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WO2025148770A1 - Monomère nucléotidique modifié et son utilisation - Google Patents

Monomère nucléotidique modifié et son utilisation

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Publication number
WO2025148770A1
WO2025148770A1 PCT/CN2025/070080 CN2025070080W WO2025148770A1 WO 2025148770 A1 WO2025148770 A1 WO 2025148770A1 CN 2025070080 W CN2025070080 W CN 2025070080W WO 2025148770 A1 WO2025148770 A1 WO 2025148770A1
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WO
WIPO (PCT)
Prior art keywords
sirna
formula
nucleotide
antisense strand
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/070080
Other languages
English (en)
Chinese (zh)
Inventor
李进
陈柳
胡勇箭
罗华东
马慧勇
刘观赛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hitgen Inc
Original Assignee
Hitgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hitgen Inc filed Critical Hitgen Inc
Publication of WO2025148770A1 publication Critical patent/WO2025148770A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing

Definitions

  • RNAi off-target effects a major factor in RNAi off-target effects is that some fragments of the siRNA sequence that binds to the target mRNA may function like microRNA (miRNA). They can bind to the 3'-untranscribed region (3'-UTR) of other mRNAs to inhibit the translation and stability of mRNA.
  • miRNA mainly recognizes target genes through base pairing between the seed region (position 2-8 at the 5'-end) and the target mRNA.
  • the off-target effects caused by siRNA mainly come from the base complementarity between the antisense chain seed region of siRNA and one or more mRNAs. Therefore, the sequence of the antisense chain seed region may affect the expression of multiple genes and become the main factor in the side effects of RNAi drugs.
  • n 1, 2 or 3; preferably, m is 1;
  • Z is selected from a hydroxyl group, a phosphate group, a phosphorothioate group or a phosphoramidite group.
  • R is selected from hydrogen or a hydroxyl protecting group
  • n 1, 2 or 3; preferably, n is 1;
  • Z is selected from a hydroxyl group, a phosphate group, a phosphorothioate group or a phosphoramidite group.
  • R is selected from hydrogen, 4,4'-bismethoxytrityl or 4-methoxytrityl
  • Z is selected from hydroxyl or
  • the compound is specifically:
  • the present invention also provides the use of any of the above-mentioned nucleotide monomer compounds as an intermediate in the preparation of oligonucleotides; preferably, the oligonucleotide is siRNA.
  • the present invention provides the use of any of the above-mentioned nucleotide monomer compounds as an intermediate in the preparation of the siRNA antisense strand seed region. More specifically, the siRNA antisense strand seed region is the 2nd to 8th nucleotides at the 5' end of the siRNA antisense strand.
  • the present invention also provides an siRNA, comprising a sense strand and an antisense strand; the sense strand and the antisense strand each comprise 15 to 45 modified or unmodified nucleotides, and the sense strand and the antisense strand are partially complementary to form a double-stranded region; wherein the seed region of the antisense strand contains at least one nucleotide having a structure shown in Formula V, and Site covalently linked to the rest of the siRNA:
  • n 1, 2 or 3; preferably, n is 1;
  • the 8th position of the seed region of the antisense strand is a nucleotide of the structure shown in Formula V or Formula VI.
  • the nucleotides at positions 2, 6, 14 and 16 of the antisense strand are each independently a 2'-fluoro-modified nucleotide.
  • the nucleotides at positions 2, 14 and 16 of the antisense strand are each independently a 2'-fluoro-modified nucleotide.
  • the nucleotides at positions 2, 6, 14 and 16 of the antisense strand are each independently a 2'-fluoro-modified nucleotide.
  • the 8th position of the seed region of the antisense strand is a nucleotide of the structure shown in Formula V or Formula VI;
  • the nucleotides at positions 2, 6, 14 and 16 of the antisense strand are each independently a 2'-fluoro-modified nucleotide.
  • the nucleotides at the remaining positions of the antisense strand are 2-methoxy modified nucleotides.
