2-[[4-[4-[4-[3,5-dihydroxy-4-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5,6-trihydroxyoxan-2-yl]methoxy]-6-(hydroxymethyl)oxane-3,4,5-triol | 37339-90-5

• 物质功能分类: 生物化工 - 生物反应调节剂
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-[[4-[4-[4-[3,5-dihydroxy-4-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5,6-trihydroxyoxan-2-yl]methoxy]-6-(hydroxymethyl)oxane-3,4,5-triol
• CAS: 37339-90-5
• 化学式: C₄₂H₇₂O₃₆
• 分子量: 1153.0
• InChiKey: MAXBMUKIXLNXGX-UHFFFAOYSA-N

物化性质

• 比旋光度：
  D20 +13.5-14.5° (in 2% NaOH); +19.5-21.5° (in 10% NaOH)
• 溶解度：
  0.1 M NaOH：33.33（最大浓度 mg/mL）；28.91（最大浓度 mM）
• LogP：
  -12.265 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  -13.3
• 重原子数：
  78
• 可旋转键数：
  19
• 环数：
  7.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  585
• 氢给体数：
  23
• 氢受体数：
  36

制备方法与用途

香菇多糖的化学性质、用途及生产方法 化学性质：

• 白色粉末，在250℃分解。
• 无臭或略有异臭，无味。
• 溶于碱溶液或甲酸，微溶于热水或二甲亚砜，不溶于冷水、醇、乙醚、氯仿、吡啶或六甲基磷酰胺。
• 对硫酸和盐酸稳定。
• 光学性质：[α]D20+13.5°～+14.5°（2%氢氧化钠）；[α]D20+19.5°～+21.5°（10％氢氧化钠）。

用途：

• 免疫增强剂。
• 可用于不能手术或复发的胃癌患者。
• 与化疗药物并用，用于胃肠道肿瘤患者时可使生存时间延长，防止白细胞减少或血清总蛋白降低。
• 对慢性乙型病毒性肝炎有一定疗效，能明显改善患者的症状，使血清谷丙转氨酶恢复正常或好转，并调整免疫功能。

注意事项：

• 偶发过敏性休克、白细胞和血红蛋白减少等症状。
• 儿童及妊娠和育龄妇女应慎用。

生产方法：

1. 提取：200kg新鲜蘑菇经水洗净，粉碎混合，用1000L沸水提取8～15h。
2. 过滤分离：得到的悬浮液过滤或离心分离以除去不溶物。
3. 浓缩与结晶：水溶液减压浓缩至出现微混浊，加入等体积乙醇。过滤或离心分离收集沉淀，得320g含香菇多糖的组分。
4. 碱性沉淀：
   • 取50g该组分悬浮于2L水中，在室温下混合使形成均匀粘稠的棕色溶液。然后加入20L水搅拌1-2h得到澄清均匀的溶液。
   • 在剧烈搅拌下，滴加0.2mol/L CTA-OH（pH值13.2）至pH值7～8出现絮状沉淀，在pH值10.5～11.5时出现大量白色沉淀。滴加0.2mol/L CTA-OH直至再无沉淀出现为止，此时溶液的pH值约为12.8。
   • 离心分离收集所有沉淀，用乙醇洗。
5. 酸性沉淀：将其悬浮于1.2L 20%乙酸，在0℃搅拌5min。过滤收集沉淀，并与1L 50%乙酸在0℃搅拌3min。离心分离收集沉淀，然后将其溶于2L 6%氢氧化钠水溶液中。
6. 洗涤与干燥：离心分离除去杂质后加入4L乙醇。收集出现的沉淀，用乙醇洗2次，再用乙醚洗1次，在室温和氯化钙存在下真空干燥。得香菇多糖粉末。
7. 纯化：通过Sevag方法以氯仿和1-丁醇展开，并加入3倍体积的乙醇使之沉淀。收集沉淀后用甲醇洗2次，乙醚洗1次，在室温与氯化钙存在下真空干燥。

从200kg原料中可提取得到约31g香菇多糖。

反应信息

• 作为反应物：
  描述：

  1-溴-2-氟乙烷 、 2-[[4-[4-[4-[3,5-dihydroxy-4-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5,6-trihydroxyoxan-2-yl]methoxy]-6-(hydroxymethyl)oxane-3,4,5-triol 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-cyclopropyl-5-(4-(2-fluoroethoxy)-2-methyl-1H-benzo[d]imidazol-1-yl)thiophene-2-carboxamide
  参考文献：
  名称：

  Optimization of Potent Inhibitors of P. falciparum Dihydroorotate Dehydrogenase for the Treatment of Malaria

  摘要：

  Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidate.

  DOI：

  10.1021/ml200143c
• 作为产物：
  描述：

  5-氨基噻吩-2-甲酸甲酯 在 tris-(dibenzylideneacetone)dipalladium(0) 、 氯化亚砜 、 20 % Pd(OH)2/C 、 水 、 氢气 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 乙醇 、 1,2-二氯乙烷 为溶剂， 反应 6.0h， 生成 2-[[4-[4-[4-[3,5-dihydroxy-4-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5,6-trihydroxyoxan-2-yl]methoxy]-6-(hydroxymethyl)oxane-3,4,5-triol
  参考文献：
  名称：

  Optimization of Potent Inhibitors of P. falciparum Dihydroorotate Dehydrogenase for the Treatment of Malaria

  摘要：

  Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidate.

  DOI：

  10.1021/ml200143c

文献信息

• Optimization of Potent Inhibitors of <i>P. falciparum</i> Dihydroorotate Dehydrogenase for the Treatment of Malaria
  作者：Renato T. Skerlj、Cecilia M. Bastos、Michael L. Booker、Martin L. Kramer、Robert H. Barker、Cassandra A. Celatka、Thomas J. O’Shea、Benito Munoz、Amar Bir Sidhu、Joseph F. Cortese、Sergio Wittlin、Petros Papastogiannidis、Inigo Angulo-Barturen、Maria Belen Jimenez-Diaz、Edmund Sybertz

  DOI：10.1021/ml200143c

  日期：2011.9.8

  Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidate.