawal(参见上述))。
在上述具体例中,如同本文所定义的任一单体L-核糖-LNA,Act分别表示-OH、-SH和-NH(RH)的活化基。该活化基例如选自取代的O-phosphoramidite、任选取代的O-磷酸三酯、任选取代的O-磷酸二酯、任选取代的H-磷酸酯和任选取代的O-磷酸酯。
在本文中,术语“phosphoramidite”表示式-P(ORx)-N(Ry)2基,其中Rx表示一任选取代的烷基,例如:甲基、2-氰基乙基或苄基,且各Ry表示任选取代的烷基,例如:乙基或异丙基或基团-N(Ry)2形成一吗啉基(-N(CH2CH2)2O)。Rx优选表示2-氰基乙基且两Ry优选为相同并表示异丙基。因此,特别有关的phosphoramidite为N,N-二异丙基-O-(2-氰基乙基)phosphoramidite。
应能理解,本文中所用于单一单体L-核糖-LNA或多个单体L-核糖-LNA的保护基可选择,以便在这个/这些L-核糖-LNA结合本发明的寡聚物时,可进行该官能基的同步脱保护或是连续脱保护作用。后一情形表现区域选择性地导入一个或数个例如DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体的“活化/官能”基的可能性,其中,该基团可经由如上所述的间隔基连接。
在一优选实施方案中,Q分别选自氢、叠氮基、卤素、氰基、硝基、羟基、Prot-O-、巯基、Prot-S-、C1-6-烷硫基、胺基、Prot-N(RH)-、一或二(C1-6-烷基)胺基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷基、任选取代的C2-6-烯基、任选取代的C2-6-烯氧基、任选取代的C2-6-炔基、任选取代的C2-6-炔氧基、一磷酸盐、二磷酸盐、三磷酸盐、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基、配体、羧基、磺酰基、羟甲基、Prot-O-CH2-、胺甲基、Prot-N(RH)-CH2-、羧甲基、磺酰甲基,其中Prot分别为-OH、-SH和-NH(RH)的保护基,且RH选自氢及C1-6-烷基;以及Q*分别选自氢、叠氮基、卤素、氰基、硝基、羟基、Act-O-、巯基、Act-S-、C1-6-烷硫基、胺基、Act-N(RH)-、一或二(C1-6-烷基)胺基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷基、任选取代的C2-6-烯基、任选取代的C2-6-烯氧基、任选取代的C2-6-炔基、任选取代的C2-6-炔氧基、DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基、配体、羧基、磺酰基,其中Act分别为-OH、-SH和-NH(RH)的活化基,且RH选自氢及C1-6-烷基。
通式II的单体L-核糖-LNA,如结合到寡聚物的L-核糖-LNA,可代表各种立体异构物。因此,相信如上述对于结合到寡聚物的L-核糖-LNA的立体化学变体同样可应用在单体L-核糖-LNA的情形(然而,应注意P应用Q取代)。
在本发明的优选实施方案中,该单体LNA具有通式IIa
其中取代基定义如上。
此外,关于取代基、双自由基、R*等的定义,如上述对于本发明寡聚物定义的相同优选实施方案也可应用在单体L-核糖-LNA的情形中。
在本发明单体L-核糖-LNA的特别令人关注的实施例中,B表示核碱基,优选选自胸腺嘧啶、胞嘧啶、尿嘧啶、腺嘌呤和鸟嘌呤(特别是腺嘌呤与鸟嘌呤)的核碱基,X为-O-,R2*与R4*一起表示选自-(CH2)0-1-O-(CH2)1-3-、-(CH2)0-1-S-(CH2)1-3-及-(CH2)-N(RN)-(CH2)1-3-,特别是-O-CH2-、-S-CH2-和-RN-CH2-的双自由基,其中RN选自氢及C1-4-烷基。Q表示Prot-O-,Q*表示Act-OH,R1*、R2、R3*、R5和R5*各表示氢。在该具体例中,RN也可选自DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体。
在本发明的单体L-核糖-LNA更特别令人关注的具体例中,B表示核碱基,优选为选自胸腺嘧啶、胞嘧啶、尿嘧啶、腺嘌呤和鸟嘌呤(特别是腺嘌呤与鸟嘌呤)的核碱基,X为-O-,R2*与R4*一起表示选自-(CH2)0-1-O-(CH2)1-3、-(CH2)0-1-S-(CH2)1-3-和-(CH2)-N(RN)-(CH2)1-3-,特别是-O-CH2-、-S-CH2-和-RN-CH2-的双自由基,其中RN选自氢及C1-4-烷基,Q选自羟基、巯基、C1-6-烷硫基、胺基、一或二(C1-6-烷基)胺基、任选取代的C1-6-烷氧基、任选取代的C2-6-烯氧基、任选取代的C2-6-炔氧基、一磷酸盐、二磷酸盐、三磷酸盐,Q*选自氢、叠氮基、卤素、氰基、硝基、羟基、巯基、C1-6-烷硫基、胺基、一或二(C1-6-烷基)胺基、任选取代的C1-6-烷氧基、任选取代的C1-6-烷基、任选取代的C2-6-烯基、任选取代的C2-6-烯氧基、任选取代的C2-6-炔基、任选取代的C2-6-炔氧基,R3*选自氢、任选取代的C1-6-烷基、任选取代的C2-6-烯基、任选取代的C2-6-炔基,R1*、R2、R5及R5*各表示氢。同样,RN也可选自DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基与配体。
本发明的一方面提供固相和/或溶液相结合到寡聚物的L-核糖-LNA不同衍生物。至于说明实例,使用phosphoramidite法、磷酸三酯法和H-膦酸酯法,分别适用于结合(1R,3R,4S,7R)-7-羟基-1-羟甲基-3(胸腺嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷、(1R,3R,4S,7R)-7-羟基-1-羟甲基-3(胞嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷、(1R,3R,4S,7R)-7-羟基-1-羟甲基-3(尿嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷、(1R,3R,4S,7R)-7-羟基-1-羟甲基-3(鸟嘌呤-1-基)-2,5-二氧杂双环[2.2.1]庚烷、(1R,3R,4S,7R)-7-羟基-1-羟甲基-3(腺嘌呤-1-基)-2,5-二氧杂双环[2.2.1]庚烷的单体分别为(1R,3R,4S,7R)-7-(氰基乙基(二异丙基-胺基)膦基氧基)-1-(4,4’-二甲氧基三苯甲基氧基甲基)-3-(胸腺嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷、(1R,3R,4S,7R)-7-羟基-1-(4,4’-二甲氧基三苯甲基氧基甲基)-3-(胸腺嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷-7-O-(2-氯苯基磷酸盐)、(1R,3R,4S,7R)-7-羟基-1-(4,4’-二甲氧基三苯甲基氧基甲基)-3-(胸腺嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷-7-O-(H-磷酸盐)及其3-(胞嘧啶-1-基)、3-(尿嘧啶-1-基)、3-(腺嘌呤-1-基)和3-(鸟嘌呤-1-基)类似物。此外,用亚甲基硫基、亚甲基胺基或1,2-亚乙基双自由基取代该单体的亚甲基氧基双自由基的类似物也期望构成本发明的特别令人关注的变体。相信该亚甲基硫基和亚甲基胺基类似物如同该亚甲基氧基类似物同样适用,因此考虑对应于所述结合(1R,3R,4S,7R)-7-羟基-1-羟甲基-3(胸腺嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷、(1R,3R,4S,7R)-7-羟基-1-羟甲基-3(胞嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷、(1R,3R,4S,7R)-7-羟基-1-羟甲基-3(尿嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷、(1R,3R,4S,7R)-7-羟基-1-羟甲基-3(鸟嘌呤-1-基)-2,5-二氧杂双环[2.2.1]庚烷、(1R,3R,4S,7R)-7-羟基-1-羟甲基-3(腺嘌呤-1-基)-2,5-二氧杂双环[2.2.1]庚烷的特定试剂也视为本发明范围内特别令人感兴趣的反应性单体。对于亚甲基胺基类似物而言,应注意二级胺带有选自任选取代的C1-6-烷基,例如甲基和苄基,任选取代的C1-6-烷基羰基,例如三氟乙酰基,任选取代的芳基羰基及任选取代的杂环芳基羰基。
本发明的另一同样令人关注的方面为通式II或IIa的变体,其中B处于“β-构型”。
单体的制备
在一优选实施方案中,含有一2’-O,4’-C-桥亚甲基的α-L-核糖-LNA是由下列步骤合成的:4-C-羟基甲基-α-D-木糖呋喃糖1的苯甲酰化(T.F.Tam and B.Fraser-Ried,Can.J.Chem.,1979,57,2818)生成二-O-苯甲酰基衍生物2,接着利用80%的乙酸进行乙酸水解,随后进行乙酰化,使该二-O-苯甲酰基衍生物转化为1,2-二-O-乙酰化的呋喃糖3。利用修改后的Vorbrüggen方法(H.Vorbrüggen and G.Chem.Ber.,1981,114,1256),由胸腺嘧啶的现场硅烷化及三氟甲磺酸三甲基硅烷酯介导的偶合立体选择性地得到该胸腺嘧啶β-构型核苷4。利用甲醇钠处理化合物4导致脱乙酰化而得到核苷三醇5。4,4’-二甲氧基三苯甲基保护接着进行甲苯磺酰化,得到5’-O-4,4’-二甲氧基三苯甲基保护的核苷衍生物7。由碱基引起环闭合而得到双环核苷衍生物8。脱苯甲基化产生双环核苷类似物9,其可转化为寡核苷酸合成的phosphoramidite衍生物10。在实施例中使用的偶合法仅为对本领域的技术人员来说显而易见的数种可能方法中的一种。