  • the phosphodiester group having a modifying group is present in at least one of the following positions:
  • the sense strand and/or the antisense strand includes a plurality of phosphodiester groups having a modification group.
  • the sense strand and/or the antisense strand comprises a plurality of phosphodiester groups with modification groups, wherein the thiophosphodiester groups are present in:
  • the sense strand is selected from a nucleotide sequence (5'-3') comprising the following formula:
  • the antisense strand is selected from a nucleotide sequence (5'-3') comprising the following formula:
  • mN represents any 2'-methoxy-modified nucleoside, such as 2'-methoxy-modified C, G, U, A, T;
  • fN represents any 2'-fluoro-modified nucleoside, such as 2'-fluoro-modified C, G, U, A, T;
  • V represents a nucleotide having a structure represented by formula V of the present invention.
  • the present invention also provides the use of any of the above siRNAs, and/or the above pharmaceutical compositions, and/or the above siRNA conjugates in the preparation of drugs.
  • the modified nucleotides of the present invention can improve the drugability of siRNA drug molecules.
  • the modified nucleotides of the present invention can enhance the effect of siRNA in degrading target genes. Therefore, the modified nucleotides of the present invention can enhance the pharmacodynamic effect of siRNA silencing.
  • the siRNA conjugate provided by the present invention is formed by conjugating siRNA and a conjugation molecule, and comprises the siRNA of the present invention and a conjugation group conjugated to the siRNA, wherein the conjugation group comprises a linker and a pharmaceutically acceptable targeting group and/or a delivery auxiliary group, and the siRNA, the linker and the targeting group or the delivery auxiliary group are sequentially covalently or non-covalently connected, each of the targeting groups is selected from a ligand capable of binding to a cell surface receptor, and each of the delivery auxiliary groups is selected from a group capable of increasing the biocompatibility of the siRNA conjugate in the target organ or tissue for delivery.
  • the sense strand is about 19 nucleotides in length, while the antisense strand is about 21 nucleotides in length. In some embodiments, the sense strand is about 21 nucleotides in length, while the antisense strand is about 23 nucleotides in length.
  • the perfect or partially complementary region between the sense strand and the antisense strand is typically 15-25 nucleotides in length and is located at or near the 5'-end of the antisense strand (e.g., the region is 1, 2, 3, or 4 nucleotides away from the 5'-end of the antisense strand, which is imperfect or partially complementary).
  • siRNA drugs if there are other sense strand nucleotides, they can be identical or different from the corresponding sequence in the target mRNA. If there are other antisense strand nucleotides, they can be complementary or non-complementary to other nucleotides (if present) of the corresponding sense strand.
  • the sense strand and antisense strand of the double-stranded siRNA drug comprising the modified nucleotides of the present invention contain the same number of nucleotides. In some embodiments, the sense strand and antisense strand of the siRNA drug of the present invention contain different numbers of nucleotides.
  • modified nucleotide disclosed in J.K.Watts, G.F.Deleavey, and M.J.Damha, Chemically modified siRNA: tools and applications. Drug Discov. Today, 2008, 13 (19-20): 842-55 can be selected.
  • oligonucleotide refers to a polymer of linked nucleosides, each of which may be independently modified or unmodified, and comprises an oligonucleotide sequence of about 10-50 single-stranded nucleotides or double-stranded nucleotide base pairs.
  • the oligonucleotide has a core base sequence that is at least partially complementary to a target gene core sequence expressed in a cell.
  • the oligonucleotide can regulate the expression of the corresponding target gene after being delivered to a cell expressing the gene. Target gene expression can be regulated in vitro or in vivo.
