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    Methods and compounds for the stereoselective enrichment of oligonucleotide diastereomers and oligonucleotides thereby produced
    1.
    发明授权
    Methods and compounds for the stereoselective enrichment of oligonucleotide diastereomers and oligonucleotides thereby produced 失效
    由此制备寡核苷酸非对映异构体和寡核苷酸的立体选择性富集的方法和化合物

    公开(公告)号：US5750674A

    公开(公告)日：1998-05-12

    申请号：US448131

    申请日：1995-05-23

    申请人： Radhakrishnan P. Iyer ,  Dong Yu ,  Sudhir Agrawal ,  Weitian Tan

    发明人： Radhakrishnan P. Iyer ,  Dong Yu ,  Sudhir Agrawal ,  Weitian Tan

    IPC分类号： C07H19/10 ,  C07H19/20 ,  C07H21/00

    CPC分类号： C07H21/00 ,  C07H19/10 ,  C07H19/20

    摘要： The present invention provides new mononucleotide synthons useful in the synthesis of oligonucleotides having from one to all P-chiral centers that are predominantly and independently in the R or S configuration. The invention also provides methods of synthesizing these synthons, methods of synthesizing oligonucleotides having from one to all P-chiral centers predominantly and independently in the R or S configuration, and such oligonucleotides. Oligonucleotides synthesized with the novel synthons are useful for modulating nucleic acid expression, both in vitro and in vivo, as well as in traditional hybridization assays.

    摘要翻译： 本发明提供了可用于合成寡核苷酸的新的单核苷酸合成子，所述寡核苷酸具有主要且独立于R或S构型的一个至所有P-手性中心。 本发明还提供了合成这些合成子的方法，合成寡核苷酸的方法，所述寡核苷酸主要以R或S构型主要且独立地具有一个至所有的P-手性中心，以及这些寡核苷酸。 用新型合成子合成的寡核苷酸可用于在体外和体内以及传统杂交测定中调节核酸表达。

    Method of synthesizing radioisotopically labeled oligonucleotides by direct solid-phase 5' phosphitylation
    2.
    发明授权
    Method of synthesizing radioisotopically labeled oligonucleotides by direct solid-phase 5' phosphitylation 失效
    通过直接固相5'磷酸化合成放射性同位素标记的寡核苷酸的方法

    公开(公告)号：US5631361A

    公开(公告)日：1997-05-20

    申请号：US447092

    申请日：1995-05-22

    申请人： Weitian Tan ,  Radhakrishnan P. Iyer ,  Zhiwei Jiang ,  Dong Yu ,  Sudhir Agrawal

    发明人： Weitian Tan ,  Radhakrishnan P. Iyer ,  Zhiwei Jiang ,  Dong Yu ,  Sudhir Agrawal

    IPC分类号： C07H21/00 ,  C07H1/02

    CPC分类号： C07H21/00

    摘要： The present invention comprises a novel method of incorporating radiolabels and other type of labels at one or more predetermined sites within an oligonucleotide. In particular, the method comprises contacting a nascent, support-bound oligonucleotide having an unprotected 5' hydroxyl group with a suitable activating agent, followed by contacting the resulting activated nascent oligonucleotide with a labeled, Y-protected mononucleotide having an unprotected 3'-hydroxyl, thereby condensing the labeled mononucleotide and nascent oligonucleotide. Normal automated synthesis can then be continued to yield the oligonucleotide of desired length having the label in the desired location. This method advantageously yields oligonucleotides with high specific activity. The oligonucleotides thereby produced are useful for determining the pharmacokinetics and biodistribution of their non-radiolabeled counterparts, both in vitro and in vivo.

    摘要翻译： 本发明包括在寡核苷酸内的一个或多个预定位点掺入放射性标记和其他类型的标记的新方法。 特别地，该方法包括将具有未保护的5'羟基的新生支持结合的寡核苷酸与合适的活化剂接触，然后将所得活化的新生寡核苷酸与具有未保护的3'-羟基的标记的受Y保护的单核苷酸接触 从而使标记的单核苷酸和新生寡核苷酸缩合。 然后可以继续进行正常的自动合成，得到所需长度的寡核苷酸，其具有所需位置的标记。 该方法有利地产生具有高比活性的寡核苷酸。 由此产生的寡核苷酸可用于在体外和体内测定其非放射性标记的对应物的药代动力学和生物分布。

