(2R,3R,4S,5R)-2-(6-amino-2-methylsulfanyl-9H-purin-9-yl)tetrahydrofuran-3,4-(O-isopropylidene) | 32976-08-2

• 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: (2R,3R,4S,5R)-2-(6-amino-2-methylsulfanyl-9H-purin-9-yl)tetrahydrofuran-3,4-(O-isopropylidene)
• 英文别名: O^2'_,O3'-isopropylidene-S-methyl-2-thio-isoguanosine；2',3'-acetonide-2-MeS-adenosine；2',3'acetonide-2-MeS-adenosine；[(3aR,4R,6R,6aR)-4-(6-amino-2-methylsulfanylpurin-9-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol
• CAS: 32976-08-2
• 化学式: C₁₄H₁₉N₅O₄S
• 分子量: 353.402
• InChiKey: ZSENLNQXAIQONE-WOUKDFQISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  143
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2R,3R,4S,5R)-2-(6-amino-2-methylsulfanyl-9H-purin-9-yl)tetrahydrofuran-3,4-(O-isopropylidene) 在 四氮唑 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 [(3aR,4R,6R,6aR)-4-(6-amino-2-methylsulfinylpurin-9-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl ditert-butyl phosphate
  参考文献：
  名称：

  Adenine Nucleotide Analogues Locked in a Northern Methanocarba Conformation:  Enhanced Stability and Potency as P2Y₁ Receptor Agonists

  摘要：

  Preference for the Northern (N) ring conformation of the ribose moiety of nucleotide 5'-triphosphate agonists at P2Y(1), P2Y(2), P2Y(4), and P2Y(11) receptors, but not P2Y(6) receptors, was established using a ring-constrained methanocarba (a 3.1.0-bicyclohexane) ring as a ribose substitute (Kim et al. J. Med. Chem. 2002, 45, 208-218.). We have now combined the ring-constrained (N)-methanocarba modification of adenine nucleotides with other functionalities known to enhance potency at P2 receptors. The potency of the newly synthesized analogues was determined in the stimulation of phospholipase C through activation of turkey erythrocyte P2Y, or human P2Y, and P2Y2 receptors stably expressed in astrocytoma cells. An (N)methanocarba-2-methylthio-ADP analogue displayed an EC50 at the hP2Y(1) receptor of 0.40 nM and was 55-fold more potent than the corresponding triphosphate and 16-fold more potent than the riboside 5'-diphosphate. 2-Cl-(N)-methanocarba-ATP and its N-6-Me analogue were also highly selective, full agonists at P2Y, receptors. The (N)-methanocarba-2-methylthio and 2-chloromonophosphate analogues were full agonists exhibiting micromolar potency at P2Y(1) receptors, while the corresponding ribosides were inactive. Although beta,y-methylene-ATP was inactive at P2Y receptors beta,y-methylene-(N)-methanocarba-ATP was a potent hP2Y1 receptor agonist with an EC50 of 160 nM and was selective versus hP2Y(2) and hP2Y(4) receptors. The rates of hydrolysis of Northern (N) and Southern (S) methanocarba analogues of AMP by rat 5'-ectonucleotidase were negligible. The rates of hydrolysis of the corresponding triphosphates by recombinant rat NTPDase 1 and 2 were studied. Both isomers were hydrolyzed by NTPDase 1 at about half the rate of ATP hydrolysis. The (N) isomer was hardly hydrolyzed by NTPDase 2, while the (S) isomer was hydrolyzed at one-third of the rate of ATP hydrolysis. This suggests that new, more stable and selective nucleotide agonists may be designed on the basis of the (N)-conformation, which greatly enhanced potency at P2Y, receptors.

  DOI：

  10.1021/jm010538v
• 作为产物：
  描述：

  2-chloro-2',3'-O-isopropylideneadenosine 、 sodium thiomethoxide 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 (2R,3R,4S,5R)-2-(6-amino-2-methylsulfanyl-9H-purin-9-yl)tetrahydrofuran-3,4-(O-isopropylidene)
  参考文献：
  名称：

  SAR around (l)-S-adenosyl-l-homocysteine, an inhibitor of human DNA methyltransferase (DNMT) enzymes

  摘要：

  The inhibitory activity of base-modified SAH analogues and the specificity of inhibiting human DNMT1 and DNMT3b2 enzymes was explored. The 6-amino group was essential while the 7-N of the adenine ring of SAH could be replaced by CH- without loss of activity against both enzymes. The introduction of small groups at the 2-position of the adenine moiety favors DNMT1 over DNMT3b2 inhibition whereas alkylation of the N-6-amino moiety favors the inhibition of DNMT3b2 enzyme. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.03.113

文献信息

• [EN] PURINE DERIVATIVES AS CD73 INHIBITORS FOR THE TREATMENT OF CANCER<br/>[FR] DÉRIVÉS DE PURINE EN TANT QU'INHIBITEURS DE CD73 POUR LE TRAITEMENT DU CANCER
  申请人：VITAE PHARMACEUTICALS INC

  公开号：WO2015164573A1

  公开（公告）日：2015-10-29

  Provided are novel compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are inhibitors of CD73 and are useful in the treatment of cancer.

