(R)-(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl-phenylmethanol

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 吡咯并嘧啶核苷和核苷酸
• 英文名称: (R)-(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl-phenylmethanol
• 英文别名: (R)-((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)(phenyl)methanol；(R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-phenylmethanol
• 化学式: C₂₀H₂₀ClN₃O₄
• 分子量: 401.849
• InChiKey: BAHODGRCXLZSRP-DINLJIAVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  78.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R)-(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl-phenylmethanol 在 氨 作用下， 以 甲醇 为溶剂， 反应 8.0h， 以78%的产率得到(R)-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-phenylmethanol
  参考文献：
  名称：

  [EN] 5'-SUBSTITUTED NUCLEOSIDE ANALOGS
  [FR] ANALOGUES NUCLÉOSIDIQUES 5'-SUBSTITUÉS

  摘要：

  本发明涉及新型5-取代核苷化合物，包括这些化合物的药物组合物，以及使用这些化合物治疗癌症的方法，更具体地用于治疗癌症，特别是对于胶质母细胞瘤、黑色素瘤、肉瘤、胃癌、胰腺癌、胆管癌、膀胱癌、乳腺癌、非小细胞肺癌、包括急性髓细胞白血病和淋巴瘤的治疗。

  公开号：

  WO2016178870A1
• 作为产物：
  描述：

  4-chloro-7-β-D-ribofuranosylpyrrolo<2,3-d>pyrimidine 在 甲酸:三乙胺 1:1 、 2,2,6,6-四甲基哌啶氧化物 、 碘苯二乙酸 、 N-[(1R,2R)-1,2-二苯基-2-(2-(4-甲基苄氧基)乙氨基)-乙基]-4-甲基苯磺酰胺(氯)钌(II) 、 对甲苯磺酸 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 、 水 、 丙酮 、 乙腈 为溶剂， 反应 81.28h， 生成 (R)-(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl-phenylmethanol
  参考文献：
  名称：

  [EN] 5'-SUBSTITUTED NUCLEOSIDE ANALOGS
  [FR] ANALOGUES NUCLÉOSIDIQUES 5'-SUBSTITUÉS

  摘要：

  本发明涉及新型5-取代核苷化合物，包括这些化合物的药物组合物，以及使用这些化合物治疗癌症的方法，更具体地用于治疗癌症，特别是对于胶质母细胞瘤、黑色素瘤、肉瘤、胃癌、胰腺癌、胆管癌、膀胱癌、乳腺癌、非小细胞肺癌、包括急性髓细胞白血病和淋巴瘤的治疗。

  公开号：

  WO2016178870A1

文献信息

• 5'-SUBSTITUTED NUCLEOSIDE COMPOUNDS
  申请人：Eli Lilly and Company

  公开号：US20160326208A1

  公开（公告）日：2016-11-10

  The present invention relates to novel 5′-substituted nucleoside compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat cancer, more particularly for the treatment of cancer, in particular glioblastomas, melanoma, sarcomas, gastric cancer, pancreatic cancer, cholangiocarcinoma, bladder cancer, breast cancer, non-small cell lung cancer, leukemias including acute myeloid leukemia, and lymphomas.
• US9840532B2
  申请人：——

  公开号：US9840532B2

  公开（公告）日：2017-12-12
• [EN] 5'-SUBSTITUTED NUCLEOSIDE ANALOGS<br/>[FR] ANALOGUES NUCLÉOSIDIQUES 5'-SUBSTITUÉS
  申请人：LILLY CO ELI

  公开号：WO2016178870A1

  公开（公告）日：2016-11-10

  The present invention relates to novel 5-substituted nucleoside compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat cancer, more particularly for the treatment of cancer, in particular glioblastomas, melanoma, sarcomas, gastric cancer, pancreatic cancer, cholangiocarcinoma, bladder cancer, breast cancer, non-small cell lung cancer, leukemias including acute myeloid leukemia, and lymphomas.

  本发明涉及新型5-取代核苷化合物，包括这些化合物的药物组合物，以及使用这些化合物治疗癌症的方法，更具体地用于治疗癌症，特别是对于胶质母细胞瘤、黑色素瘤、肉瘤、胃癌、胰腺癌、胆管癌、膀胱癌、乳腺癌、非小细胞肺癌、包括急性髓细胞白血病和淋巴瘤的治疗。
• LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity
  作者：Zahid Q. Bonday、Guillermo S. Cortez、Michael J. Grogan、Stephen Antonysamy、Ken Weichert、Wayne P. Bocchinfuso、Fengling Li、Steven Kennedy、Binghui Li、Mary M. Mader、Cheryl H. Arrowsmith、Peter J. Brown、Mohammad S. Eram、Magdalena M. Szewczyk、Dalia Barsyte-Lovejoy、Masoud Vedadi、Ernesto Guccione、Robert M. Campbell

  DOI：10.1021/acsmedchemlett.8b00014

  日期：2018.7.12

  Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the formation of symmetric dimethylarginine in a number of nuclear and cytoplasmic proteins. Although the cellular functions of PRMT5 have not been fully unraveled, it has been implicated in a number of cellular processes like RNA processing, signal transduction, and transcriptional regulation. PRMT5 is ubiquitously expressed in most tissues and its expression has been shown to be elevated in several cancers including breast cancer, gastric cancer, glioblastoma, and lymphoma. Here, we describe the identification and characterization of a novel and selective PRMT5 inhibitor with potent in vitro and in vivo activity. Compound 1 (also called LLY-283) inhibited PRMT5 enzymatic activity in vitro and in cells with IC50 of 22 +/- 3 and 2S +/- 1 nM, respectively, while its diastereomer, compound 2 (also called LLY-284), was much less active. Compound 1 also showed antitumor activity in mouse xenografts when dosed orally and can serve as an excellent probe molecule for understanding the biological function of PRMT5 in normal and cancer cells.