N-{3-[(2R,3R,4R,5R)-2-(6-Amino-purin-9-yl)-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-3-yloxy]-propyl}-2,2,2-trifluoro-acetamide | 165381-35-1

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: N-{3-[(2R,3R,4R,5R)-2-(6-Amino-purin-9-yl)-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-3-yloxy]-propyl}-2,2,2-trifluoro-acetamide
• 英文别名: N-[3-[(2R,3R,4R,5R)-2-(6-aminopurin-9-yl)-4-hydroxy-5-(hydroxymethyl)oxolan-3-yl]oxypropyl]-2,2,2-trifluoroacetamide
• CAS: 165381-35-1
• 化学式: C₁₅H₁₉F₃N₆O₅
• 分子量: 420.348
• InChiKey: BZMIYONQTTZZSZ-QYVSTXNMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  158
• 氢给体数：
  4
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  N-{3-[(2R,3R,4R,5R)-2-(6-Amino-purin-9-yl)-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-3-yloxy]-propyl}-2,2,2-trifluoro-acetamide 在 吡啶 作用下， 反应 24.0h， 生成 N-Benzoyl-N-(9-{(2R,3R,4R,5R)-5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-hydroxy-3-[3-(2,2,2-trifluoro-acetylamino)-propoxy]-tetrahydro-furan-2-yl}-9H-purin-6-yl)-benzamide
  参考文献：
  名称：

  2‘-O-Aminopropyl Ribonucleotides:  A Zwitterionic Modification That Enhances the Exonuclease Resistance and Biological Activity of Antisense Oligonucleotides

  摘要：

  Oligonucleotides containing 2'-O-aminopropyl-substituted RNA have been synthesized. The 2'-O-(aminopropyl)adenosine (APA), 2'-O-(aminopropyl)cytidine (APC), 2'-O-(aminopropyl)guanosine (APG), and 2'-O-(aminopropyl)uridine (APU) have been prepared in high yield from the ribonucleoside, protected, and incorporated into an oligonucleotide using conventional phosphoramidite chemistry. Molecular dynamics studies of a dinucleotide in water demonstrates that a short alkylamine located off the 2'-oxygen of ribonucleotides alters the sugar pucker of the nucleoside but does not form a tight ion pair with the proximate phosphate. A 5-mer with the sequence ACTUC has been characterized using NMR. As predicted from the modeling results, the sugar pucker of the APU moiety is shifted toward a C3'-endo geometry. In addition, the primary amine rotates freely and is not bound electrostatically to any phosphate group, as evidenced by the different sign of the NOE between sugar proton resonances and the signals from the propylamine chain. Incorporation of aminopropyl nucleoside residues into point-substituted and fully modified oligomers does not decrease the affinity for complementary RNA compared to 2'-O-alkyl substituents of the same length. However, two APU residues placed at the 3'-terminus of an oligomer gives a 100-fold increase in resistance to exonuclease degradation, which is greater than observed for phosphorothioate oligomers. These structural and biophysical characteristics make the 2'-O-aminopropyl group a leading choice for incorporation into antisense therapeutics. A 20-mer phosphorothioate oligonucleotide capped with two phosphodiester aminopropyl nucleotides targeted against C-raf mRNA has been transfected into cells via electroporation. This oligonucleotide has 5-10-fold greater activity than the control phosphorothioate for reducing the abundance of C-raf mRNA and protein.

  DOI：

  10.1021/jm950937o
• 作为产物：
  描述：

  三氟乙酸乙酯 、 (2R,3R,4R,5R)-4-(3-Amino-propoxy)-5-(6-amino-purin-9-yl)-2-hydroxymethyl-tetrahydro-furan-3-ol; compound with acetic acid 在 三乙胺 作用下， 以 甲醇 为溶剂， 反应 16.0h， 以54%的产率得到N-{3-[(2R,3R,4R,5R)-2-(6-Amino-purin-9-yl)-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-3-yloxy]-propyl}-2,2,2-trifluoro-acetamide
  参考文献：
  名称：

  2‘-O-Aminopropyl Ribonucleotides:  A Zwitterionic Modification That Enhances the Exonuclease Resistance and Biological Activity of Antisense Oligonucleotides