可使用如图3所示合成序列的另一途径。因此,三甲磺酰基化核苷5得到可使用NaOH/EtOH/H2O环化的核苷11。在使用的实验条件下,发现该剩余的甲磺酰氧基伴随转变成羟基,生成核苷12。如在实施例14所述的标准DMT保护,预期会生成核苷8,是合成α-L-核糖-LNA核苷phosphoramidite衍生物10(图2)的常规的中间物。
该所述实例用来说明本发明的步骤和实施例。并利用1D NMR来证实合成化合物的结构。
图1、2和3所述的方法可同样用来合成胸腺嘧啶之外的其它嘧啶碱基,例如:尿嘧啶、胞嘧啶、5-取代尿嘧啶、5-取代胞嘧啶和同样取代嘧啶的α-L-核糖-LNA核苷衍生物。或者,利用已知方法(Koshin,A.A.,Singh,S.K.,Nielsen,P.,Rajwanshi,V.K.Kumar,R.,Meldgaard,M.,Olsen,C.E.,Wengel.J.Tetrahedron 1998,54,3607;Obika,S.,Nanbu,D.,Hari,Y.,Andoh,J.,Morio,K.,Doi,T.,Imanishi,T.TetrahedronLett.1998,39,5401)使该尿嘧啶衍生物可转化为对应的胞嘧啶衍生物,以及将该胸腺嘧啶衍生物转化为对应的5-甲基胞嘧啶衍生物。
对于嘌呤α-L-核糖-LNA核苷衍生物的合成而言,可以设计一些合适的合成方法。应注意,以下提到术语“α-面”是指天然RNA核苷单体的α-面,以下提到术语“β-面”是指天然RNA核苷单体的β-面,术语“β-嘌呤核苷”或“β-嘧啶核苷”表示该核碱基位于如天然RNA核苷单体中。至于该嘌呤α-L-核糖-LNA核苷衍生物的可能的合成途径的实例,可采用arabino-构型类似物(位于该呋喃糖环的β-面的2’-OH基)的环化。这些核苷可由对应的arabino-构型母体核苷经由5’-氧化、醛醇缩合和还原而制备。
5’-OH基(位于该呋喃糖环的β-面)的保护基的控制与活化应该为上述所需的环化准备。或者,β-嘌呤核糖呋喃糖基核苷(具有位于该呋喃糖环α-面的2’-OH与3’-OH基及位于该呋喃糖环β-面的3’-OH(或可选择位于该呋喃糖环α-面)利用在C-3’位置的伴随转变)的4’-C-羟甲基衍生物的2’-OH基的2’-氧化接着立体选择性还原(使用例如NaBH4),将产生在2’-碳原子具有转化构型的希望的核苷。5’-OH基(位于该呋喃糖环的β-面)的保护基的控制与活化应该为上述所需要的环化而准备。可预期其它步骤有助于在β-嘌呤核糖呋喃糖基核苷(具有位于该呋喃糖环α-面的2’-OH与3’-OH基及位于该呋喃糖环β-面的3’-OH(或可选择位于该呋喃糖环α-面)利用在C-3’位置的伴随转变)的4’-C-羟甲基衍生物的2’-碳原子的构型转化,例如Mitsunobu反应或具有如乙酸酯、苯甲酸酯、烷氧化物等O-亲核基的2’-O-活化衍生物(例如:2’-O-甲磺酰基、2’-O-苯甲酰基或2’-O-三氟甲磺酰基)亲核置换反应。然后进行脱保护以得到5’-羟基-4’-C-羟甲基衍生物,活化以准备进行环化(例如:通过一或二甲磺酰基化、一或二苯甲酰基化或一或二三氟甲磺酰基化),环化(如有需要则在2’-OH基脱保护后进行),脱保护,将产生所需要的嘌呤α-L-核糖-LNA核苷。应注意,该嘌呤碱基优选应在目标单体中受到保护,在所选择步骤,或如最后步骤的合成途径期间,通过三甲基硅烷基化保护该嘌呤碱基的游离胺基而可完成该保护。在一实施方案中,可采用已知Vorbrüggen型偶合法(参见例如核苷4的合成,图1)(Koshkin,A.A.,Singh,S.K.,Nielsen,P.,Rajwanshi,V. K.,Kumar,R.,Meldgaard,M.,Olsen,C.E.,Wengel,J,Tetrahedon 1998,54,3607),通过偶合呋喃糖衍生物3(图1)与适合的受保护的腺嘌呤或鸟嘌呤衍生物,制备β-嘌呤核苷的起始4’-C-羟甲基衍生物。
预期可在天然β-嘌呤核糖呋喃糖基核苷(具有位于该呋喃糖环α-面的2’-OH及位于该呋喃糖环β-面的3’-OH(或可选择位于该呋喃糖环α-面)利用在C-3’位置的伴随转变)上导入附加的4’-C-羟甲基,从而进行上述构型的转化,接着使用如上述的那些已知步骤。可预期,在适当衍生与保护的嘧啶核苷上的酶或化学转糖苷化反应,或是arabino-构型β-嘧啶呋喃糖基核苷、arabino-构型4’-C-羟甲基-β-嘧啶呋喃糖基核苷、或已环化的α-L-核糖-LNA嘧啶核苷为该嘌呤α-L-核糖-LNA核苷衍生物的可能合成途径。或者,可由呋喃糖或己醣起始,在2-碳原子的构型转化以及环化,或这些步骤之一或这些步骤之二(所需的步骤视所用的起始物质而定)进行4-C-羟甲基化。随后,在环化之前或之后,用不同的碱基偶合(如有需要而受保护的嘌呤或嘧啶),产生有助于在必需保护基控制和/或OH-基活化之后完成用于合成α-L-核糖-LNA嘧啶和嘌呤核苷的核苷衍生物。至于合成α-L-核糖-LNA嘧啶或嘌呤核苷的另一步骤,可能为自适当衍生的呋喃糖衍生物,例如呋喃糖胺,在两个或多个化学步骤中直接合成所要的核碱基。
在一优选实施方案中,在实施例15、16和17(图4)中所述的步骤可用来制备嘌呤α-L-LNA单体,例如腺嘌呤或鸟嘌呤衍生物。因此,利用N-6-苯甲酰基腺嘌呤糖3得到选择性脱乙酰化及其后转变为2’-O-三氟甲磺酰基衍生物的核苷13。利用乙酸钾伴随反应得到具有在C2’转化的2’-O-乙酰衍生物14。完成脱乙酰化后,重新保护腺嘌呤部分,选择性甲磺酰化两个一级羟基,用氢氧化钠水:二噁烷溶液处理生成α-L-LNA腺嘌呤核苷15。核苷15的DMT保护后接着脱苯甲基化及3’-O-phosphitylation(Koshkin,A.A.,Singh,S.K.,Nielsen,P.,Rajwanshi,V.K.,Kumar.R.,Meldgaard,M.,Olsen,C.E.,Wengel,J,Tetrahedon 1998,54,3607)为获得phosphoramidite衍生物16的一种可能途径。15的脱苯甲基化之后接着一级羟基的选择性DMT-保护及3’-O-phosphitylation为生成phosphoramidite 16的另一途径。
上述对于α-L-核糖-LNA嘌呤核苷合成的所有方法和步骤也可选择用作α-L-核糖-LNA嘧啶核苷合成的方法。
上述合成α-L-核糖-LNA嘧啶与嘌呤核苷的方法自然导致有助于α-L-核糖-LNA核苷的2’-胺基与2’-硫基衍生物合成的方法。至于实例,通过攻击位于在适当活化的5’-OH基上呋喃糖环β-面的2’-胺基或2’-硫基的环化将产生2’-胺基或2’-硫基α-L-核糖-LNA嘧啶或嘌呤核苷。或者,通过攻击位于在呋喃糖环α-面适当活化的2’-OH基上呋喃糖环β-面的5’-胺基或5’-硫基的环化将产生2’-胺基或2’-硫基α-L-核糖-LNA嘧啶或嘌呤核苷。至于另一方法,使用胺基或硫基亲核基(分别如苄胺和硫乙酸钾)环化适当经活化、受保护及构型的衍生物如2’-O,5-二甲酰基、2’-O,5-二苯甲酰基或2’-O,5-二三氟甲酰基核苷,将产生α-L--LNA核苷的2’-胺基与2’-硫基衍生物。
预期用于α-L-核糖-LNA嘧啶核苷寡聚合化的方法可成功地用于α-L-核糖-LNA嘌呤核苷。或者,也可应用任何作为寡核苷酸及类似物的自动或溶液相合成的已知方法如磷酸三酯法、H-磷酸盐法或任何用于α-L-核糖-LNA嘧啶核苷寡聚合化方法的变体。
寡聚物的制备
使用有机化学领域中的普通技术人员公知的核酸化学聚合技术可制备本发明的线型-、支链-(M.and B.S.Sproat,J.Chem.Soc.,Chem.Commun.,1995,495;R.H.E.Hudson and M.J.Damha,J.Am.Chem.Soc.,1993,115,2119;M.Von Būren,G.V.Petersen,K.Rasmussen,G.Brandenburg,J.Wengel and F.Kirpekar,Tetrahedron,1995,51,8491)及环形-(G.Prakash and E.T.Kool,J.Am.Chem.Soc.,1992,114,3523)寡与聚核苷酸。可使用phosphoramidite化学(S.L.Beaucage and R.P.lyer,Tetrahedron,1993,49,6123;S.L.Beaucage and R.P.lyer,Tetrahedron,1992,48,2223),但也可使用例如H-磷酸盐化学、磷酸三酯化学或酶合成。利用盐酸吡啶代替1H-四唑作为在寡核苷酸合成期间活化核苷phosphoramidite的高效率试剂稍微修改Phosphoramidite法的标准偶合条件,并延长该偶合时间至10至30分钟之间。
在合成所要的序列之后,由固体载体脱保护与裂解(使用浓氨的甲醇溶液在室温下从固体载体裂解及去除保护基,历时12小时),然后使用市售可处理滤筒(包含脱三苯甲基化)反相纯化,产生最终寡聚合产物。或者,可利用可处理反相HPLC和/或从乙醇或丁醇沉淀进行L-核糖-LNA寡核苷酸纯化。利用毛细管凝胶电泳证实该合成聚核苷酸类似物的纯度与组成,但也可利用反相HPLC及MALDI-MS证实纯度与组成。
总之,本发明提供了如本文定义L-核糖-LNA改性寡核苷酸制备的L-核糖-LNA的应用。应理解,L-核糖-LNA改性寡核苷酸可包括正常核苷(例如:天然核苷如核糖核苷和/或脱氧核糖核苷)和不同于那些如通式II所定义的改性核苷。