    Detritylation of DMT-oligonucleotides using cationic ion-exchange resin
    3.
    发明授权
    Detritylation of DMT-oligonucleotides using cationic ion-exchange resin 失效
    使用阳离子离子交换树脂的DMT-寡核苷酸的不连续性

    公开(公告)号：US5808042A

    公开(公告)日：1998-09-15

    申请号：US447760

    申请日：1995-05-23

    申请人： Radhakrishnan P. Iyer ,  Zhiwei Jiang ,  Dong Yu ,  Weitian Tan ,  Sudhir Agrawal

    发明人： Radhakrishnan P. Iyer ,  Zhiwei Jiang ,  Dong Yu ,  Weitian Tan ,  Sudhir Agrawal

    IPC分类号： C07H21/00 ,  C07H1/00 ,  C07H21/04

    CPC分类号： C07H21/00

    摘要： The present invention comprises a method for quickly and efficiently detritylating oligonucleotides synthesized by standard chemical techniques. The method comprises contacting a 5'-DMT oligonucleotide with the H.sup.+ form of a "DOWEX," "AMBERLYST" or "AMBERLITE" ion-exchange resin for about 10 minutes to about 2 hours. The method is particularly advantageous when used in large scale synthesis. The method is quicker than the standard acetic acid method and eliminates much of the post-detritylation processing associated with the acetic acid method.

    摘要翻译： 本发明包括通过标准化学技术快速有效地去除寡核苷酸的方法。 该方法包括使5'-DMT寡核苷酸与H +形式的“DOWEX”，“AMBERLYST”或“AMBERLITE”离子交换树脂接触约10分钟至约2小时。 当用于大规模合成时，该方法是特别有利的。 该方法比标准乙酸方法快，消除了与乙酸法相关的大量后脱硝作用。

    Procedure for the solid phase synthesis of .sup.35 S-labeled oligonucleotides with 3H-1,2-benzodithiol-3-one-1,1-dioxide
    4.
    发明授权
    Procedure for the solid phase synthesis of .sup.35 S-labeled oligonucleotides with 3H-1,2-benzodithiol-3-one-1,1-dioxide 失效
    用3H-1,2-苯并二硫醇-3-酮-1,1-二氧化物固相合成35S标记寡核苷酸的方法

    公开(公告)号：US5833944A

    公开(公告)日：1998-11-10

    申请号：US335100

    申请日：1994-11-07

    申请人： Radhakrishnan P. Iyer ,  Sudhir Agrawal ,  Weitian Tan

    发明人： Radhakrishnan P. Iyer ,  Sudhir Agrawal ,  Weitian Tan

    IPC分类号： C07B59/00 ,  C07H21/00 ,  A61K51/00 ,  A61M36/14

    CPC分类号： C07H21/00 ,  C07B59/002

    摘要： This invention provides a novel compound for .sup.35 S-labelling oligonucleotides. The compound is .sup.35 S-3H-1,2-benzodithiol-3-one-1,1 dioxide (1) ##STR1## wherein the asterisk indicates the position of the .sup.35 S. Also provided is a method of synthesizing this compound, comprising first contacting .sup.35 S-thiobenzoic acid (4) with thiosalicylic acid (5) in acid medium to yield the condensation product, .sup.35 S-3 H 1,2-benzodithiol-3-one (2). .sup.35 S-3 H 1,2-benzodithiol-3-one (2) is then oxidized with a suitable oxidating agent such as trifuoroacetic acid and hydrogen perioxide to yield the desired product, .sup.35 S-3H-1,2-benzodithiol-3-one-1,1 dioxide (1). Any oligonucleotide susceptible to oxidative sulfurized by 3H-1,2-benzodithiol-3-one-1,1 dioxide can be labeled by .sup.35 S-3H-1,2-benzodithiol-3-one-1,1 dioxide (1). Accordingly, this invention also provides novel methods for .sup.35 S-labelling oligonucleotides. The compound and methods are useful for tracing biodistribution and degradation of antisense oligonucleotides in pharmacokinetic studies.