  摘要：

  Oligonucleotides containing 2'-O-aminopropyl-substituted RNA have been synthesized. The 2'-O-(aminopropyl)adenosine (APA), 2'-O-(aminopropyl)cytidine (APC), 2'-O-(aminopropyl)guanosine (APG), and 2'-O-(aminopropyl)uridine (APU) have been prepared in high yield from the ribonucleoside, protected, and incorporated into an oligonucleotide using conventional phosphoramidite chemistry. Molecular dynamics studies of a dinucleotide in water demonstrates that a short alkylamine located off the 2'-oxygen of ribonucleotides alters the sugar pucker of the nucleoside but does not form a tight ion pair with the proximate phosphate. A 5-mer with the sequence ACTUC has been characterized using NMR. As predicted from the modeling results, the sugar pucker of the APU moiety is shifted toward a C3'-endo geometry. In addition, the primary amine rotates freely and is not bound electrostatically to any phosphate group, as evidenced by the different sign of the NOE between sugar proton resonances and the signals from the propylamine chain. Incorporation of aminopropyl nucleoside residues into point-substituted and fully modified oligomers does not decrease the affinity for complementary RNA compared to 2'-O-alkyl substituents of the same length. However, two APU residues placed at the 3'-terminus of an oligomer gives a 100-fold increase in resistance to exonuclease degradation, which is greater than observed for phosphorothioate oligomers. These structural and biophysical characteristics make the 2'-O-aminopropyl group a leading choice for incorporation into antisense therapeutics. A 20-mer phosphorothioate oligonucleotide capped with two phosphodiester aminopropyl nucleotides targeted against C-raf mRNA has been transfected into cells via electroporation. This oligonucleotide has 5-10-fold greater activity than the control phosphorothioate for reducing the abundance of C-raf mRNA and protein.

  DOI：

  10.1021/jm950937o

文献信息

• AMINE-DERIVATIZED NUCLEOSIDES AND OLIGONUCLEOSIDES
  申请人：ISIS PHARMACEUTICALS, INC.

  公开号：EP0728139A1

  公开（公告）日：1996-08-28
• US7037646B1
  申请人：——

  公开号：US7037646B1

  公开（公告）日：2006-05-02
• [EN] AMINE-DERIVATIZED NUCLEOSIDES AND OLIGONUCLEOSIDES<br/>[FR] NUCLEOSIDES ET OLIGONUCLEOSIDES A FONCTION(S) AMINE
  申请人：ISIS PHARMACEUTICALS, INC.

  公开号：WO1995006659A1

  公开（公告）日：1995-03-09

  (EN) Nucleosides and oligonucleosides functionalized to include alkylamino functionality, and derivatives thereof. In certain embodiments, the compounds of the invention further include steroids, reporter molecules, reporter enzymes, lipophilic molecules, peptides or proteins attached to the nucleosides through the alkylamino group.(FR) L'invention concerne des nucléosides et des oligonucléosides modifiés par l'adjonction de fonctions alkylamino, ainsi que leurs dérivés. Dans certaines formes d'exécution, les composés de l'invention comportent en outre des stéroïdes, des molécules reporteurs, des enzymes reporteurs, des molécules lipophiles, des peptides ou des protéines, fixés aux nucléosides par le groupe alkylamino.
• 2‘-<i>O</i>-Aminopropyl Ribonucleotides:  A Zwitterionic Modification That Enhances the Exonuclease Resistance and Biological Activity of Antisense Oligonucleotides
  作者：Richard H. Griffey、Brett P. Monia、Lendall L. Cummins、Susan Freier、Michael J. Greig、Charles J. Guinosso、Elena Lesnik、Sherilynn M. Manalili、Venkatraman Mohan、Steven Owens、Bruce R. Ross、Henri Sasmor、Ed Wancewicz、Kurt Weiler、Patrick D. Wheeler、P. Dan Cook

  DOI：10.1021/jm950937o

  日期：1996.1.1

  Oligonucleotides containing 2'-O-aminopropyl-substituted RNA have been synthesized. The 2'-O-(aminopropyl)adenosine (APA), 2'-O-(aminopropyl)cytidine (APC), 2'-O-(aminopropyl)guanosine (APG), and 2'-O-(aminopropyl)uridine (APU) have been prepared in high yield from the ribonucleoside, protected, and incorporated into an oligonucleotide using conventional phosphoramidite chemistry. Molecular dynamics studies of a dinucleotide in water demonstrates that a short alkylamine located off the 2'-oxygen of ribonucleotides alters the sugar pucker of the nucleoside but does not form a tight ion pair with the proximate phosphate. A 5-mer with the sequence ACTUC has been characterized using NMR. As predicted from the modeling results, the sugar pucker of the APU moiety is shifted toward a C3'-endo geometry. In addition, the primary amine rotates freely and is not bound electrostatically to any phosphate group, as evidenced by the different sign of the NOE between sugar proton resonances and the signals from the propylamine chain. Incorporation of aminopropyl nucleoside residues into point-substituted and fully modified oligomers does not decrease the affinity for complementary RNA compared to 2'-O-alkyl substituents of the same length. However, two APU residues placed at the 3'-terminus of an oligomer gives a 100-fold increase in resistance to exonuclease degradation, which is greater than observed for phosphorothioate oligomers. These structural and biophysical characteristics make the 2'-O-aminopropyl group a leading choice for incorporation into antisense therapeutics. A 20-mer phosphorothioate oligonucleotide capped with two phosphodiester aminopropyl nucleotides targeted against C-raf mRNA has been transfected into cells via electroporation. This oligonucleotide has 5-10-fold greater activity than the control phosphorothioate for reducing the abundance of C-raf mRNA and protein.