此外,具有固定在一任选地经核碱基保护及任选地经5’-OH保护的LNA的固体载体材料,特别令人关注,如作为在3’-端基包含LNA单体的LNA改性寡核苷酸的合成材料。在此情形中,该固体载体优选为CPG,例如容易得到(市售)的CPG材料,其利用如供货商所述对于特殊材料的条件,将一3’-经官能基化、任选地经核碱基保护及任选地经5’-OH保护的LNA连接在该材料上。例如可以使用BioGenexUniversial CPG载体(BioGenex,U.S.A.)。该5’-OH保护基可为如DMT基。应根据关于所讨论的CPG材料的应用条件来选择3’-官能基。
应用
本发明公开了当L-核糖-LNA衍生物结合到部分改性寡核苷酸时,比未改性寡核苷酸会减少这种改性寡核苷酸对于互补DNA与RNA两者的亲合性。然而,当结合经L-核糖-LNA完全改性寡核苷酸时,会观察到戏剧性地增加对于互补ssDNA与ssRNA的杂交性能。除所述性能之外,该L-核糖-LNA的一特殊变体-α-L-核糖-LNA具有在杂交时辨别RNA与DNA目标物的能力。完全改性L-核糖-LNA寡核苷酸因此提供不需放弃特异性而大幅增加标准寡核苷酸的亲合性(固定的寡核苷酸尺寸),不需放弃亲合性而显著增加特异性(减少寡核苷酸尺寸),或对RNA目标物特定杂交的可能性。
除大幅增加杂交性能之外,还相信L-核糖-LNA改性寡核苷酸表现出正常DNA与RNA寡核苷酸许多有用的物理化学性能。包括优异的溶解度、LNA改性寡核苷酸的反应对于象氯化钠和氯化四甲铵的盐类,表现与未改性寡核苷酸相似的反应、对于各种聚合酶LNA改性寡核苷酸扮演前体的能力、LNA改性寡核苷酸在使用热稳定DNA聚合酶的目标扩增反应中扮演前体的能力、LNA改性寡核苷酸对于T4聚核苷酸激酶扮演基质的能力、生物素化的LNA对于序列特定捕获PCR扩增基因序列到一抗生蛋白链菌素涂层的固体表面上的能力、固定LNA改性寡核苷酸对于序列特定捕获扩增基因序列的能力及LNA改性寡核苷通过由链入侵以序列特定靶标双链的非常重要的能力。因此,对于本领域的技术人员而言,这些新型核苷类似物在治疗、诊断及分子生物学中对于改善一般以寡核苷酸为基础的技术的性能来说,是非常有用的工具。
本发明的一个目的在于提供本发明的单体L-核糖-LNA,该单体L-核糖-LNA可利用寡核苷酸合成领域的技术人员公知的步骤与设备使其结合到寡核苷酸。
本发明的另一目的在于提供经L-核糖-LNA完全或部分改性的寡核苷酸(寡聚物),其可以序列特定的方式杂交至互补寡核苷酸,形成比由未改性寡核苷酸所形成的对应复合物有大大提高的亲合性的双显性组合或三显性组合。
本发明的另一目的为使用经L-核糖-LNA完全改性的寡核苷酸以获得不需放弃亲合性而提高的寡核苷酸特异性。
本发明的另一目的在于提供包含两个L-核糖-LNA-正常核苷及其它核苷类似物的经L-核糖-LNA完全或部份改性的寡核苷酸。
本发明的又一目的为开发高亲合性L-核糖-LNA以产生可通过“链置换”方法键合到dsDNA分子中目标序列的具有度亲合性的完全改性寡核苷酸。
本发明的又一目的在于提供不同等级的L-核糖-LNA,当结合到寡核苷酸时,对其互补核苷的亲合性不同。例如可以具有如经修改过的氢键可能衍生物取代正常核碱基G、T、C和U来完成。
本发明的又一目的在于提供L-核糖-LNA改性寡核苷酸,较其未改性等同物具有更好的抗核酸酶性质。
本发明的又一目的在于提供L-核糖-LNA完全改性的寡核苷酸,其可在杂交时辨别出DNA和RNA目标物。通过Tm量测,令人惊讶地显示L-核糖-LNA的Tm对于互补RNA寡核苷酸为每改性增加5.7℃,相较于对于互补DNA为每改性仅增加2.7℃(如实施例11、表3所示)。因此,和对于DNA相比,α-L-核糖-LNAoligos对于RNA具有增加的亲合性,使得α-L-核糖-LNA将特定杂交特定的RNA而不杂交具有相同碱基序列的DNA。在以下所述的一些情形中可表现出辨别RNA与DNA的能力。
本发明的另一目的在于提供可补充RNAseH的L-核糖-LNA改性寡核苷酸。
本发明的另一目的在于提供可作为DNA与RNA聚合酶基质而使该类似物可结合到成长中的核酸链或作为链互变异构物的L-核糖-LNA。
本发明的又一目的在于提供可作为治疗剂的L-核糖-LNA。已知有许多治疗用的核苷类似物实例,且本文中公开利用从文献已知的步骤可以合成核苷类似物的相似衍生物(E.De Clercq,J.Med.Chem.1995,382491;P.Herdewijn and E.DeClercq:Classical Antiviral Agents and Design of New Antiviral Agents.In:A Textbookof Drug Design and Development;Eds.P.Krogsgaard-Larsen,T.Liljefors and U.Madsen;Harwood Academic Publishers,Amsterdam,1996,p.425;I.K.Larsen:Anticancer Agents.In:A Textbook of Drug Design and Development;Eds.P.Krogsgaard-Larsen,T.Liljefors and U.Madsen;Harwood Academic Publishers,Amsterdam,1996,p 460)。
已证实,双链RNA具有抗病毒活性及肿瘤抑制活性(Sharp et al.,Eur.J.Biochem.230(1):97-103,1995,Lengyel-P.et al.,Proc.Natl.Acad.Sci.U.S.A.,90(13):5893-5,1993,and Laurent-Crawford et al.,AIDS Res.Hum.Retroviruses,8(2):285-90,1992)。双链LNA可能与有疗效活性的双链RNA的效果相似,所以,这种双链LNA具有作为治疗剂的潜力。
本文中使用术语“天然核酸”时,表示含义最广的核酸,例如存在于任何来源的完整细胞或病毒或由化学或物理方式从这种来源释放的核酸或由扩增从这种原始来源衍生的核酸。该天然核酸可为单、双或部分双链,且可为相对的纯种核酸或不同核酸的混合物。其也可为包含其它核酸及其它细胞成分的粗制生物样品的组成。另一方面,术语“合成核酸”表示任何由化学合成制备的核酸。
本发明还提供L-核糖-LNA改性寡核苷酸在以核酸为基础的治疗、诊断及分子生物学的应用。该L-核糖-LNA改性寡核苷酸可用于天然或合成核酸的检测、辨识、捕获、特征描述、定量和分段,并且在活体内或在试管内作为转译作用或转录作用的阻隔剂。在许多情况中,令人感兴趣的是使不同分子连接到L-核糖-LNA改性寡核苷酸。可将此种分子连接到寡核苷酸的末端或连接到单一或多个内部部位。或者,可将这种分子通过间隔基连接到寡核苷酸5’-或3’-端基。这种分子的代表性基团为DNA嵌体、光化学活性基、热化学活性基、螯合基、信息基和配体。通常,利用这些分子来标记未改性DNA与RNA寡核苷酸的所有方法也可用来标记L-核糖-LNA改性寡核苷酸。同样地,用于检测经标记的寡核苷酸的所有方法一般可应用于相应经标记的L-核糖-LNA改性寡核苷酸。
L-核糖-LNA改性寡核苷酸可用来标记细胞,其中该标记使该细胞得以区别或从未经标记的细胞中被分离出来。
治疗
术语“链置换”涉及寡核苷酸由此键接到双链DNA或RNA中其互补的目标序列,以便由该目标链置换其它链。
本发明的一方面,在以“抗原”法为基础的新型医药的发展中,开发可以进行“链置换”的L-核糖-LNA改性寡核苷酸。与可以制造三链的寡核苷酸相比,这种“链置换”的寡核苷酸允许在dsDNA中任何序列可被靶标以及可存在于生理离子强度与pH下。
“链置换”寡核苷酸也优选用于反信息手段,用于分子内氢键造成的RNA目标序列无法接近的情况。这种分子内结构可能出现于mRNAs,当试图通过反信息手段“关闭”mRNA的转译时将造成重大问题。
细胞RNA的其它种类,例如tRNAs、rRNAs、snRNAs和scRNAs,含有对于其功能而言重要的分子内结构。这种高度结构化RNA不能,但却能参与例如mRNA切片、聚腺苷化、转译、编辑、维持染色体末端完整等一连串的细胞功能。由于其高级结构赋予或防止正常寡核苷酸有效地杂交,至今仍难以使用这种RNA作为反信息目标物。然而,本文提供的具有新型、惊人效果的α-L-核糖-LNA,如下所述,靶标具有α-L-核糖-LNA的RNA是有可能的。
已知一些抗体会和细菌核糖体相互作用并因此而抑制转译作用。已知某些抗体(例如:链霉素、四环素、放线壮观素、伊短菌素、潮霉素与新霉素)键合到细菌16S rRNA的特定区域(Moazed D and Noller HF,Nature,1987,327(6121),389)。同样地,其它抗体(例如:氯霉素、红霉素、碳霉素和春霉素B)会和细菌中23S rRNA的特定区域相互作用(Moazed D and Noller HF,Biochimie,1987,69(8),879)。类似的方法似乎也适用于较高等的生物体(Spangler EA and Blackburn EH,J.Biol.Chem.,1985,260(10),6334)。
此外,已知PNAs-PNAs(肽核酸)为特定与呈Watson-Crick碱基对形式的DNA相互作用,并可略为增加热稳定性(Tm)-靶标核糖RNA的官能性及可接近的位置的分子,该分子可抑制大肠杆菌中的转译作用(Good L and Nielsen PE,Proc NatlAcad Sci U.S.A,1998,95(5),2073),可指出,键合到rRNA特定区域的高亲合性的寡核苷酸,该寡核苷酸与rRNA键结抗体的效果相似。由于LNA比PNA更能键合到具有更高Tm的RNA,因此很有可能将LNA用于特定键合到细菌rRNA以及抑制细菌中的转译作用。至于该方法的延伸,可能在较高等生物之间开发出小型却有显著差异的rRNA序列,以设计可抑制其中之一,但却不抑制另一个生物的转译作用的LNAoligos。本方法的一个显而易见的应用为特定开发抑制Plasmodium属(疟疾杆菌)、Schistosoma属(引起Bilharzia)、各种filariae(引起Elephantiasis及River Blindness)、钩虫(引起anaemia)和其它致病寄生虫的转译作用的LNA。
