2-amino-3-[N-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxysulfonyl]-S-methylsulfonimidoyl]propanoic acid

• 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: 2-amino-3-[N-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxysulfonyl]-S-methylsulfonimidoyl]propanoic acid
• 化学式: C₁₄H₂₁N₇O₉S₂
• 分子量: 495.5
• InChiKey: DZGWZSGCTNTBBN-OXHMMZOSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.8
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  277
• 氢给体数：
  4
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  tert-butyl 2-(N-tert-butoxycarbonyl)amino-3-{N-[(N(6),N(6)-bis(tert-butoxycarbonyl)-2',3'-O-isopropylideneadenosin-5'-yl)-5'-O-sulfonyl]-S-methyl-sulfonimidoyl}propanoate 在 水 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 6.0h， 以71%的产率得到2-amino-3-[N-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxysulfonyl]-S-methylsulfonimidoyl]propanoic acid
  参考文献：
  名称：

  A critical electrostatic interaction mediates inhibitor recognition by human asparagine synthetase

  摘要：

  The first sulfoximine-based inhibitor of human asparagine synthetase (ASNS) with nanomolar potency has been shown to suppress proliferation of asparaginase-resistant MOLT-4 cells in the presence of L-asparaginase. This validates literature hypotheses concerning the viability of human ASNS as a target for new drugs against acute lymphoblastic leukemia and ovarian cancer. Developing structure-function relationships for this class of human ASNS inhibitors has proven diffcult, however, primarily because of the absence of rapid synthetic procedures for constructing highly functionalized sulfoximines. We now report conditions for the efficient preparation of these compounds by coupling sulfoxides and sulfamides in the presence of a rhodium catalyst. Access to this methodology has permitted the construction of two new adenylated sulfoximines, which were expected to exhibit similar binding affinity and better bioavailability than the original human ASNS inhibitor. Steady-state kinetic characterization of these compounds, however, has revealed the importance of a localized negative charge on the inhibitor that mimics that of the phosphate group in a key acyl-adenylate reaction intermediate. These experiments place an important constraint on the design of sulfoximine libraries for screening experiments to obtain ASNS inhibitors with increased potency and bioavailability. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.07.071

文献信息

• A critical electrostatic interaction mediates inhibitor recognition by human asparagine synthetase
  作者：Hideyuki Ikeuchi、Megan E. Meyer、Yun Ding、Jun Hiratake、Nigel G.J. Richards

  DOI：10.1016/j.bmc.2009.07.071

  日期：2009.9

  The first sulfoximine-based inhibitor of human asparagine synthetase (ASNS) with nanomolar potency has been shown to suppress proliferation of asparaginase-resistant MOLT-4 cells in the presence of L-asparaginase. This validates literature hypotheses concerning the viability of human ASNS as a target for new drugs against acute lymphoblastic leukemia and ovarian cancer. Developing structure-function relationships for this class of human ASNS inhibitors has proven diffcult, however, primarily because of the absence of rapid synthetic procedures for constructing highly functionalized sulfoximines. We now report conditions for the efficient preparation of these compounds by coupling sulfoxides and sulfamides in the presence of a rhodium catalyst. Access to this methodology has permitted the construction of two new adenylated sulfoximines, which were expected to exhibit similar binding affinity and better bioavailability than the original human ASNS inhibitor. Steady-state kinetic characterization of these compounds, however, has revealed the importance of a localized negative charge on the inhibitor that mimics that of the phosphate group in a key acyl-adenylate reaction intermediate. These experiments place an important constraint on the design of sulfoximine libraries for screening experiments to obtain ASNS inhibitors with increased potency and bioavailability. (C) 2009 Elsevier Ltd. All rights reserved.