  • siRNA drug molecules described in the present invention are used to treat cells, tissues, organs or animals for direct administration, compared with cells, tissues, organs or animals that have not been treated in this way, The level of expression of the gene is reduced or decreased.
  • sequence or “nucleotide sequence” refers to the order or sequence of nucleobases or nucleotides, expressed in alphabetical order using standard nucleotide nomenclature.
  • Complementary sequences contain Watson-Crick base pairing or non-Watson-Crick base pairing, and contain natural or modified nucleotides or nucleotide analogs to at least the extent that they meet the above hybridization requirements.
  • monomers a and Af are complementary to U (or T) and are equivalent to A.
  • sense strand refers to the strand on the RNA molecule that carries the nucleotide sequence encoding protein amino acid information, which is called the sense strand, also known as the coding strand, sense strand or positive strand, and the other nucleotide sequence that is complementary to it is the antisense strand.
  • antisense strand refers to a nucleotide sequence in mRNA expressed by a target gene that is substantially reverse complementary or essentially reverse complementary to the antisense strand and has the same length as the antisense strand.
  • a heterocyclic group optionally substituted with an alkyl group means that the alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.
  • substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions by means of the prior art and experimental conditions. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g. olefinic) bond.
  • the minimum and maximum carbon atom content of the hydrocarbon group is indicated by a prefix, for example, the prefix Ca - Cb alkyl indicates any alkyl group containing from "a" to "b” carbon atoms.
  • C1-6 alkyl refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms.
  • Alkyl refers to a straight or branched hydrocarbon group in an alkane molecule, such as methyl-CH 3 , ethyl-CH 2 CH 3 , methylene-CH 2 -; the alkyl group may also be part of other groups, such as C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, etc.
  • the alkyl group may be substituted or unsubstituted.
  • hydroxyl protecting groups in the present invention are disclosed in Beaucage et al., Tetrahedron 1992, 48, 2223-2311, and Greene and Wuts, Protective Groups in Organic Synthesis, Chapter 2, 2d ed, John Wiley & Sons, New York, 1991, each of which is incorporated herein by reference in its entirety.
  • the protecting group is stable under alkaline conditions but can be removed under acidic conditions.
  • the compounds and compositions described herein may have certain atoms (e.g., N, O, or S atoms) in a protonated or deprotonated state, depending on the environment in which the compound or composition is located.
  • the structures described herein take into account that certain functional groups, such as OH, SH, or NH, may be protonated or deprotonated.
  • the disclosure of the present invention is intended to encompass the above-described compounds and compositions, regardless of their protonation state based on the ambient pH, as will be readily appreciated by those of ordinary skill in the art.
  • salts and “usable salts” refer to acidic and/or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compounds. They can also be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may be precipitated in the solution and collected by filtration, or recovered after solvent evaporation, or obtained by freeze drying after reaction in an aqueous medium.
  • FIG1 is a 1 H NMR spectrum of compound HG_NA02
  • FIG4 is a LCMS diagram of compound HG_NA02
  • Figures 5 and 6 are LCMS diagrams of compounds HG_NA03a and HG_NA03b;
  • FIG. 7 is a diagram of the detection of on-target activity of siRNA in Experimental Example 1;
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10-6 (ppm).
  • NMR measurements were performed using (Bruker AvanceIII 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • LC-MS was determined using a Shimadzu LC-MS2020 (ESI).