高亲合性L-核糖-LNA单体的应用可促使充分热稳定性的反信息探针的建构,以便有效杂交至这种目标RNA。因此,在一优选实施方案中,使用L-核糖-LNA赋予该寡核苷酸充分的亲合性以允许该寡核苷酸杂交至这些RNA种类,由此调整在发现该RNA的粒子的定性和/或定量功能。
将想要用在反信息治疗中的L-核糖-LNA改性寡核苷酸设计成有高亲合性与补充RNAseH能力的双重目的。例如通过L-核糖-LNA片段侧接一未经改性的中间DNA片段可达到此目的。此外,由于α-L-核糖-LNA优于RNA,因此可以在各种一般治疗用的反信息应用中,开发出α-L-核糖-LNA辨别RNA和DNA的特殊能力。避免设计对于所关注的RNA特定键合的α-L-核糖-LNA,而非特定键合到具有如目标RNA相似核苷酸序列的DNA片段,从而防止该α-L-核糖-LNA寡核苷酸稳定结合至可改变DNA结构及诱导所讨论的基因突变的染色体DNA。这种DNA结构的改变与相关突变可能引起不希望的毒性副作用。
本发明又一具体例设计具有提高特异性的核酸代酶。核酸代酶为结合RNAse催化活性及与互补RNA目标物的序列特定相互作用能力的寡脱氧核糖核苷酸及其类似物。这种核酸代酶已引起作为治疗分子的许多关注,并表现出可利用α-L-核糖-LNA寡核苷酸引人注意的特性来改善导向特定RNA的核酸代酶的高度可能。
本发明又一具体例为与细胞特定核蛋白特定相互作用的L-核糖-LNA寡核苷酸,该细胞特定核蛋白含有作为活性蛋白整体及主要成分的RNA,其两个实例为核糖体和端粒酶(telomerase)。可将L-核糖-LNA寡核苷酸抑制端粒酶的能力运用到重要的应用上。
较高等真核生物(包括人类)的染色体为线型。已说明该染色体末端的基本结构(DNA序列),结果证明所有染色体末端的DNA序列-在特殊生物中-由具有突出的单链末端的简单重复单元构成。该染色体末端称之为端粒。在人类端粒中含有双链多重重复5’-TTAGGG-3’序列(单链序列,位于着丝点朝染色体末端的方向)的延长。由于所有DNA聚合酶需要模板链及寡核苷酸前体来起始互补DNA的合成。DNA本身无法复制该染色体的末端。当复制染色体时,将会导致染色体逐渐缩短。注意在正常体细胞中端粒的长度,该端粒长度在复制的每个周期确实似乎变短直到该端粒仅有5至15kb长度为止。当该端粒如此短的时候,细胞通常会停止分段并且逐渐进入衰老阶段。干细胞是仅有的一个例外。干细胞为特殊化细胞,可在生物的一生中能不断的分段。有趣的是干细胞的端粒可持续保持长度(10至15kb)。干细胞能够如此是由于一特殊酶-端粒酶的活性。端粒酶是一个能特定延长端粒突出单链末端的独特酶,因此能维持稳定长度。端粒酶为一核糖核苷酶,即含有RNA的蛋白质且其酶活性取决于该RNA。端粒酶的结构与逆转录酶(能利用RNA作为模板合成DNA的病毒蛋白)有点类似。
端粒酶可延长该端粒的能力取决于在RNA分子上游离端粒3’末端的位置正确与否。能特定和端粒末端或端粒的RNA成分相互作用的分子将会抑制该酶。α-L-核糖-LNA可用来满足这些需求。在例如癌症治疗如-除干细胞之外-正常体细胞,相对于大部分含有容易检测的端粒酶活性的癌细胞,在血管中不含可检测的端粒酶活性。癌细胞是不死的,即它们不会衰老却会不断增生并形成肿瘤直到生物死亡为止。可确定此一看法的完整证据是端粒酶活性对于癌细胞的不死而言是不可或缺的。有趣的是,癌细胞的端粒实质上要比干细胞短,显示癌细胞将比干细胞提早达到“端粒长度障碍”,故提出特定抑制端粒酶活性的药物用于作为抗癌药物。
在此观点中,开发α-L-核糖-LNA的优异性能来设计抑制人类癌细胞端粒酶活性为目的的,可导向抗端粒酶RNA组成的特定部分的短α-L-核糖-LNA寡聚物将成为重要的议题。
本发明的另一实施例为利用L-核糖-LNA寡核苷酸特别是α-L-核糖-LNA寡核苷酸作为调适剂。在试管内选择治疗用寡核苷酸有希望的新品种特定地键合到具有高亲合性的给定目标物。其键合特征为寡核苷酸能力的适当反映,通过分子内核碱基配对同时形成三维结构。含有α-L-核糖-LNA寡核苷酸的调适剂显示出能开发成为治疗用途的有利特征。
在一些情况中,向下调节基因的表达可能有利,反之在其它情况中活化该基因可能有利。如等人所示(N..E.;Buchardt,O.;Egholm,M.;Nielsen,P.E.Proc.Natl.Acad.Sci.U.S.A.1994,91,3892),具有“链置换”能力的寡聚物可当作RNA转录作用的激活体。在本发明的一方面,利用具有“链置换”能力的LNA来活化治疗体的基因。
在许多病毒感染及癌症的化学治疗中,已证明各种形态的核苷及核苷类似物有效。L-核糖-LNA核苷可能用来作为此类以核苷为基础的药物。
在一些情况中,已报导双链RNA(DS-RNA)具有特定的医药活性。与经L-核糖-LNA完全改性的寡核苷酸有关的双显性组合可能用来作为这种双链的药物。此外极有可能双链α-L-核糖-LNA寡核苷酸会将重要分子添加至类似生物活性双链RNA分子的所有组成(repertoire)中。
因此,双链LNA(DS-LNA)的治疗潜能可用于如下说明的癌症或病毒感染的治疗。
已报导单独或是与干扰素-γ协和作用的各种类型的DS-RNA可抑制数种癌细胞的生长(Borecky et al.Tex Rep Biol Med,1981,41,575;Sharp et al.Eur J Biochem,1995,230(1),97)。DS-RNA抑制培养中的癌细胞生长如同抑制在试验动物中肿瘤的癌细胞生长一般。至少有两个双链RNA可活化酶似乎与DS-RNA(双链RNA-可活化蛋白质激酶(PKR)及核糖核苷酶L)的肿瘤抑制活性有关(Lengyel-P,Proc.Natl.Acad.Sci USA,1993,90(13),5893)。反之,PKR直接由DS-RNA活化,RnaseL通过(2’-5’)寡腺嘌呤核苷酸合成酶由DS-RNA活化,该(2’-5’)寡腺嘌呤核苷酸合成酶除非通过DS-RNA活化否则处于潜伏状态。DS-RNA也会诱发天然杀手(NK)细胞的活性且此活性很可能促成DS-RNA的抗肿瘤活性。
尽管天然DS-RNA通常与病毒感染有关。已证实,DS-RNA也具有抗病毒活性。DS-RNA已显示其对于人体免疫缺乏病毒HIV-1与HIV-2的抗病毒活性(Haineset al.J Cell Biochem,1991,46(1),9)。因此,DS-RNA与DS-LNA可作为治疗AIDS治疗剂的可能的候选者。
DS-RNA还证明了其在实用上的临床功效。然而,喃乳细胞含有一些DS-RNA特定核酸酶,并且可能因为这些活性DS-RNA会从病患身上迅速地消失。LNA相当类似RNA,并且具有RNA大部分的化学特征(Koshkin et al.,Tetrahedron,1998,54,3607)。LNA形成稳定的双显性组合而且由RNA变为LNA的结构改变相当微妙。由于已证明LNA本身表现出外核溶解的稳定性,因此适合的双链LNA很可能与特定DS-RNA的效果相仿且因此活化PKR和/或(2’-5’)寡腺嘌呤核苷酸合成酶(Singh et al.,Chem.Commun.,1998,455),与DS-RNA相比,DS-LNA-分子可能表现出改善的治疗功效。
本发明还涉及一种药物组合物,该药物组合物包含药物活性的L-核糖-LNA改性寡核苷酸或如上定义的药物活性的L-核糖-LNA单体与药用可接受的结合。
这种组合物可适合口服、肠外(静脉内、腹膜内)、肌内、直肠、鼻内、皮肤、***内、颊、眼睛或肺部投药的形式,优选口服的形式,可以本领域的技术人员公知的方法制备该组合物,如“Remington’s Pharmaceutical Science”,17.Ed.AlfonsoR.Gennaro(Ed.).Mark Publishing Company,Easton,PA,U.S.A.,1985和最新版本及Marcel Dekker著“Drugs and the pharmaceutical Science”系列中的专题论文所概括说明的方法。
诊断
已经研究了许多诊断及分子生物学步骤,利用不同寡核苷酸嵌板同步分析存在的过多可能突变的目标核酸。通常,将寡核苷酸嵌板固定在固体载体上的预定图案中,以便能通过固体载体上的杂交位置显示出在目标核酸中特殊突变的存在。在核酸分析中,成功使用不同寡核苷嵌板的一个重要前提为在单一施加的杂交条件下,对于其特殊目标序列而言,不同寡核苷嵌板全部都是特定嵌板。由于对其互补目标序列而言,标准寡核苷酸的亲合性与特异性取决于其序列及尺寸,因此至今仍难以达到此标准。
此外,已研究了一些特征化各种类型RNA的技术,而该RNA可能被细胞所含有。特征化中常见的一种方法为核酸杂交,这类技术的实例为:现场杂交、印迹杂交、反印迹杂交、northern杂交和逆转录作用聚合酶链反应(rtPCR)。这些技术经常在含有DNA和RNA的样本上制备,该事实常常造成检验的问题,但如果存在能充分辨别DNA和RNA的探针,则能轻易避免这个问题。特别是在不同组织样本进行现场杂交时是个问题。可设计对RNA具有高度可辨别的杂交性能的α-L-核糖-LNAoligos与样本中的RNA特定杂交,从而消除由杂交至具有相同序列的不恰当DNA而导致错误结果的可能。
因此,在一优选实施方案中,L-核糖-LNA可用来作为增加探针亲合性和/或特异性的手段以及使不同寡核苷酸对其互补序列亲合性均等的手段。如本文所公开的,可通过例如:在寡核苷酸用带有相似核碱基的L-核糖-LNA取代所选择的核苷来完成这种亲合性的调整。特别是应用在α-L-核糖-LNA寡核苷酸。