    摘要翻译： 本发明提供了一种用于35S标记寡核苷酸的新型化合物。 化合物是35S-3H-1,2-苯并二硫醇-3-酮二氧化物（1），其中星号表示35S的位置。 还提供了一种合成该化合物的方法，包括首先在酸性介质中将35S-硫代苯甲酸（4）与硫代水杨酸（5）接触以产生缩合产物，35S-3 H 1,2-苯并二硫酚-3-酮（2 ）。 然后用合适的氧化剂如三氟乙酸和二氧化碳氧化35S-3 H 1,2-苯并二硫醇-3-酮（2），得到所需产物，35S-3H-1,2-苯并二硫醇-3-酮 -1二氧化物（1）。 任何对3H-1,2-苯并二硫酚-3-酮二氧化物进行氧化硫化的寡核苷酸可用35S-3H-1,2-苯并二硫酚-3-酮二氧化物（1）进行标记。 因此，本发明还提供了35S标记寡核苷酸的新方法。 该化合物和方法可用于在药代动力学研究中追踪反义寡核苷酸的生物分布和降解。

    Method of tritium labeling oligonucleotides
    5.
    发明授权
    Method of tritium labeling oligonucleotides 失效
    氚标记寡核苷酸的方法

    公开(公告)号：US5668262A

    公开(公告)日：1997-09-16

    申请号：US485112

    申请日：1995-06-07

    申请人： Weitian Tan ,  Radhakrishnan P. Iyer ,  Zhiwei Jiang ,  Dong Yu ,  Sudhir Agrawal

    发明人： Weitian Tan ,  Radhakrishnan P. Iyer ,  Zhiwei Jiang ,  Dong Yu ,  Sudhir Agrawal

    IPC分类号： A61K51/04 ,  C07H21/00 ,  C07H19/00 ,  C07H21/02 ,  C07H21/04

    CPC分类号： A61K51/0491 ,  C07H21/00

    摘要： The present invention comprises a novel method of incorporating a tritium label at one or more predetermined sites within an oligonucleotide. In particular, the method comprises contacting a nascent, support-bound oligonucleotide having a free 5' hydroxyl group with a suitable oxidizing agent to oxidize the alcohol to an aldehyde, followed by reducing the aldehyde thereby formed with a suitable tritium labeled reducing agent such as [.sup.3 H]NaBH.sub.4 to yield the 5' terminal alcohol with a 5' tritium label. Normal automated synthesis can then be continued to yield the oligonucleotide of desired length having the tritium label in the desired location. The oligonucleotides thereby produced have higher specific activity than those previously known in the art. According, in a second aspect, the present invention provides oligonucleotides having high specific activity. The oligonucleotides of the present invention are useful for determining the pharmacokinetics and biodistribution of their non-radiolabeled counterparts, both in vitro and in vivo.

    摘要翻译： 本发明包括在寡核苷酸内的一个或多个预定位点掺入氚标记的新方法。 特别地，该方法包括将具有游离的5'羟基的新生载体结合的寡核苷酸与合适的氧化剂接触以将醇氧化成醛，然后用合适的氚标记还原剂形成还原醛， [3H] NaBH 4，得到具有5'氚标记的5'末端醇。 然后可以继续进行正常的自动化合成，得到所需长度的寡核苷酸，其中所述氚标记具有所需位置。 由此产生的寡核苷酸比本领域已知的寡核苷酸具有更高的比活性。 根据第二方面，本发明提供具有高比活性的寡核苷酸。 本发明的寡核苷酸可用于在体外和体内测定其非放射性标记的对应物的药代动力学和生物分布。

    Synthons for oligonucleotide synthesis
    7.
    发明授权
    Synthons for oligonucleotide synthesis 失效
    合成寡核苷酸合成