  • HPLC was determined using a Shimadzu LC-20A high pressure liquid chromatograph.
  • MPLC medium pressure preparative chromatography
  • the thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications used for thin layer chromatography separation and purification products were 0.4mm to 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200 to 300 mesh silica gel as a carrier.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology. Unless otherwise specified, the materials and reagents used in the examples of the present invention are all commercially available products.
  • the reaction is carried out under a nitrogen atmosphere.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature.
  • M is moles per liter.
  • HG_NA01-2 (1.00 g, 4.42 mmol) to a 100 mL single-mouth bottle and dissolve it in THF (30 mL). Slowly add concentrated hydrochloric acid (15 mL, 12 M) while stirring. After the addition, heat the reaction overnight and monitor with LC-MS. After the reaction is completed, the reaction solution is concentrated, and dry pyridine (50 mL) is added to the residue, and HG_NA01-3 (0.89 g, 108.14% yield) is obtained by concentration under reduced pressure. LCMS (E+) m/z: 187.1 [M+H] + .
  • HG_NA01-3 (0.89 g, 4.78 mmol) to a 100 mL three-necked flask, dissolve it in pyridine (30 mL), and then add DMTrCl (1.62 g, 4.78 mmol). After the addition, stir at room temperature for 3 hours and monitor by LC-MS. After the reaction, the reaction solution is concentrated, and the residue is prepared by MPLC to obtain HG_NA01-4 (2.20 g, 94.30% yield). LCMS (E+) m/z: 489.2 [M+H] + .
  • HG_NA01-4 (1.20 g, 2.46 mmol) to a 100 mL three-necked flask and dissolve it in dry DCM (20 mL). Then add CEPCl (0.70 g, 2.94 mmol) and DIPEA (0.63 g, 4.92 mmol). After the addition, stir at room temperature for 2 hours and monitor by LC-MS. After the reaction is completed, directly prepare HG_NA01 (0.24 g, 14.19% yield) by MPLC. LCMS (E+) m/z: 689.2 [M+H] + .
  • HG_NA02-2 (1.00 g, 4.42 mmol) to a 100 mL single-mouth bottle and dissolve it in THF (30 mL). Slowly add concentrated hydrochloric acid (15 mL, 12 M) while stirring. After the addition, heat the reaction overnight and monitor with LC-MS. After the reaction is completed, the reaction solution is concentrated, and dry pyridine (50 mL) is added to the residue, and concentrated under reduced pressure to obtain HG_NA02-3 (0.87 g, 98.35% yield). LCMS (E+) m/z: 186.1 [M+H] + .
  • HG_NA02-3 (0.87 g, 4.69 mmol) to a 100 mL three-necked flask, dissolve it in pyridine (20 mL), and then add DMTrCl (1.58 g, 4.69 mmol). After the addition, stir at room temperature for 3 hours and monitor by LC-MS. After the reaction, the reaction solution is concentrated, and the residue is prepared by MPLC to obtain HG_NA02-4 (0.90 g, 39.38% yield). LCMS (E+) m/z: 488.2 [M+H] + .
  • HG_NA03-3 (613.00 mg, 3.06 mmol) to a 100 mL single-mouth bottle and dissolve it in dry pyridine (20 mL). Then add DMTrCl (1.04 g, 3.06 mmol). After the addition, stir at room temperature for 2 hours and monitor by LC-MS. After the reaction, the reaction solution is concentrated and purified by column chromatography to obtain HG_NA03-4 (1.24 g, 80.58% yield). LCMS (E+) m/z: 503.2 [M+H] + .
  • HG_NA03-4 489.00 mg, 0.97 mmol
  • DCM 20 mL
  • DIPEA 251.51 mg, 1.95 mmol
  • CEPCl 253.32 mg, 1.07 mmol
  • column chromatography purification gave HG_NA03a and HG_NA03b (150.00 mg each, 46.65% yield).
  • SS represents the sense strand
  • AS represents the antisense strand
  • lowercase letter m represents that the nucleotide adjacent to the right of letter m is a 2'-methoxy-modified nucleotide
  • lowercase letter f represents that the nucleotide adjacent to the right of letter f is a 2-fluoro-modified nucleotide
  • "*" represents that the connection between the two adjacent nucleotides on the left and right is a phosphorothioate connection
  • GNA represents (S)-ethylene glycol nucleotide
  • HG_NA02 is the nucleoside phosphoramidite monomer HG_NA02 obtained by solid phase synthesis in Example 2
  • HG_NA03a and HG_NA03b are the nucleoside phosphoramidite monomers HG_NA03a and HG_NA03b obtained by solid phase synthesis in Example 3.