在另一优选实施方案中,在序列特定捕获及天然或合成核酸的纯化中,开发L-核糖-LNA改性寡核苷酸的高亲合性与特异性。一方面,使天然或合成核酸与固定在固体载体上的L-核糖-LNA改性寡核苷酸接触。在此情形中,同时发生杂交和捕获作用。例如,被捕获的核酸可通过本领域中公知的种种方法直接在表面上被检测、被特征化、被定量或被扩增或在这种特征化或扩增作用发生之前对固定、经改性寡核苷酸及被捕获的核酸施加杂交条件,例如加热或使用低离子强度的缓冲液,使被捕获的核酸由表面释放。
可从大量聚合材料例如CPG(经控制的多孔玻璃)、聚丙烯、聚苯乙烯、聚碳酸酯或聚乙烯选择固体载体,且可制成各种形式例如管状、微滴定板、棒状、珠状、过滤器等。可将L-核糖-LNA改性寡核苷酸利用在固定寡核苷酸常用的各种化学或光化学方法,或利用如经由使生物素化的L-核糖-LNA改性寡核苷酸键合到抗生蛋白链菌素的非共价偶合,经由其5’或3’末端(或经连接基和终端连接到5’或3’末端)固定到固体载体。在不同固体载体上固定L-核糖-LNA改性寡核苷酸的一个优选方法如(WO 96/31557)所述,是利用光化学活泼的蒽醌共价连接到该改性寡核苷酸5’-或3’-端基(任选地经由键)的光化学方法。因此,本发明也提供带有一L-核糖-LNA改性寡核苷酸的表面。
在另一方面,L-核糖-LNA改性寡核苷酸带有共价连接在5’-或3’-端基的配体。在此情形中,使L-核糖-LNA改性寡核苷酸与天然或合成核酸在溶液中接触,然后所形成的杂交被固体载体上带有可键合该配体的分子所捕获。
在又一方面,具有进行“链置换”能力的L-核糖-LNA改性寡核苷酸可用来捕获天然及合成核酸而不需要预先变性。在目标序列不同或由于快速形成稳定的分子内结构而不可能通过正常寡核苷酸达到的情况中,这种改性寡核苷酸特别有用。包含这种结构的核酸实例为rRNA、tRNA、snRNA和scRNA。
在另一优选实施方案中,设计具有高特异性的L-核糖-LNA改性寡核苷酸用来作为核酸序列中的前体或是在许多周知的扩增反应(如PCR反应)的任一反应中作为前体。如本文所示,L-核糖-LNA改性寡核苷酸的设计决定其是否将维持一指数或线性的目标扩增。可通过各种应用在分析由标准DNA前体所产生的扩增产物的方法分析扩增反应的产物。在设计L-核糖-LNA改性寡核苷酸前体以维持线性扩增的特殊情况中,最终的扩增基因将带有无需变性即可通过互补探针选定的单链末端。可利用例如这类末端通过连接到一固体表面的其它互补L-核糖-LNA改性寡核苷酸来捕获扩增基因。
自另一方面,可使用具有“链置换”能力的L-核糖-LNA改性oligos作为线性或指数扩增反应的前体。预期使用这种oligos会通过与扩增反应后期中的扩增基因重新杂交的有效竞争而提高整体扩增基因的产率。Demers等人在Nucl.Acid Res.1995,23,3050-3055中公开了,使用高亲合性、不可延长的oligos作为增加PCR反应整体产率的手段。相信该寡聚物通过介入PCR反应后期中的扩增基因重新杂交而引起这样的结果。预料在3’末端经封阻的L-核糖-LNA改性oligos将具有相同的优势。可以用许多方法例如通过该3’羟基与氢或磷酸盐交换来达到3’末端的封阻。也可使用这种3’封阻的L-核糖-LNA改性oligos,用类似Yu等人(Biotechniques,1997,23,714-716)所述的方法选择性地扩增紧密相关的核酸序列。
最近几年中,已发明例如可用在实时检测由目标扩增反应所产生的扩增基因的新型探针。一种这类探针被称为“分子信号(Molecular Beacons)”。这种探针合成为部分自行互补寡核苷酸,在一端包含萤光基团,而在另一端包含淬熄分子。当在溶液中游离时,探针折叠成为发夹结构(由自行互补区所引导),这样,使淬熄基充分接近萤光基团,从而可淬熄萤光信号。当探针杂交到目标核酸时,发夹形状打开,从而让萤光基团与淬熄基团分开而发出萤光信号。
另一类探针定名为”Taqman探针”。Taqman探针也包含一个萤光基团与一个淬熄分子。但与分子信号相反,淬熄基淬熄来自萤光基团的萤光信号的能力在探针杂交至其目标序列后仍然维持。取而代之,由聚合酶的5’核酸外切酶活性(引发由位于Taqman探针结合位置5’位置的前体开始合成)作用而以物理方式由探针卸下淬熄基或萤光基团杂交后产生萤光信号。
对目标位置的高度亲和力是两种探针的主要特色,所以,这种探针倾向于相当大(通常30至40mers)。结果,在制造高品质探针时可能遭遇严重问题。因此,在优选实施方案中,LNA用以改良生产以及随后通过缩小尺寸同时维持要求的亲和力而改善Taqman探针和分子信号效能。
在另一方面,L-核糖-LNA用以构成新亲和对(完全或部分改性寡核苷酸)。亲和常数容易在宽范围内调整,可设计和合成大量亲和对。亲和对的一部分可由标准方法连接到感兴趣的分子(例如蛋白质、扩增基因、酶、多醣、抗体、半抗原、肽、PNA等),而亲和对的另一部分例如连接到固体载体例如珠、膜、微滴定板、棒、管等。固体载体可选自宽范围的聚合物料例如聚丙烯、聚苯乙烯、聚碳酸酯或聚乙烯。亲和对可用于选择性分离、纯化、捕获以及检测前述多种目标分子。
利用与其它互补L-核糖-LNA寡核苷酸(完全或部分改性)相互作用捕获L-核糖-LNA-标记分子的原则可用来产生无限的新型亲合性配对。
在另一优选实施方案中,在建构用于现场杂交的探针中,开发L-核糖-LNA改性寡核苷酸的高亲合性及特异性。例如,可使用L-核糖-LNA减少传统DNA探针尺寸,同时保持所要的亲合性,由此增加探针动力学及穿透试样样本的能力。
纯化
本发明的另一具体例是在RNA特定纯化步骤中使用L-核糖-LNA寡核苷酸特别是α-L-核糖-LNA寡核苷酸。传统上用来从原核细胞、真核细胞或从复杂生物样本分离核酸的方法是使用如酚和氯仿的有机溶剂。核酸的分离由通常用蛋白酶进行样本的酶消化开始,接着利用离子洗洁剂进行细胞溶解,然后利用酚或酚/氯仿的混合物萃取。分离有机相和水相,并利用酒精通过沉淀将分在水相的核酸回收。但酚或酚/氯仿混合物对人类皮肤有腐蚀性,被认为是有害废弃物,必须小心处理与适当丢弃。此外,利用酚/氯仿法的标准萃取会产生RNA与DNA的混合物。因此,通过开发可辨别RNA与DNA的α-L-核糖-LNA有利于制备核酸分离,由此得到纯RNA样本。
试剂盒
本发明也提供天然或合成核酸的分离、纯化、扩增、检测、辨识、定量或捕获的试剂盒,其中该试剂盒包含一反应主体以及如本文所定义的单一或多个L-核糖-LNA改性寡核苷酸(寡聚物)。该L-核糖-LNA改性寡核苷酸优选固定在该反应主体上。
本发明也提供天然或合成核酸的分离、纯化、放大、检测、辨识、定量或捕获的试剂盒,该试剂盒包含一反应主体以及如本文所定义的单一或多个L-核糖-LNA。该L-核糖-LNA优选固定在该反应主体上(例如利用上述的固定技术)。
对于本发明的试剂盒而言,反应主体优选为固体载体材料,例如选自硼硅酸盐玻璃、钠钙玻璃、聚苯乙烯、聚碳酸酯、聚苯烯、聚乙烯、聚乙二醇对苯二甲酸酯、聚乙酸乙烯酯、聚乙烯基咯啶酮、聚甲基丙烯酸甲酯和聚乙烯基氯,优选为聚苯乙烯和聚碳酸酯。该反应主体可呈样本管、小瓶、切片、薄片、薄膜、珠、丸、圆盘、板、环、柱、网、滤片、托盘、微滴定板、杆或多叶片杆的形式。
试剂盒通常附有书面说明书来说明试剂盒的最佳使用条件。
实验
综论
当使用无水溶剂时在氮气气氛下进行反应。利用硅胶60(0.040-0.063mm)在玻璃管柱中进行柱层析法。在管柱层析之后,收集含有产物的部分,减压下蒸发干燥及真空干燥而得到产物。在利用Na2SO4使有机相干燥之后进行过滤。使用蒸馏范围60至80℃的石油醚。以ppm表示相对于以四甲基硅烷作为内标参考值(1H与13C NMR)以及相对于85%H3PO4(31p NMR)的化学位移值δ。微量分析在TheMicroanalytical Laboratory,Department of Chemistry,University of Copenhagen进行。
下面结合图1-4和表1-3进行具体说明。
L-核糖-LNA单体的制备
实施例1
5-O-苯甲酰基-4-C-苯甲酰基氧基甲基-3-O-苄基-1,2-O-异亚丙基-α-D-葡萄呋喃糖(2)
将苯甲酰氯(4.1cm3,0.035mol)添加到3-O-苄基-4-C-羟基甲基-1,2-异亚丙基-α-D-葡萄呋喃糖(1)(5.00g,0.016mol)的无水吡啶(60cm3)的搅拌冰***液。在室温下搅拌4小时后,将反应混合物冷却至0℃,添加H2O(50cm3),并用二氯甲烷(100cm3 x 3次)萃取该混合物。利用碳酸氢钠饱和水溶液(30cm3 x 3次)和盐水(20cm3 x3次)洗涤结合的有机相,干燥(Na2SO4)并在减压下蒸发干燥。在减压蒸发溶剂之后,该残留物先使用石油醚/二氯甲烷(1∶1,v/v)然后用二氯甲烷/甲醇(99∶1,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到黄色油状物的呋喃糖2(7.50g,90%)。δH(CDCl3)8.02-7.23(15H,m),6.08(1H,d,J4.2),4.81-4.50(7H,m),4.22(1H,d,J1.0),1.59(3H,s),1.37(3H,s),δC(CDCl3)166.1,165.8,136.7,133.1,133.0,129.9,129.7,129.6,129.5,128.5,128.4,128.3,128.0,127.9,113.3,105.4,86.4,85.1,83.8,72.3,64.3,63.8,27.0,26.4,FAB-MS m/z 521[M+H]+。实测值(%)C,69.1;H,5.9;C30H32O6要求值C,69.2;H,6.2
实施例2
5-O-苯甲酰基-4-C-苯甲酰基氧基甲基-3-O-苄基-1,2-二-O-乙酰基-D-葡萄呋喃糖(3)
