N-(2-amino-6-methyl-pyridin-3-ylmethyl)-N-{2-[2-[(2-amino-6-methyl-pyridin-3-ylmethyl)-formyl-amino]-1-(2-hydroxyethyl)-propenyldisulfanyl]-4-hydroxy-1-methyl-but-1-enyl}-formamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: N-(2-amino-6-methyl-pyridin-3-ylmethyl)-N-{2-[2-[(2-amino-6-methyl-pyridin-3-ylmethyl)-formyl-amino]-1-(2-hydroxyethyl)-propenyldisulfanyl]-4-hydroxy-1-methyl-but-1-enyl}-formamide
• 英文别名: N-(2-amino-6-methylpyridin-3-ylmethyl)-N-{2-[2-[(2-amino-6-methylpyridin-3-ylmethyl)formylamino]-1-(2-hydroxyethyl)propenyldisulfanyl]-4-hydroxy-1-methylbut-1-enyl}formamide；N-(2-amino-6-methyl-pyridin-3-ylmethyl)-N-{2-[2-[(2-amino-6-methyl-pyridin-3-ylmethyl)-formyl-amino]-1-(2-hydroxy-ethyl)-propenyldisulfanyl]-4-hydroxy-1-methyl-but-1-enyl}-formamide；N-[(2-amino-6-methylpyridin-3-yl)methyl]-N-[(Z)-3-[[(Z)-2-[(2-amino-6-methylpyridin-3-yl)methyl-formylamino]-5-hydroxypent-2-en-3-yl]disulfanyl]-5-hydroxypent-2-en-2-yl]formamide
• 化学式: C₂₆H₃₆N₆O₄S₂
• 分子量: 560.742
• InChiKey: CIXZEXIARPVKCP-SRPFLQSCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  38
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  210
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N-(2-amino-6-methyl-pyridin-3-ylmethyl)-N-{2-[2-[(2-amino-6-methyl-pyridin-3-ylmethyl)-formyl-amino]-1-(2-hydroxyethyl)-propenyldisulfanyl]-4-hydroxy-1-methyl-but-1-enyl}-formamide 以 仲丁醇 为溶剂， 反应 2.0h， 生成 3-[(2-Amino-6-methylpyridin-3-yl)methyl]-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-2-one
  参考文献：
  名称：

  Non-charged thiamine analogs as inhibitors of enzyme transketolase

  摘要：

  Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.11.098
• 作为产物：
  描述：

  3-[(2-氨基-6-甲基-3-吡啶基)甲基]-5-(2-羟基乙基)-4-甲基噻唑鎓氯化物盐酸盐 在 sodium hydroxide 、 potassium ferricyanide 、 水 作用下， 反应 0.02h， 以83%的产率得到N-(2-amino-6-methyl-pyridin-3-ylmethyl)-N-{2-[2-[(2-amino-6-methyl-pyridin-3-ylmethyl)-formyl-amino]-1-(2-hydroxyethyl)-propenyldisulfanyl]-4-hydroxy-1-methyl-but-1-enyl}-formamide
  参考文献：
  名称：

  [EN] THIOALKENEAMIDES AS TRANSKETOLASE INHIBITORS
  [FR] THIOALKENEAMIDES TENANT LIEU D'INHIBITEURS DE TRANSKETOLASE

  摘要：

  本发明提供了式(I)的硫代烯酰胺，其可用作转酮醇酶抑制剂：其中R1、R2、R3、R4、R5、R6、Ra-Rd、n和环A如本文所定义。本发明还提供了包括式(I)化合物的药物组合物。该发明提供了抑制转酮醇酶活性、降低细胞核糖-5-磷酸水平、抑制核酸合成、抑制体外和体内细胞增殖和肿瘤细胞生长、刺激肿瘤细胞凋亡以及通过给予式(I)的化合物或其药物组合物来治疗癌症的方法。

  公开号：

  WO2005095344A1

文献信息

• [EN] THIOALKENEAMIDES AS TRANSKETOLASE INHIBITORS<br/>[FR] THIOALKENEAMIDES TENANT LIEU D'INHIBITEURS DE TRANSKETOLASE
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2005095344A1