  提供的是新颖化合物、其药学上可接受的盐以及其药物组合物，这些化合物是CD73的抑制剂，并可用于癌症治疗。
• [EN] NON-HYDROLYZABLE NUCLEOSIDE DI- OR TRI-PHOSPHATE DERIVATIVES AND USES THEREOF<br/>[FR] DÉRIVÉS DE NUCLÉOSIDES DI- OU TRI-PHOSPHATES NON HYDROLYSABLES ET LEURS UTILISATIONS
  申请人：UNIV BAR ILAN

  公开号：WO2009066298A1

  公开（公告）日：2009-05-28

  The invention provides non-hydrolyzable nucleoside polyphosphate derivatives, e.g., 2MeS-adenosine- β,γ-CH2-5'-O-(1-boranotriphosphate), 2MeS-adenosine- β,γ-CC12-5'-O-(1-boranotriphosphate), 2-MeS-adenosine-5'-dichloro methylene-diphosphate, 2-MeS-adenosine-5'-difluoromethylene- diphosphate and 2MeS-adenosine-5'-O-(1-boranodiphosphate), as well as pharmaceutical compositions thereof. These compounds are useful for prevention or treatment of diseases or disorders modulated by P2Y-receptors such as type 2 diabetes, and for pain control.

  该发明提供了非水解核苷酸多聚物衍生物，例如2MeS-腺苷-β，γ-CH2-5'-O-(1-硼酸三磷酸盐)、2MeS-腺苷-β，γ-CC12-5'-O-(1-硼酸三磷酸盐)、2-MeS-腺苷-5'-二氯甲基二磷酸盐、2-MeS-腺苷-5'-二氟甲基二磷酸盐和2MeS-腺苷-5'-O-(1-硼二磷酸盐)，以及其制备的药物组合物。这些化合物对于预防或治疗由P2Y受体调节的疾病或紊乱，如2型糖尿病，以及疼痛控制非常有用。
• Purine derivatives as CD73 inhibitors for the treatment of cancer
  申请人：Vitae Pharmaceuticals, Inc.

  公开号：US10654884B2

  公开（公告）日：2020-05-19

  Provided are novel purine nucleoside/nucleotide analogues compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are inhibitors of CD73 and are useful in the treatment of cancer.

  本文提供了新型嘌呤核苷/核苷酸类似物化合物、其药学上可接受的盐及其药物组合物，它们是 CD73 的抑制剂，可用于治疗癌症。
• 2-MeS-β,γ-CCl₂-ATP is a Potent Agent for Reducing Intraocular Pressure
  作者：Shay Eliahu、Alba Martín-Gil、María Jesús Perez de Lara、Jesús Pintor、Jean Camden、Gary A. Weisman、Joanna Lecka、Jean Sévigny、Bilha Fischer

  DOI：10.1021/jm100030u

  日期：2010.4.22

  Extracellular nucleotides can modify the production or drainage of the aqueous humor via activation of P2 receptors and therefore affect the intraocular pressure (IOP). We have synthesized slowly hydrolyzable nucleoside di- and triphosphate analogues, 1, and 8-14. Analogues 8-14 were completely resistant to hydrolysis by alkaline phosphatase over 30 min at 37 degrees C. In human blood serum, analogues 8-14 exhibited high stability, e.g., analogues 9 and 10-14 were only 15% and 0% degraded after 24 h, respectively. Moreover, analogues 8-14 were highly stable at pH 1.4 (t(1/2) 1 h-30 days). Analogues 8-14 were agonists of the P2Y(1) receptor (EC50 0.57-9.54 mu M). Ocular administration of most analogues into rabbits reduced IOP, e.g., analogue 9 reduced IOP by 32% (EC50 95.5 nM). Analogue 9 was more effective at reducing IOP than several common glaucoma drugs and represents a promising alternative to timolol maleate, which cannot be used for the treatment of patients suffering from asthma or cardiac problems.
• PURINE DERIVATIVES AS CD73 INHIBITORS FOR THE TREATMENT OF CANCER
  申请人：Vitae Pharmaceuticals, Inc.

  公开号：EP3134411A1

  公开（公告）日：2017-03-01