将呋喃糖2(7.40g,0.014mol)的80%乙酸(60cm3)溶液在90℃下搅拌9小时。将反应混合物在减压下蒸发干燥,残留物利用甲苯(10cm3 x 3次)共同蒸发并溶于无水吡啶(80cm3)。添加乙酸酐(5.5cm3),溶液在室温下搅拌46小时。将反应混合物在减压下蒸发干燥,残留物利用甲苯(10cm3 x 3次)共同蒸发并溶于二氯甲烷(150cm3)。利用碳酸氢钠饱和水溶液(30cm3 x 3次)和盐水(30cm3 x 3次)洗涤该溶液,干燥(Na2SO4),减压浓缩。在减压蒸发溶剂之后,该残留物先使用石油醚/二氯甲烷(1∶1,v/v)然后用二氯甲烷/甲醇(99∶1,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到透明油状物的异构体混合物3(α∶β=3∶1,7.33g,92%)。该油状物不经进一步纯化用于下个步骤。δC(CDCl3)169.4,169.0,165.8,165.6,137.0,133.2,133.1,133.0,129.6,129.5,129.2,128.3,127.8,127.7,127.4,99.4,92.3,87.0,83.2,82.2,80.7,77.4,76.9,76.3,73.2,72.4,20.9,20.8,20.6,20.3,FAB-MS m/z 562[M+H]+。
实施例3
1-(2-O-乙酰基-5-O-苯甲酰基-4-C-苯甲酰基氧基甲基-3-O-苄基-β-D-木糖呋喃糖基)胸腺嘧啶(4)
将N,O-双(三甲基硅烷基)乙酰胺(19.1cm3,0.077mol)添加到异构体混合物3(7.25g,0.013mol)和胸腺嘧啶(3.25g,0.028mol)的无水乙腈(80cm3)的搅拌悬浮液中。将反应混合物在60℃下搅拌1小时,然后冷却至0℃。滴加三氟甲磺酸三甲基硅烷酯(4.1cm3,0.023mol),历时10分钟,然后该混合物在回流下加热22小时。冷却至室温后,添加碳酸氢钠饱和水溶液(30cm3)并且利用二氯甲烷(100cm3 x 3次)进行萃取。利用碳酸氢钠饱和水溶液(30cm3 x 3次)和盐水(50cm3 x 3次)洗涤结合的有机相,干燥(Na2SO4),减压浓缩。在减压蒸发溶剂之后,该残留物使用二氯甲烷/甲醇(0.5-2.0%甲醇,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到白色固体物的核苷4(6.88g,85%)。
δH(CDCl3)8.97(1H,br,s),8.04-7.23(16H,m),6.37(1H,d,J3.6),5.42(1H,t,J3.1),4.89-4.56(6H,m),4.22(1H,d,J2.6),2.13(3H,s),1.74(1H,d,J0.8),δC(CDCl3)169.9,166.0,165.7,163.4,150.4,136.2,135.2,133.5,133.4,129.8,129.7,129.6,129.5,129.0,128.6,128.4,128.2,112.0,87.4,86.0,81.3,80.3,72.6,63.1,62.9,20.8,12.3,FAB-MSm/z 629[M+H]+。实测值(%)C,64.4;H,4.9;N,4.4;C34H32N2O100.25H2O要求值C,64.5;H,5.1;N4.4。
实施例4
1-(3-O-苄基-4-C-羟甲基-β-D-木糖呋喃糖基)胸腺嘧啶(5)
将甲醇钠(3.87g,0.0716mol)添加到核苷4(9.00g,0.014mol)的甲醇(130cm3)搅拌溶液中。将反应混合物在室温下搅拌4小时,然后用稀盐酸中和。混合物减压蒸发干燥后,接着利用甲苯(15cm3 x 3次)共同蒸发。在减压蒸发溶剂之后,该残留物使用二氯甲烷/甲醇(4-15%甲醇,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到白色固体物的核苷三醇5(4.82g,89%)。δH(CD3OD)7.89(1H,d,J1.2),7.40-7.24(5H,m),5.97(1H,d,J6.2),4.83-4.65(2H,m),4.53(1H,t,J6.2),4.21(1H,d,J6.2),3.84(1H,d,J12.0),3.63(1H,d,J12.0),3.59(2H,d,J2.6),1.82(1H,d,J1.1)δC(CD3OD)164.4,150.9,137.5,136.6,127.5,127.0,125.9,109.8,86.7,86.4,82.8,78.0,72.1,62.3,61.1,10.5(CH3)。FAB-MS m/z 379[M+H]+。实测值(%)C,56.2;H,6.0;N,7.0;C18H22N2O70.25H2O要求值C,56.5;H,5.9;N 7.3。
实施例5
1-(3-O-苄基-4-C-(4,4’-二甲氧基三苯甲基氧基甲基)-β-D-木糖呋喃糖基)胸腺嘧啶(6)
将AgNO3(2.66g,15.7mmol)添加到1-(3-O-苄基-4-C-羟甲基-β-D-木糖呋喃糖基)胸腺嘧啶5(5.38g,14.2mmol)的无水四氢呋喃(400cm3)溶液中,随后再添加无水吡啶(5.7cm3)和4,4’-二甲氧基三甲苯基氯(5.30g,15.6mmol)。将混合物在黑暗中在氮气及室温下搅拌18小时。添加碳酸氢钠饱和水溶液(10cm3)终止该反应,并以二氯甲烷萃取所得混合物。减压蒸发干燥结合的有机相后,利用甲苯共同蒸发,在减压蒸发溶剂之后,该残留物使用二氯甲烷/甲醇/吡啶(0.5%甲醇;0.5吡啶,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到白色发泡物的核苷6(3.13g,31%)。δC((CD3)2SO)164.1(C-4),158.4,145.1,138.5,137.0,135.9,135.7,130.1,130.1,129.2,128.5,128.5,128.2,128.1,127.7,127.6,127.0,125.7,113.5,(DMT,苄基,C-8),151.4(C-2),110.1(C-5),85.5,85.2,84.6,83.5(C-1’,C-3’,C-4’,DMT),76.8(C-2’),72.3(CH2Ph),65.2(C-5”),55.4(2xCH3O),12.6(5-CH3)。
实施例6
1-(3-O-苄基-4-C-(4,4’-二甲氧基三苯甲基氧基甲基)-2,5-二-O-(对-甲苯磺酰基)-β-D-木糖呋喃糖基)胸腺嘧啶(7)
将催化量的4-(N,N-二甲基胺基)吡啶和对-甲苯磺酰氯(6.50g,34mmol)添加到核苷6(2.79g,3.9mmol)的无水吡啶(50cm3)溶液中。将混合物在黑暗中在氮气及室温下搅拌24小时。添加碳酸氢钠饱和水溶液(100cm3)终止该反应,并用二氯甲烷萃取所得混合物。用碳酸氢钠饱和水溶液(3次 x 75cm3)和氯化钠(2次 x 75cm3)洗涤结合的有机相。将分离的有机相干燥(Na2SO4),减压蒸发干燥。该残留物使用二氯甲烷/甲醇/吡啶(0.5%甲醇;0.5吡啶,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到黄色发泡物的核苷7(2.40g,62%)。δC((CD3)2SO),163.2(C-4),158.2,145.9,145.1,144.3,136.8,135.0,134.9,134.8,131.8,131.6,130.2,130.0,129.7,128.2,127.9,127.8,127.6,127.5,127.5,127.4,126.8,113.3(DMT,C-6,2 x Ts,苄基),150.2(C-2),110.8(C-5),95.0,86.2(DMT,C-4’),82.2,81.9(C-1’,C-2’),81.2(C-3’),72.9(CH2Ph),79(C-5”),64(C-5”),55.1(2xCH3O),21.2,21.2(2 x CH3),12.0(5-CH3)。
实施例7
(1R,3R,4S,7R)-7-苯甲酰基-(4,4’-二甲氧基三苯甲基氧基甲基)-3-(胸腺嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷(8)
将NaOH水溶液(2M,8cm3)添加到核苷7(3.87g,3.92mmol)的乙醇与H2O混合物(1∶1,v/v)的溶液中。将混合物回流加热24小时,冷却后用二氯甲烷萃取。利用碳酸氢钠饱和水溶液(2次 x 75cm3)洗涤结合的有机相,减压蒸发干燥。在蒸发溶剂之后,该残留物使用二氯甲烷/甲醇/吡啶(0.5%甲醇;0.5吡啶,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到核苷8(2.10g,81%)。δC((CD3)2SO),163.8(C-4),158.2,158.1,144.7,137.7,135.9,135.2,135.1,129.8,129.7,128.3,127.9,127.7,127.7,127.4,126.7,113.35(DMT,苄基,C-6),150.3(C-2),108.1(C-5),88.4,85.5(C-4’,DMT),86.4(C-1’),79.5(C-2’),76.3(C-3’),72.6(C-5”),71.2(CH2Ph),58.9(C-5”),55.1(2 xCH3O),12.4(5-CH3)。
实施例8
(1R,3R,4S,7R)-1-(4,4’-二甲氧基三苯甲基氧基甲基)-7-羟基-3-(胸腺嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷(9)