  公开（公告）日：2005-10-13

  The present invention provides thioalkeneamides of formula (I) which are useful as transketolase inhibitors: wherein R1, R2, R3, R4, R5, R6, Ra-Rd, n and ring A are as defined herein. The present invention also provides pharmaceutical compositions comprising the compounds of formula (I). The invention provides methods for inhibiting transketolase activity, reducing cellular ribose-5-phosphate levels, inhibiting nucleic acid synthesis, inhibiting cell proliferation and tumor cell growth in vitro and in vivo, stimulating apoptosis in tumor cells and treating cancer by administering a compound of formula (I) or a pharmaceutical composition thereof.

  本发明提供了式(I)的硫代烯酰胺，其可用作转酮醇酶抑制剂：其中R1、R2、R3、R4、R5、R6、Ra-Rd、n和环A如本文所定义。本发明还提供了包括式(I)化合物的药物组合物。该发明提供了抑制转酮醇酶活性、降低细胞核糖-5-磷酸水平、抑制核酸合成、抑制体外和体内细胞增殖和肿瘤细胞生长、刺激肿瘤细胞凋亡以及通过给予式(I)的化合物或其药物组合物来治疗癌症的方法。
• Thioalkeneamides as Transketolase Inhibitors
  申请人：Boyd A. Steven

  公开号：US20070293501A1

  公开（公告）日：2007-12-20

  The present invention provides thioalkeneamides of formula (I) which are useful as transketolase inhibitors: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a -R d , n and ring A are as defined herein. The present invention also provides pharmaceutical compositions comprising the compounds of formula (I). The invention provides methods for inhibiting transketolase activity, reducing cellular ribose-5-phosphate levels, inhibiting nucleic acid synthesis, inhibiting cell proliferation and tumor cell growth in vitro and in vivo, stimulating apoptosis in tumor cells and treating cancer by administering a compound of formula (I) or a pharmaceutical composition thereof.

  本发明提供了式(I)的硫代烯酰胺，其可用作转酮醇酸酶抑制剂：其中R1、R2、R3、R4、R5、R6、Ra-Rd、n和环A的定义如本文所述。本发明还提供了包括式(I)化合物的药物组合物。本发明提供了通过给予式(I)化合物或其药物组合物来抑制转酮醇酸酶活性、降低细胞核糖-5-磷酸水平、抑制核酸合成、抑制体外和体内细胞增殖和肿瘤细胞生长、刺激肿瘤细胞凋亡和治疗癌症的方法。
• US7879885B2
  申请人：——

  公开号：US7879885B2

  公开（公告）日：2011-02-01
• Non-charged thiamine analogs as inhibitors of enzyme transketolase
  作者：Allen A. Thomas、J. De Meese、Y. Le Huerou、Steven A. Boyd、Todd T. Romoff、Steven S. Gonzales、Indrani Gunawardana、Tomas Kaplan、Francis Sullivan、Kevin Condroski、Joseph P. Lyssikatos、Thomas D. Aicher、Josh Ballard、Bryan Bernat、Walter DeWolf、May Han、Christine Lemieux、Darin Smith、Solly Weiler、S. Kirk Wright、Guy Vigers、Barb Brandhuber

  DOI：10.1016/j.bmcl.2007.11.098

  日期：2008.1

  Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented. (c) 2007 Elsevier Ltd. All rights reserved.
• Prodrug thiamine analogs as inhibitors of the enzyme transketolase
  作者：Yvan Le Huerou、Indrani Gunawardana、Allen A. Thomas、Steven A. Boyd、Jason de Meese、Walter deWolf、Steven S. Gonzales、May Han、Laura Hayter、Tomas Kaplan、Christine Lemieux、Patrice Lee、Jed Pheneger、Gregory Poch、Todd T. Romoff、Francis Sullivan、Solly Weiler、S. Kirk Wright、Jie Lin

  DOI：10.1016/j.bmcl.2007.11.100

  日期：2008.1

  Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and C-max linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported. (c) 2007 Elsevier Ltd. All rights reserved.