N⁶-(2,3-dimethylbenzyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine

• 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: N⁶-(2,3-dimethylbenzyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine
• 英文别名: N-[(2R,3R,4S,5R)-2-[6-[(2,3-dimethylphenyl)methylamino]purin-9-yl]-4-hydroxy-5-(hydroxymethyl)oxolan-3-yl]-3-methoxybenzamide
• 化学式: C₂₇H₃₀N₆O₅
• 分子量: 518.572
• InChiKey: DHCRXJUAWSNOPW-AERZDHHNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  144
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  间甲氧基苯甲酰氯 在 吡啶 、 氟化铵 、 异丙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 41.0h， 生成 N⁶-(2,3-dimethylbenzyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine
  参考文献：
  名称：

  Selective Tight Binding Inhibitors of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase via Structure-Based Drug Design

  摘要：

  Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the sleeping sickness parasite Trypanosoma brucei is a rational target for anti-trypanosomatid drug design because glycolysis provides virtually all of the energy for the bloodstream form of this parasite. Glycolysis is also an important source of energy for other pathogenic parasites including Trypanosoma cruzi and Leishmania mexicana. The current study is a continuation of our efforts to use the X-ray structures of T. brucei and L. mexicana GAPDHs containing bound NAD(+) to design adenosine analogues that bind tightly to the enzyme pocket that accommodates the adenosyl moiety of NAD(+). The goal was to improve the affinity, selectivity, and solubility of previously reported 2'-deoxy-2'-(3-methoxybenzamido)adenosine (1). It was found that introduction of hydroxyl functions on the benzamido ring increases solubility without significantly affecting enzyme inhibition. Modifications at the previously unexploited N-6-position of the purine not only lead to a substantial increase in inhibitor potency but are also compatible with the 2'-benzamido moiety of the sugar. For N-6-substituted adenosines, two successive rounds of modeling and screening provided a 330-fold gain in affinity versus that of adenosine. The combination of N-6- and 2'-substitutions produced significantly improved inhibitors. N-6-Benzyl (9a) and N-6-2-methylbenzyl (9b) derivatives of 1 display IC50 values against L. mexicana GAPDH of 16 and 4 mu M, respectively (3100- and 12500-fold more potent than adenosine). The adenosine analogues did not inhibit human GAPDH. These studies underscore the usefulness of structure-based drug design for generating potent and species-selective enzyme inhibitors of medicinal importance starting from a weakly binding lead compound.

  DOI：

  10.1021/jm9802620

文献信息

• Selective Tight Binding Inhibitors of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase via Structure-Based Drug Design
  作者：Alex M. Aronov、Christophe L. M. J. Verlinde、Wim G. J. Hol、Michael H. Gelb

  DOI：10.1021/jm9802620

  日期：1998.11.1

  Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the sleeping sickness parasite Trypanosoma brucei is a rational target for anti-trypanosomatid drug design because glycolysis provides virtually all of the energy for the bloodstream form of this parasite. Glycolysis is also an important source of energy for other pathogenic parasites including Trypanosoma cruzi and Leishmania mexicana. The current study is a continuation of our efforts to use the X-ray structures of T. brucei and L. mexicana GAPDHs containing bound NAD(+) to design adenosine analogues that bind tightly to the enzyme pocket that accommodates the adenosyl moiety of NAD(+). The goal was to improve the affinity, selectivity, and solubility of previously reported 2'-deoxy-2'-(3-methoxybenzamido)adenosine (1). It was found that introduction of hydroxyl functions on the benzamido ring increases solubility without significantly affecting enzyme inhibition. Modifications at the previously unexploited N-6-position of the purine not only lead to a substantial increase in inhibitor potency but are also compatible with the 2'-benzamido moiety of the sugar. For N-6-substituted adenosines, two successive rounds of modeling and screening provided a 330-fold gain in affinity versus that of adenosine. The combination of N-6- and 2'-substitutions produced significantly improved inhibitors. N-6-Benzyl (9a) and N-6-2-methylbenzyl (9b) derivatives of 1 display IC50 values against L. mexicana GAPDH of 16 and 4 mu M, respectively (3100- and 12500-fold more potent than adenosine). The adenosine analogues did not inhibit human GAPDH. These studies underscore the usefulness of structure-based drug design for generating potent and species-selective enzyme inhibitors of medicinal importance starting from a weakly binding lead compound.