将甲酸铵(0.33g,5.29mmol)添加到核苷8(1.09g,1.65mmol)的甲醇(30cm3)溶液中。添加催化量的Pd/C的甲醇(10cm3)悬浮液,将混合物回流加热2小时。在冷却至室温后减压蒸发干燥,在蒸发溶剂之后,该残留物使用二氯甲烷/甲醇/吡啶(2%甲醇;0.5吡啶,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到核苷9(0.76g,80%)。δC((CD3)2SO),163.9(C-4),158.2,144.8,135.8,135.4,135.3,129.8,127.9,127.7,126.8,113.3(DMT,C-6),150.4(C-2),108.0(C-5),89.2,85.4(C-4’,DMT),86.4(C-1’),78.9(C-2’),72.9(C-3’),72.3(C-5”),59.9(C-5”),55.1(2 x CH3O),12.5(5-CH3)。
实施例9
(1R,3R,4S,7R)-7-(2-氰基乙氧基(二异丙基胺基)膦氧基)-1-(4,4’-二甲氧基三苯甲基氧基甲基)-3-(胸腺嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷(9)
将N,N-二异丙基乙基胺(0.4cm3)和2-氰基乙基N,N-二异丙基-偶磷酰胺次氯化物(0.4cm3)添加到核苷9(420g,0.73mmol)的无水二氯甲烷(4cm3)溶液中。将混合物在黑暗中在氮气及室温下搅拌18小时。添加甲醇终止该反应并以乙酸乙酯(10cm3)稀释,利用碳酸氢钠饱和水溶液(3次 x 10cm3)和氯化钠(2次 x 10cm3)洗涤,减压蒸发干燥。该残留物用无水乙腈共同蒸发,使用石油醚/乙酸乙酯/吡啶(30至40%乙酸乙酯;0.2吡啶,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到油状物。将此油状物溶于二氯甲烷(1cm3)并在-40℃下激烈搅拌从石油醚沉淀产物。通过过滤收集沉淀物,并以无水乙腈共同蒸发得到核苷10(117g,21%)。δP((CH3CN)149.9,149.3。
实施例10
未经改性寡核苷酸以及包含由phosphoramidite 10(式X)衍生的L-核糖-LNA寡核苷酸的合成
在Biosearch 8750 DNA合成器上制备L-核糖-LNA与对比寡核苷酸。利用“手工偶合”(在乙腈中以注射方式预先混合amidite与活化剂,然后在偶合时间内持续以每分钟大约两次冲洗该管柱反应器;CPG固体载体)进行amidite 10偶合。利用盐酸吡啶作为活化剂(10至30分钟偶合时间;amidite逐步偶合产率为96至99%)完成L-核糖-LNA的合成。除了依据合成器RNA步骤所进行的X单体的立即偶合外,利用合成器的标准DNA步骤以偶合未经改性的2’-脱氧核苷2-氰基乙基N,N-二异丙基phosphoramidites。在完成序列之后,利用浓氨的甲醇溶液(32%(w/w),室温,12小时)进行5’-O-DMT-ON oligos的脱保护,随后进行反相纯化(市售可处理滤筒(Cruachem);包含脱三苯甲基化的步骤),产生最终寡聚产物。然而,在完成序列之后,立刻去除未经改性的寡核苷酸及包含唯一X单体5’-O-DMT基的L-核糖-LNA。用浓氨的甲醇溶液(32%(w/w),12小时,55℃)后处理,乙醇沉淀产生产物寡聚物。利用毛细管凝胶电泳分析合成L-核糖-LNA的纯度。
杂交数据
实施例11
含有单体X寡核苷酸的热稳定性
利用装置热调节Peltier组件的分光光度计用光谱测定L-核糖-LNA改性寡核苷酸的热稳定性。使用介质盐缓冲溶液(10mM Na2HPO4,pH 7.0,100mM NaCl,0.1mM EDTA)制备1ml杂交混合物与等莫耳(1μM或1.5μM)量的L-核糖-LNA寡核苷酸及其互补DNA或RNA寡核苷酸。如参考文献利用未经改性的寡核苷酸制备相同的杂交混合物。记录在260nm的吸光度,同时由10至90℃(1℃/min)线性升高温度。由熔解曲线一次导数最大值(+/-1℃)得到熔体温度(Tm值)。表1至3总结该结果(L-核糖-LNA以粗体字标示)。图2说明所使用的L-核糖-LNA单体。
由表1可看出单一或多个连续的α-L-核糖-LNA单体X结合到寡核苷酸序列(A)与(B),不会改变α-L-核糖-LNA对互补DNA的亲合性,同时对互补DNA的键合亲合性强烈地增加。
表2显示homo-tyhmine非镜像异构的LNA对于RNA(rA14)、单错配RNA(5’-r(A6CA7))、镜像RNA(ent-rA14)及单错配的镜像RNA(ent-5’-r(A6CA7))的键合研究。
表3显示混合-序列9-聚物DNA、LNA和α-L-核糖-LNA的键合研究。
另外的方法
实施例12
1-(3-O-苄基-2,5-二-O-甲磺酰基)-4-C-(甲磺酰基氧基甲基)-β-D-木糖呋喃糖基)胸腺嘧啶(11)
将无水吡啶(5cm3)添加到核苷5(1100mg,2.91mmol)的无水四氢呋喃(20cm3)溶液中,然后添加甲磺酰氯(1.2ml,15.5mmol)。将混合物在氮气及室温下搅拌18小时。反应混合物在减压下蒸发干燥并溶于乙酸乙酯。有机相用碳酸氢钠饱和水溶液(3次 x 10cm3)洗涤,然后干燥(Na2SO4)。将有机相减压蒸发干燥。该残留物使用二氯甲烷/甲醇(2%甲醇,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到核苷11(908mg,51%)。δC(CDCl3)163.3,150.6,135.6,134.6,128.7,128.3,112.2,87.9,85.0,83.1,80.9,77.2,76.9,76.6,73.3,66.6,66.2,38.6,37.6,37.6,12.2。
实施例13:
(1R,3R,4S,7R)-1-(羟甲基)-7-苄氧基-3-(胸腺嘧啶-1-基)-2,5-二氧杂双环[2.2.1]庚烷(12)
将6M NaOH(aq)(0.9ml,5.4mmol)添加到核苷11(329mg,0.54mmol)的乙醇/水(10cm3,1∶1,v/v)溶液中。混合物在80℃回流43小时,接着减压蒸发干燥。该残留物使用二氯甲烷/甲醇(2.4%甲醇,v/v)作为洗脱剂通过硅凝胶管柱层析法纯化,得到核苷12(85mg,44%)。δC((CD3)2SO)163.8,150.3,138.0,135.8,128.3,127.7,127.6,127.5,108.0,90.2,86.5,86.4,79.3,76.5,72.5,71.2,57.2,40.2,40.0,39.8,39.6,39.4,39.2,39.0,12.3。
实施例14
由核苷12合成核苷8
对核苷12的主要羟基进行标准DMT-保护(例如利用如DMT-保护核苷5的主要羟甲基制备核苷6的相同步骤)将得到可用于合成α-L-核糖-LNA核苷phosphoramidite衍生物10的核苷8(参见图2及相关实施例)。
实施例15
9-(2-O-乙酰基-5-O-苯甲酰基-4-C-(苯甲酰基氧基甲基)-3-O-苄基-α-L-核糖呋喃糖基)-6-N-苯甲酰腺嘌呤(14)
在无水乙腈(30mL)中溶解糖3(2.05g)。添加N-6-苯甲酰腺嘌呤(1.86g),接着加入SnCl4(1.3mL),所得混合物在室温下搅3.7小时,随后添加NaHCO3饱和水溶液直到中和为止。在通过Celite过滤之后,依序用NaHCO3饱和水溶液(3次 x 150mL)和H2O(2次 x 150mL)洗涤过滤物,干燥(Na2SO4),减压蒸发干燥。该残留物通过硅凝胶管柱层析法(40至60%NaOAc在石油醚中)纯化,得到完全受保护的核苷中间物(1.40g,52%产率)。将该中间物(1.29g)溶于甲醇(35mL)并添加NH3的甲醇(35mL)饱和溶液。在0℃搅拌2.3小时后,将该混合物减压蒸发干燥,该残留物通过硅凝胶管柱层析法(1%甲醇溶在二氯甲烷中)纯化,得到溶于无水二氯甲烷(40mL)的一中间物。冷却至-50℃之后,添加无水吡啶(3mL)与三氟甲磺酰无水物(0.65mL)。搅拌50分钟之后,添加附加的无水三氟甲磺酰物(0.65mL)并继续在-10℃搅拌1小时。添加二氯甲烷(100mL),利用NaHCO3饱和水溶液(3次 x 100mL)进行洗涤。将分离的有机相干燥(Na2SO4),减压蒸发干燥得到一中间物。将该中间物溶于甲苯(20mL)中,添加KOAc(0.85g)和18-冠-6(0.92g),所得混合物在80搅拌7小时,随后减压蒸发干燥生成一残留物,该残留物通过硅凝胶管柱层析法(0至1.5%甲醇溶在二氯甲烷中)纯化,得到核苷14。δC(CDCl3)168.8,165.8,142.7,136.0,133.5,133.3,132.7,129.6,129.6,128.8,128.6,128.5,128.4,128.4,128.1,127.8,83.8,82.2,78.4,74.3,70.8,64.7,63.4,20.5,MS(m/z)742.0[M+H]+。
实施例16
(1R,3R,4S,7R)-7-苄氧基1-羟甲基-3-(N-6-苯甲酰基腺嘌呤-9-基)-2,5-二氧杂双环[2.2.1]庚烷(15)
在NH3的甲醇(200mL)饱和溶液中溶解核苷14(3.05g),在室温下搅拌4天,添加NH3的甲醇(200mL)的33%水溶液(60mL)继续搅拌4小时。混合物减压蒸发干燥得到一中间物,该中间物溶于无水吡啶(100mL)。添加TMSCl(7.8mL)并且在室温下继续搅拌5小时。冷却至0℃之后,添加苯甲酰氯(2.4mL),在室温下继续搅拌16小时。添加H2O(50mL),5分钟之后接着添加NH3饱和水溶液(25mL)。在室温搅拌20分钟之后,混合物减压蒸发干燥,该残留物通过硅凝胶管柱层析法(2至5%甲醇溶在二氯甲烷中)纯化,得到一中间物(1.76g,87%历经两步骤)。该中间物(326mg)溶于无水吡啶(50mL)并于0℃在搅拌下添加甲磺酰氯(0.11mL)。搅拌2小时之后,添加H2O(5mL),减压蒸发使混合物体积减少至大约50%。添加二氯甲烷(100mL),用NaHCO3饱和水溶液(3次x 20mL)进行洗涤。将有机相干燥(Na2SO4),减压蒸发干燥。该残留物通过由硅凝胶管柱层析法(2至4%甲醇溶在二氯甲烷中)纯化,得到一中间物(284mg)。将该中间物溶于二噁烷(15mL)、H2O(15mL)和2M NaOH(5.5mL)中。回流搅拌72小时后,添加HCl的二噁烷的7%溶液,直到中和为止。利用NaHCO3饱和水溶液(2次 x 100mL)进行洗涤,有机相干燥(Na2SO4),减压蒸发干燥。该残留物通过硅凝胶管柱层析法(0至4%甲醇溶在二氯甲烷中)纯化,得到双环核苷15。