    公开(公告)号：US6117993A

    公开(公告)日：2000-09-12

    申请号：US15472

    申请日：1998-01-29

    申请人： Radhakrishnan P. Iyer ,  Dong Yu ,  Mao-Jun Guo ,  Sudhir Agrawal

    发明人： Radhakrishnan P. Iyer ,  Dong Yu ,  Mao-Jun Guo ,  Sudhir Agrawal

    IPC分类号： C07H19/11 ,  C07H19/10 ,  C07H19/16 ,  C07H19/20 ,  C07H19/213 ,  C07H21/00 ,  C07H19/04

    CPC分类号： C07H19/10 ,  C07H19/16 ,  C07H19/20 ,  C07H21/00

    摘要： The invention provides new reagents and processes for synthesizing oligonucleotides, including stereoselective oligonucleotide synthesis. In a first aspect, the invention provides novel monomer synthons for the synthesis of oligonucleotides. Monomer synthons according to this aspect of the invention are useful in the synthesis of oligonucleotides and can be used in place of the well known beta-cyanoethyl phosphoramidite monomer synthon in the phosphoramidite synthesis procedure. Certain monomer synthons according to this aspect of the invention are useful in this procedure for producing oligonucleotides having defined stereochemistry.In a second aspect, the invention provides processes for synthesizing monomer synthons according to the invention, including diastereomerically enriched or purified monomer synthons. In the processes according to this aspect of the invention, the chemical reactions are stereoretentive so that the products of each reaction retain the same stereoconfiguration as their precursor reagent.In a third aspect, the invention provides processes for synthesizing oligonucleotides using the well known phosphoramidite approach. In the processes according to this aspect of the invention, any of the monomer synthons according to the invention is used in place of the conventional beta-cyanoethyl phosphoramidite.

    摘要翻译： 本发明提供用于合成寡核苷酸的新试剂和方法，包括立体选择性寡核苷酸合成。 在第一方面，本发明提供了用于合成寡核苷酸的新型单体合成子。 根据本发明该方面的单体合成子可用于寡核苷酸的合成，并可用于代替在亚磷酰胺合成方法中众所周知的β-氰乙基亚磷酰胺单体合成子。 根据本发明该方面的某些单体合成子可用于制备具有确定的立体化学的寡核苷酸的该方法中。 在第二方面，本发明提供了合成根据本发明的单体合成子的方法，包括非对映体富集或纯化的单体合成子。 在根据本发明的这个方面的方法中，化学反应是立体反应性的，使得每个反应的产物保持与其前体试剂相同的立体构型。 在第三方面，本发明提供使用公知的亚磷酰胺方法合成寡核苷酸的方法。 在根据本发明的这个方面的方法中，使用根据本发明的任何单体合成物代替常规的β-氰基乙基亚磷酰胺。

    Method of tritium labeling oligonucleotide
    10.
    发明授权
    Method of tritium labeling oligonucleotide 失效
    氚标记寡核苷酸的方法

    公开(公告)号：US5847104A

    公开(公告)日：1998-12-08

    申请号：US447203

    申请日：1995-05-22

    申请人： Weitan Tan ,  Radhakrishnan P. Iyer ,  Zhiwei Jiang ,  Dong Yu ,  Sudhir Agrawal

    发明人： Weitan Tan ,  Radhakrishnan P. Iyer ,  Zhiwei Jiang ,  Dong Yu ,  Sudhir Agrawal

    IPC分类号： A61K51/04 ,  C07H21/00 ,  C07H21/02 ,  C07H21/04

    CPC分类号： A61K51/0491 ,  C07H21/00

    摘要： The present invention comprises a novel method of incorporating a tritium label at one or more predetermined sites within an oligonucleotide. In particular, the method comprises contacting a nascent, support-bound oligonucleotide having a free 5' hydroxyl group with a suitable oxidizing agent to oxidize the alcohol to an aldehyde, followed by reducing the aldehyde thereby formed with a suitable tritium labeled reducing agent such as �.sup.3 H!NaBH.sub.4 to yield the 5' terminal alcohol with a 5' tritium label. Normal automated synthesis can then be continued to yield the oligonucleotide of desired length having the tritium label in the desired location. The oligonucleotides thereby produced have higher specific activity than those previously known in the art. According, in a second aspect, the present invention provides oligonucleotides having high specific acitivity. The oligonucleotides of the present invention are useful for determining the pharmacokinetics and biodistribution of their non-radiolabeled counterparts, both in vitro and in vivo.

    摘要翻译： 本发明包括在寡核苷酸内的一个或多个预定位点掺入氚标记的新方法。 特别地，该方法包括将具有游离的5'羟基的新生载体结合的寡核苷酸与合适的氧化剂接触以将醇氧化成醛，然后用合适的氚标记还原剂形成还原醛， [3H] NaBH 4，得到具有5'氚标记的5'末端醇。 然后可以继续进行正常的自动化合成，得到所需长度的寡核苷酸，其中所述氚标记具有所需位置。 由此产生的寡核苷酸比本领域已知的寡核苷酸具有更高的比活性。 根据第二方面，本发明提供具有高比活度的寡核苷酸。 本发明的寡核苷酸可用于在体外和体内测定其非放射性标记的对应物的药代动力学和生物分布。