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Abstract

La présente invention concerne une classe de composés monomères nucléotidiques représentés par la formule (I), et leur utilisation dans des molécules de médicament d'acide nucléique. Après l'introduction du monomère nucléotidique selon la présente invention dans une région de germe de brin antisens d'ARNsi, il peut réduire de manière significative les effets hors cible potentiels d'une région de germe de brin antisens et maintenir ou améliorer l'activité de l'ARNsi, ce qui permet d'obtenir un silençage sélectif plus élevé d'ARNm de gène cible, d'étendre la fenêtre de sécurité pour des médicaments d'ARNsi, et d'améliorer la pharmacopotentialité de l'ARNsi, ce qui permet un traitement plus efficace de maladies associées provoquées par l'ARNm du gène cible.
PCT/CN2025/070080 2024-01-08 2025-01-02 Monomère nucléotidique modifié et son utilisation Pending WO2025148770A1 (fr)

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Application Number Priority Date Filing Date Title
CN202410024142 2024-01-08
CN202410024142.5 2024-01-08

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018820A1 (fr) * 1994-01-11 1995-07-13 Isis Pharmaceuticals, Inc. Diols monomeres et oligomeres a liaison phosphate formes a partir de ces derniers
WO2009120878A2 (fr) * 2008-03-26 2009-10-01 Alnylam Pharmaceuticals, Inc. Ribonucléotides non naturels, et procédés pour les utiliser
WO2011133876A2 (fr) * 2010-04-22 2011-10-27 Alnylam Pharmaceuticals, Inc. Oligonucléotides comprenant des nucléosides acycliques et abasiques, et analogues
CN103880877A (zh) * 2012-12-21 2014-06-25 中国科学院上海有机化学研究所 含氟固相合成试剂及其应用
WO2024208249A1 (fr) * 2023-04-06 2024-10-10 上海舶望制药有限公司 Analogue nucléosidique pour modification de 5'-phosphonate et oligonucléotide préparé à partir de celui-ci
CN119285688A (zh) * 2023-08-22 2025-01-10 成都先衍生物技术有限公司 修饰的核苷酸单体及其用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018820A1 (fr) * 1994-01-11 1995-07-13 Isis Pharmaceuticals, Inc. Diols monomeres et oligomeres a liaison phosphate formes a partir de ces derniers
WO2009120878A2 (fr) * 2008-03-26 2009-10-01 Alnylam Pharmaceuticals, Inc. Ribonucléotides non naturels, et procédés pour les utiliser
WO2011133876A2 (fr) * 2010-04-22 2011-10-27 Alnylam Pharmaceuticals, Inc. Oligonucléotides comprenant des nucléosides acycliques et abasiques, et analogues
CN103880877A (zh) * 2012-12-21 2014-06-25 中国科学院上海有机化学研究所 含氟固相合成试剂及其应用
WO2024208249A1 (fr) * 2023-04-06 2024-10-10 上海舶望制药有限公司 Analogue nucléosidique pour modification de 5'-phosphonate et oligonucléotide préparé à partir de celui-ci
CN119285688A (zh) * 2023-08-22 2025-01-10 成都先衍生物技术有限公司 修饰的核苷酸单体及其用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 1 August 1987 (1987-08-01), ANONYMOUS : "1H-1,2,4-Triazole-3-carboxamide, 1-(2,3-dihydroxypropyl)-", XP093335538, retrieved from STN Database accession no. 109629-20-1 *
MARK K. SCHLEGEL, DONALD J. FOSTER, ALEXANDER V. KEL’IN, IVAN ZLATEV, ANNA BISBE, MUTHUSAMY JAYARAMAN, JEREMY G. LACKEY, KALLANTHO: "Chirality Dependent Potency Enhancement and Structural Impact of Glycol Nucleic Acid Modification on siRNA", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 139, no. 25, 28 June 2017 (2017-06-28), pages 8537 - 8546, XP055602525, DOI: 10.1021/jacs.7b02694 *

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