(R)-2-(2,6-dioxo-piperidin-3-yl)-5-hydroxy-isoindole-1,3-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: (R)-2-(2,6-dioxo-piperidin-3-yl)-5-hydroxy-isoindole-1,3-dione
• 英文别名: (R)-5-hydroxythalidomide；(R)-HYydroxythalidomide；2-[(3R)-2,6-dioxopiperidin-3-yl]-5-hydroxyisoindole-1,3-dione
• 化学式: C₁₃H₁₀N₂O₅
• 分子量: 274.233
• InChiKey: LJBQRRQTZUJWRC-SECBINFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  反应停 在 D-葡萄糖-6-磷酸 、 yeast glucose 6-phosphate dehydrogenase 、 human P₄₅₀ 2C₁₉ 、 烟酰胺腺嘌呤双核苷酸磷酸盐 作用下， 生成 (R)-2-(2,6-dioxo-piperidin-3-yl)-5-hydroxy-isoindole-1,3-dione
  参考文献：
  名称：

  Human Liver Microsomal Cytochrome P450 3A Enzymes Involved in Thalidomide 5-Hydroxylation and Formation of a Glutathione Conjugate

  摘要：

  (R)-Thalidomide was oxidized to 5-hydroxythalidomide and 5'-hydroxythalidomide by NADPH-fortified liver microsomes from humans and monkeys. (R)-Thalidomide was hydroxylated more efficiently than (S)-thalidomide. Recombinant human P450s 3A4, 3A5, and 3A7 and monkey P450s 3A8 and 3A5 (coexpressed with NADPH-P450 reductase in bacterial membranes) also catalyzed (R)-thalidomide 5-hydroxylation. Purified human P450s 2C19, 3A4, and 3A5 mediated (R)-thalidomide 5-hydroxylation at similar rates in reconstituted systems. P450 2C19 showed a rather nonsaturable substrate-velocity curve; however, P450s 3A4 and 3A5 showed sigmoidal curves. P450 also oxidized 5-hydroxythalidomide to an epoxide or dihydroxy compound. Liquid chromatography mass spectrometry analysis revealed the formation of a glutathione conjugate from (R)- and (S)-5-hydroxythalidomide, catalyzed by liver microsomal P450s 3A4 and 3A5 in the presence of glutathione (assigned as a conjugate of 5-hydroxythalidomide formed on the phenyl ring). These results indicate that human P450s 3A4 and 3A5 mediate thalidomide 5-hydroxylation and further oxidation leading to a glutathione conjugate, which may he of relevance in the pharmacological and toxicological actions of thalidomide.

  DOI：

  10.1021/tx900367p

文献信息

• Synthesis, configurational stability and stereochemical biological evaluations of (S)- and (R)-5-hydroxythalidomides
  作者：Takeshi Yamamoto、Norio Shibata、Daisuke Sukeguchi、Masayuki Takashima、Shuichi Nakamura、Takeshi Toru、Nozomu Matsunaga、Hideaki Hara、Motohiro Tanaka、Tohru Obata、Takuma Sasaki

  DOI：10.1016/j.bmcl.2009.02.108

  日期：2009.7

  The first asymmetric synthesis of (S)- and (R)-5-hydroxythalidomides, one of thalidomide’s major metabolites, was achieved using HMDS/ZnBr2-induced imidation as a key reaction. 5-Hydroxythalidomide was found to be configurationally more stable than thalidomide at physiological pH. Stereochemical biological effects of thalidomide and 5-hydroxythalidomide on anti-angiogenesis and antitumor activities

  沙利度胺的主要代谢产物之一（S）-和（R）-5-羟基沙利度胺的首次不对称合成是使用HMDS / ZnBr 2诱导的酰亚胺化为关键反应而实现的。发现5-羟基沙利度胺在生理pH下比沙利度胺在结构上更稳定。还使用外消旋和纯对映体研究了沙利度胺和5-羟基沙利度胺对抗血管生成和抗肿瘤活性的立体化学生物学作用。
• Human Liver Microsomal Cytochrome P450 3A Enzymes Involved in Thalidomide 5-Hydroxylation and Formation of a Glutathione Conjugate
  作者：Goutam Chowdhury、Norie Murayama、Yusuke Okada、Yasuhiro Uno、Makiko Shimizu、Norio Shibata、F. Peter Guengerich、Hiroshi Yamazaki

  DOI：10.1021/tx900367p

  日期：2010.6.21

  (R)-Thalidomide was oxidized to 5-hydroxythalidomide and 5'-hydroxythalidomide by NADPH-fortified liver microsomes from humans and monkeys. (R)-Thalidomide was hydroxylated more efficiently than (S)-thalidomide. Recombinant human P450s 3A4, 3A5, and 3A7 and monkey P450s 3A8 and 3A5 (coexpressed with NADPH-P450 reductase in bacterial membranes) also catalyzed (R)-thalidomide 5-hydroxylation. Purified human P450s 2C19, 3A4, and 3A5 mediated (R)-thalidomide 5-hydroxylation at similar rates in reconstituted systems. P450 2C19 showed a rather nonsaturable substrate-velocity curve; however, P450s 3A4 and 3A5 showed sigmoidal curves. P450 also oxidized 5-hydroxythalidomide to an epoxide or dihydroxy compound. Liquid chromatography mass spectrometry analysis revealed the formation of a glutathione conjugate from (R)- and (S)-5-hydroxythalidomide, catalyzed by liver microsomal P450s 3A4 and 3A5 in the presence of glutathione (assigned as a conjugate of 5-hydroxythalidomide formed on the phenyl ring). These results indicate that human P450s 3A4 and 3A5 mediate thalidomide 5-hydroxylation and further oxidation leading to a glutathione conjugate, which may he of relevance in the pharmacological and toxicological actions of thalidomide.