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 | 13860-66-7

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 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
• 中文名称: 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
• 中文别名: 3-[(2-氨基-6-甲基-3-吡啶基)甲基]-5-(2-羟基乙基)-4-甲基噻唑氯化物盐酸盐
• 英文名称: 3-(2-amino-6-methyl-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride
• 英文别名: 3-(2-amino-6-methyl-pyridin-3-ylmethyl)-5-(2-hydroxyethyl)-4-methyl-thiazol-3-ium chloride hydrochloride；3-(2-amino-6-methylpyridin-3-ylmethyl)-5-(2-hydroxyethyl)-4-methylthiazol-3-ium chloride hydrochloride；3-(2-amino-6-methyl-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazolium; chloride hydrochloride；3-(2-amino-6-methyl-[3]pyridylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazolium; chloride-hydrochloride；3-(2-Amino-6-methyl-[3]pyridylmethyl)-5-(2-hydroxy-aethyl)-4-methyl-thiazolium; Chlorid-hydrochlorid；Thiazolium, 3-[(2-amino-6-methyl-3-pyridinyl)methyl]-5-(2-hydroxyethyl)-4-methyl-, chloride, hydrochloride (1:1:1)；2-[3-[(2-amino-6-methylpyridin-3-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl]ethanol;chloride;hydrochloride
• CAS: 13860-66-7
• 化学式: C₁₃H₁₈N₃OS*ClH*Cl
• 分子量: 336.285
• InChiKey: ZLGKCAQWOASSTP-UHFFFAOYSA-M

物化性质

• 熔点：
  225℃
• 溶解度：
  DMSO：2.86 mg/mL（8.50 mM；需要超声波）

计算性质

• 辛醇/水分配系数(LogP)：
  -1.36
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  91.3
• 氢给体数：
  3
• 氢受体数：
  5

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性方面，N3PT (N3-吡啶基硫胺素) 是一种转酮醇酶（TK）抑制剂，其对apo-TK的半数抑制浓度（IC50）为22 nM。

反应信息

• 作为反应物：
  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
• 作为产物：
  描述：

  (2-amino-6-methylpyridin-3-yl)methanol 在 氯化亚砜 、 乙醚 、 硝基甲烷 作用下， 生成 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
  参考文献：
  名称：

  Dornow; Hargesheimer, Chemische Berichte, 1953, vol. 86, p. 461,464

  摘要：

  DOI：

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。
• Studies on Pyrimidine Derivatives and Related Compounds. LXXVII. Reaction of Thiamine Analogues with Diethyl Benzoylphosphonate
  作者：AKIRA TAKAMIZAWA、HIROSHI HARADA

  DOI：10.1248/cpb.21.770

  日期：——

  Reaction of thiamine analogues (8, 14, and 17) with diethyl benzoylphosphonate (20) was carried out and an interesting difference in reactivity in aprotic solvent according to substituents and nuclei was observed.

  硫胺素类似物（8、14和17）与二乙基苯甲酰膦酸酯（20）的反应进行了研究，在非质子溶剂中观察到了根据取代基和核的不同而产生的反应活性的有趣差异。
• 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。
• 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.
• Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors
  作者：Allen A. Thomas、Y. Le Huerou、J. De Meese、Indrani Gunawardana、Tomas Kaplan、Todd T. Romoff、Stephen S. Gonzales、Kevin Condroski、Steven A. Boyd、Josh Ballard、Bryan Bernat、Walter DeWolf、May Han、Patrice Lee、Christine Lemieux、Robin Pedersen、Jed Pheneger、Greg Poch、Darin Smith、Francis Sullivan、Solly Weiler、S. Kirk Wright、Jie Lin、Barb Brandhuber、Guy Vigers

  DOI：10.1016/j.bmcl.2007.11.101

  日期：2008.3

  Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxyethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes alpha-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described. (C) 2007 Elsevier Ltd. All rights reserved.