5'-deoxy-5'-[(N-methylcarbamoyl)amino]-N6-(N-phenylcarbamoyl)adenosine | 1092548-23-6

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 5'-脱氧核糖核苷
• 英文名称: 5'-deoxy-5'-[(N-methylcarbamoyl)amino]-N6-(N-phenylcarbamoyl)adenosine
• 英文别名: 1-[9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(methylcarbamoylamino)methyl]oxolan-2-yl]purin-6-yl]-3-phenylurea
• CAS: 1092548-23-6
• 化学式: C₁₉H₂₂N₈O₅
• 分子量: 442.434
• InChiKey: NMSJYYWINFJZKG-LSCFUAHRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  176
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  丁酸酐 、 5'-deoxy-5'-[(N-methylcarbamoyl)amino]-N6-(N-phenylcarbamoyl)adenosine 在 吡啶 作用下， 以63%的产率得到2',3'-bis-O-butanoyl-5'-deoxy-5'-[(N-methylcarbamoyl)amino]-N⁶-(N-phenylcarbamoyl)-adenosine
  参考文献：
  名称：

  Synthesis and SAR of 2′,3′-bis-O-substituted N6, 5′-bis-ureidoadenosine derivatives: Implications for prodrug delivery and mechanism of action

  摘要：

  A series of 2',3'-bis-O-silylated or -acylated derivatives of lead compound 3a (2',3'-bis-O-tert-butyl-dimethylsilyl-5'-deoxy-5'-(N-methylcarbamoyl)amino-N-6-(N-phenylcarbamoyl)adenosine) were prepared and evaluated for antiproliferative activity against a panel of murine and human cancer cell lines (L1210, FM3A, CEM, and HeLa). 2',3'-O-Silyl groups investigated included triethylsilyl (10a), tert-butyldiphenylsilyl (10b), and triisopropylsilyl (10c). 2',3'-O-Acyl groups investigated included acetyl (13a), benzoyl (13b), isobutyryl (13c), butanoyl (13d), pivaloyl (13e), hexanoyl (13f), octanoyl (13g), decanoyl (13h), and hexadecanoyl (13i). IC50 values ranged from 3.0 +/- 0.3 to > 200 mu g/mL, with no improvement relative to lead compound 3a. Derivative 10a was approximately equipotent to 3a, while compounds 13e-g were from three to fivefold less potent, and all other compounds were significantly much less active. A desilylated derivative (5'-deoxy-5'-(N-methylcarbamoyl) amino-N-6-(N-phenylcarbamoyl) adenosine; 5) and several representative derivatives from each subgroup (10a-10c, 13a-13c) were screened for binding affinity for bone morphogenetic protein receptor 1b (BMPR1b). Only compound 5 showed appreciable affinity (K-d = 11.7 +/- 0.5 mu M), consistent with the inference that 3a may act as a prodrug depot form of the biologically active derivative 5. Docking studies (Surflex Dock, Sybyl X 1.3) for compounds 3a and 5 support this conclusion. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.08.050
• 作为产物：
  描述：

  5'-deoxy-2',3'-O,O-isopropylidene-5'-[(N-methylcarbamoyl)amino]-N6-(N-phenylcarbamoyl)adenosine 在 水 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以75%的产率得到5'-deoxy-5'-[(N-methylcarbamoyl)amino]-N6-(N-phenylcarbamoyl)adenosine
  参考文献：
  名称：

  SomeN6, 5'-bis-ureido 5'-Amino-5'-Deoxyadenosine 衍生物的抗增殖和蛋白激酶结合活性

  摘要：

  两种新型 N6,5'-双脲基 5'-氨基-5'-脱氧腺苷衍生物显示可抑制 NCI 60 人肿瘤细胞组中的肿瘤细胞生长。化合物 2c 和 2d 分别在 35 和 14 个细胞系中表现出 1-6 μM 的 GI50 值。化合物 2c 显示通过竞争性结合测定选择性抑制蛋白激酶与固定化 ATP 结合位点配体的结合（353 种蛋白激酶中的 11 种在 10 μM 化合物浓度下被抑制≥30%）。酶抑制试验揭示了对 PAK4 和 FMS 的适度抑制（分别为 21% 和 17%）。一项简短的 SAR 研究表明，2'-O-TBDMS 是抗增殖活性所必需的。