δC((CD3)2SO)156.0,152.6,149.4,138.8,138.0,128.3,127.7,127.5,118.3,89.7,83.9,79.7,77.0,73.0,71.2,57.2,δH((CD3)2SO)8.38(1H,s),8.14(1H,s),7.40-7.30(7H,m),6.37(1H,s),5.06(1H,t,J5.8Hz),4.73-4.66(3H,m),4.46(1H,s),4.15(1H,d,J8.4Hz),4.04(1H,d,J8.2Hz),3.75(2H,d,J5.7Hz)。
实施例17:
(1R,3R,4S,7R)-7-(2-氰基乙氧基(二异丙基胺基)膦氧基)-1-(4,4’-二甲氧基三苯甲基氧基甲基)-3-(6-N-苯甲酰基腺嘌呤-9-基)-2,5-二氧杂双环[2.2.1]庚烷(16)
DMT-保护核苷15接着脱苄基化及3’-O-磷酸基化,预期得到phosphoramidite衍生物16。由核苷15得到16的另一可能途径为脱苄基化15接着选择性地DMT-保护主要羟基及最后进行3’-磷酸基化。本实施例说明的反应依照标准步骤(参见如Koshkin,A.A.,Singh,S.K.,Nielsen,P.,Rajwanshi,V.K.,Kumar,R.,Meldgaard,M.,Olsen,C.E.,Wengel,J.Tetrahedron 1998,54,3607)。
表1:
aX=衍生自phosphoramidite 10的单体
Y=含有2’-O,4’-C-桥亚甲基的LNA单体,cf.Singh等人(如上所述)
bC与5,-d-A14复合
c与5’-rA14复合
表2:
a如表1
d在温度范围10-95℃没有测量到共同的熔点Tm
表3:
*两个相同实验的结果
Claims (24)
1.一种寡聚物,含有至少一种通式Ia的核苷类似物,
其中X选自-O-;
B为核碱基,选自腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶、尿嘧啶、嘌呤、黄嘌呤、二胺基嘌呤、8-氧基-N6-甲基腺嘌呤、7-脱氮黄嘌呤、7-脱氮鸟嘌呤、N4,N4-乙醇胞嘧啶、N6,N6-乙醇-2,6-二胺基嘌呤、5-甲基胞嘧啶、5-(C3-C6)炔基胞嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、拟异-胞嘧啶、2-羟基-5-甲基-4-***吡啶、异胞嘧啶、异鸟嘌呤或肌苷;
P表示与后一单体连接的核苷间键的自由基位置、或5’-端基;
P*表示与前一单体连接的核苷间键的自由基位置、或3’-端基;
R2*与R4*一起表示-O-CH2-的双自由基,
在此取代基R1*、R2、R3*、R5、R5*分别为氢;
和其碱性盐类和酸加成盐类。
2.如权利要求1所述的寡聚物,包括1至9个通式Ia的核苷类似物及0至13个选自天然产生的核苷。
3.如权利要求2所述的寡聚物,其中该寡核苷酸包括至少7个连续所述核苷类似物单体。
4.如权利要求2所述的寡聚物,其中该寡聚物的所有核苷单体为所述核苷类似物。
5.如权利要求1所述的寡聚物,其中所述核苷类似物的任一核苷间键选自由2至4个选自-CH2-、-O-、-PO(R”)-、和-PO(NHRH)-的基团/原子组成的键,其中RH选自氢或C1-4-烷基,R”选自C1-6-烷基。
6.如权利要求1所述的寡聚物,其中P为选自氢、羟基、C1-6-烷基、C1-6-烷氧基、或芳氧基的5’-端基。
7.如权利要求1所述的寡聚物,其中P*为选自氢、羟基或芳氧基的3’-端基。
8.如权利要求1所述的寡聚物,其中B为核碱基,选自腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶、5-甲基胞嘧啶或尿嘧啶。
9.如权利要求1所述的寡聚物,具有下式III:
G-[Nu-L]n(0)-{[(L-核糖-LNA)-L]m(q)-[Nu-L]n(q)}q-G* III
其中
q为1至50;
各n(0),...,n(q)分别为0至10000;
各m(1),...,m(q)分别为1至10000;
条件为n(0),...,n(q)及m(1),...,m(q)的总和为2至15000;
G表示5’-端基;
各Nu分别表示选自天然核苷的核苷;
各L分别表示介于选自Nu或L-核糖-LNA两基团之间的核苷间键,或L与G*表示3’-端基;且各L-核糖-LNA-L分别表示该通式Ia的L-核糖-LNA核苷。
10.一种含有至少一种通式IIa的核苷类似物的核苷,
其中取代基B为核碱基,选自腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶、尿嘧啶、嘌呤、黄嘌呤、二胺基嘌呤、8-氧基-N6-甲基腺嘌呤、7-脱氮黄嘌呤、7-脱氮鸟嘌呤、N4,N4-乙醇胞嘧啶、N6,N6-乙醇-2,6-二胺基嘌呤、5-甲基胞嘧啶、5-(C3-C6)炔基胞嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、拟异-胞嘧啶、2-羟基-5-甲基-4-***吡啶、异胞嘧啶、异鸟嘌呤或肌苷;
X选自-O-;
各Q和Q*分别选自氢、羟基、Prot-O-、Act-O-、C1-6-烷氧基、C1-6-烷基、Prot-O-CH2-、或Act-O-CH2-、其中Prot为选自二甲氧三苯甲基、一甲氧三苯甲基、三苯甲基、9-(9-苯基)吨基、或四羟基吡喃基,而Act为选自O-亚磷酰胺、O-磷酸三酯、O-磷酸二酯、H-磷酸酯或O-磷酸酯;和
R2*与R4*一起表示-O-CH2的双自由基;
各存在的取代基R1*、R2、R3*、R5和R5*分别为氢;
和其碱性盐类和酸加成盐类。
11.如权利要求10所述的核苷,其中B为核碱基,选自腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶、5-甲基胞嘧啶或尿嘧啶。
12.如权利要求10所述的核苷,其中该核苷应用在制备权利要求1中的寡聚物。
13.如权利要求10所述的核苷,其中核苷的结合调整寡核苷酸作为核酸活化酶基质的能力。
14.如权利要求10所述的核苷,其中该核苷应用在制备寡聚物的轭合物以及选自蛋白质、扩增基因、酶、多醣类、抗体、半抗原、肽和PNA的化合物。
15.如权利要求10所述的核苷,其中该核苷作为核酸上酶活性基质的应用。
16.如权利要求15所述的核苷,其中该核酸上酶活性为DNA与RNA聚合酶。
17.如权利要求10所述的核苷,其中该核苷应用在制备治疗药物。
18.如权利要求10所述的核苷,其中该核苷应用在构成固体表面,该固体表面上已经连接不同序列的经LNA改性的寡核苷酸。
19.如权利要求1所述的寡聚物在目标核酸序列特异性裂解中的应用。
20.如权利要求1所述的寡聚物,其中该寡聚物应用在用作为反讯息、反基因或基因活化的药物组合物。
21.如权利要求20所述的寡聚物,其中该寡聚物补充RNAseH。
22.如权利要求1所述的寡聚物,其中该寡聚物包括多于一种该通式Ia的核苷类似物改性的寡核苷酸复合物在用作为反讯息、反基因或基因活化的药物组合物。
23.如权利要求1所述的寡聚物在制备用于治疗癌症的药物中的应用,其中该寡聚物会特定地与选自tRNAs、rRNAs、snRNAs和scRNAs的RNA相互作用,从而抑制任何选自翻译、RNA拼接、RNA处理及其它主要细胞处理的细胞处理。
24.如权利要求1所述的寡聚物在用于天然或合成核酸的分离、纯化、扩增、检测、辨识、定量或捕获中的应用。
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KR100782896B1 (ko) | 2007-12-06 |
EP1178999A2 (en) | 2002-02-13 |
ATE356824T1 (de) | 2007-04-15 |
CA2372085C (en) | 2009-10-27 |
HK1048322A1 (zh) | 2003-03-28 |
WO2000066604A2 (en) | 2000-11-09 |
IL145497A0 (en) | 2002-06-30 |
JP2002543214A (ja) | 2002-12-17 |
AU776362B2 (en) | 2004-09-09 |
AU4391800A (en) | 2000-11-17 |
KR20020013515A (ko) | 2002-02-20 |
CA2372085A1 (en) | 2000-11-09 |
ES2283298T3 (es) | 2007-11-01 |
US20030087230A1 (en) | 2003-05-08 |
WO2000066604A3 (en) | 2001-01-11 |
NZ514348A (en) | 2004-05-28 |
PT1178999E (pt) | 2007-06-26 |
DK1178999T3 (da) | 2007-08-06 |
EP1178999B1 (en) | 2007-03-14 |
US7053207B2 (en) | 2006-05-30 |
DE60033927T2 (de) | 2007-11-29 |
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