  DOI：

  10.1080/15257770903044432

文献信息

• Synthesis and SAR of 2′,3′-bis-O-substituted N6, 5′-bis-ureidoadenosine derivatives: Implications for prodrug delivery and mechanism of action
  作者：Jadd R. Shelton、Christopher E. Cutler、Megan S. Browning、Jan Balzarini、Matt A. Peterson

  DOI：10.1016/j.bmcl.2012.08.050

  日期：2012.10

  A series of 2',3'-bis-O-silylated or -acylated derivatives of lead compound 3a (2',3'-bis-O-tert-butyl-dimethylsilyl-5'-deoxy-5'-(N-methylcarbamoyl)amino-N-6-(N-phenylcarbamoyl)adenosine) were prepared and evaluated for antiproliferative activity against a panel of murine and human cancer cell lines (L1210, FM3A, CEM, and HeLa). 2',3'-O-Silyl groups investigated included triethylsilyl (10a), tert-butyldiphenylsilyl (10b), and triisopropylsilyl (10c). 2',3'-O-Acyl groups investigated included acetyl (13a), benzoyl (13b), isobutyryl (13c), butanoyl (13d), pivaloyl (13e), hexanoyl (13f), octanoyl (13g), decanoyl (13h), and hexadecanoyl (13i). IC50 values ranged from 3.0 +/- 0.3 to > 200 mu g/mL, with no improvement relative to lead compound 3a. Derivative 10a was approximately equipotent to 3a, while compounds 13e-g were from three to fivefold less potent, and all other compounds were significantly much less active. A desilylated derivative (5'-deoxy-5'-(N-methylcarbamoyl) amino-N-6-(N-phenylcarbamoyl) adenosine; 5) and several representative derivatives from each subgroup (10a-10c, 13a-13c) were screened for binding affinity for bone morphogenetic protein receptor 1b (BMPR1b). Only compound 5 showed appreciable affinity (K-d = 11.7 +/- 0.5 mu M), consistent with the inference that 3a may act as a prodrug depot form of the biologically active derivative 5. Docking studies (Surflex Dock, Sybyl X 1.3) for compounds 3a and 5 support this conclusion. (C) 2012 Elsevier Ltd. All rights reserved.
• Antiproliferative and Protein Kinase Binding Activities of Some <i>N</i> ⁶, 5′-bis-ureido 5′-Amino-5′-Deoxyadenosine Derivatives
  作者：Matt A. Peterson、Marcelio Oliveira、Michael A. Christiansen

  DOI：10.1080/15257770903044432

  日期：2009.8.11

  Two novel N6,5′-bis-ureido 5′-amino-5′-deoxyadenosine derivatives are shown to inhibit tumor cell growth in the NCI 60 human tumor cell panel. Compounds 2c and 2d exhibited GI50 values of 1–6 μM in 35 and 14 cell lines, respectively. Compound 2c was shown to selectively inhibit binding of protein kinases to immobilized ATP-binding site ligands via a competitive binding assay (11 of 353 protein kinases

  两种新型 N6,5'-双脲基 5'-氨基-5'-脱氧腺苷衍生物显示可抑制 NCI 60 人肿瘤细胞组中的肿瘤细胞生长。化合物 2c 和 2d 分别在 35 和 14 个细胞系中表现出 1-6 μM 的 GI50 值。化合物 2c 显示通过竞争性结合测定选择性抑制蛋白激酶与固定化 ATP 结合位点配体的结合（353 种蛋白激酶中的 11 种在 10 μM 化合物浓度下被抑制≥30%）。酶抑制试验揭示了对 PAK4 和 FMS 的适度抑制（分别为 21% 和 17%）。一项简短的 SAR 研究表明，2'-O-TBDMS 是抗增殖活性所必需的。