(4S)-4,11-二乙基-3,4,12,14-四氢-4-羟基-3,14-二氧代-1H-吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-9-基-beta-D-吡喃葡糖苷酸 | 121080-63-5

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 喜树碱
• 中文名称: (4S)-4,11-二乙基-3,4,12,14-四氢-4-羟基-3,14-二氧代-1H-吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-9-基-beta-D-吡喃葡糖苷酸
• 中文别名: SN-38葡萄糖醛酸苷；SN-38葡糖苷酸
• 英文名称: SN-38 glucuronide
• 英文别名: 7-ethyl-10-hydroxycamptothecin glucuronide；SN-38, C10-(β)-glucuronide；SN-38 G；SN-38；SN-38 glucuronide (lactone)；SN38 β-D-glucuronide；SN38 glucuronide；(2S,3S,4S,5R,6S)-6-[[(19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-7-yl]oxy]-3,4,5-trihydroxyoxane-2-carboxylic acid
• CAS: 121080-63-5
• 化学式: C₂₈H₂₈N₂O₁₁
• 分子量: 568.537
• InChiKey: SSJQVDUAKDRWTA-CAYKMONMSA-N

物化性质

• 熔点：
  >250°C (dec.)
• 沸点：
  1019.7±65.0 °C(Predicted)
• 密度：
  1.67±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  41
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  196
• 氢给体数：
  5
• 氢受体数：
  12

制备方法与用途

SN-38葡糖苷酸是癌症药物伊立替康的一种非活性代谢产物。伊立替康是一种拓扑异构酶I抑制剂，常用于研究结肠癌和直肠癌。

反应信息

• 作为反应物：
  描述：

  (4S)-4,11-二乙基-3,4,12,14-四氢-4-羟基-3,14-二氧代-1H-吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-9-基-beta-D-吡喃葡糖苷酸 以 phosphate buffer 为溶剂， 以99%的产率得到SN 38 carboxylate glucuronide
  参考文献：
  名称：

  Chu, Xiao-Yan; Kato, Yukio; Niinuma, Kayoko, Journal of Pharmacology and Experimental Therapeutics, 1997, vol. 281, # 1, p. 304 - 314

  摘要：

  DOI：
• 作为产物：
  描述：

  7-乙基-10-羟基喜树碱 在 sodium hydroxide 、 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 8.0h， 生成 (4S)-4,11-二乙基-3,4,12,14-四氢-4-羟基-3,14-二氧代-1H-吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-9-基-beta-D-吡喃葡糖苷酸
  参考文献：
  名称：

  Chemical Modification of an Antitumor Alkaloid, 20(S)-Camptothecin: Glycosides, Phosphates and Sulfates of 7-Ethyl-10-hydroxycamptothecin.

  摘要：

  从 7-乙基-10-羟基喜树碱（1）开始，合成了内酯环完整的水溶性衍生物。1 的酚羟基糖苷（2）是在丙酮或丙酮水溶液中，在碳酸钾的存在下，与乙酰化的 α-溴糖反应，然后进行脱保护而得到的。单磷酸盐（3p）和硫酸盐（4a 和 4b）的有机铵盐对体内的 L1210 具有显著的活性。

  DOI：

  10.1248/cpb.40.131

文献信息

• Human liver UDP-glucuronosyltransferase isoforms involved in the glucuronidation of 7-ethyl-10-hydroxycamptothecin
  作者：N. Hanioka、S. Ozawa、H. Jinno、M. Ando、Y. Saito、J. Sawada

  DOI：10.1080/00498250110057341

  日期：2001.1

  1. The human liver UDP-glucuronosyltransferase (UGT) isoforms involved in the glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan (CPT-11), have been studied using microsomes from human liver and insect cells expressing human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B15).2. The glucuronidation of SN-38 was catalysed by UGT1A1, UGT1A3, UGT1A6 and UGT1A9 as well as by liver microsomes. Among these UGT isoforms, UGT1A1 showed the highest activity of SN-38 glucuronidation at both low (1 muM) and high (200 muM) substrate concentrations. The ranking in order of activity at low and high substrate concentrations was UGT1A1 > UGT1A9 > UGT1A6 > UGT1A3 and UGT1A1 > UGT1A3 > UGT1A6 greater than or equal to UGT1A9, respectively.3. The enzyme kinetics of SN-38 glucuronidation were examined by means of Lineweaver-Burk analysis. The activity of the glucuronidation in liver microsomes exhibits a monophasic kinetic pattern, with an apparent K-m and V-max of 35.9 muM and 134 pmol min(-1) mg(-1) protein, respectively. The UGT isoforms involved in SN-38 glucuronidation could be classified into two types: low-K-m types such as UGT1A1 and UGT1A9, and high-K-m types such as UGT1A3 and UGT1A6, in terms of affinity toward substrate. UGT1A1 had the highest V-max followed by UGT1A3. V-max of UGT1A6 and UGT1A9 were approximately 1/9 to 1/12 of that of UGT1A1.4. The activity of SN-38 glucuronidation by liver microsomes and UGT1A1 was effectively inhibited by bilirubin. Planar and bulky phenols substantially inhibited the SN-38 glucuronidation activity of liver microsomes and UGT1A9, and/or UGT1A6. Although cholic acid derivatives strongly inhibited the activity of SN-38 glucuronidation by UGT1A3, the inhibition profile did not parallel that in liver microsomes.5. These results demonstrate that at least four UGT1A isoforms are responsible for SN-38 glucuronidation in human livers, and suggest that the role and contribution of each differ substantially.
• Chemical Modification of an Antitumor Alkaloid, 20(S)-Camptothecin: Glycosides, Phosphates and Sulfates of 7-Ethyl-10-hydroxycamptothecin.
  作者：Takashi YAEGASHI、Ken-ichiro NOKATA、Seigo SAWADA、Tomio FURUTA、Teruo YOKOKURA、Tadasi MIYASAKA

  DOI：10.1248/cpb.40.131

  日期：——

  Water-soluble derivatives having the lactone ring intact were synthesized starting from 7-ethyl-10-hydroxycamptothecin (1). Glycosides (2) of the phenolic hydroxyl group of 1 were obtained by reaction with acetylated α-bromosugars in acetone or aqueous acetone in the presence of potassium carbonate, followed by deprotection.Phosphates (3) were prepared by reaction of 1 with phosphoryl chloride in pyridine or with dibenzylchlorophosphoridate.Sulfates (4) were obtained by reaction of 1 with sulfur trioxide-pyridine complex in the presence of a tertiary amine.The organic ammonium salts of monophosphate (3p) and sulfates (4a and 4b) showed significant activity against L1210 in vivo.

  从 7-乙基-10-羟基喜树碱（1）开始，合成了内酯环完整的水溶性衍生物。1 的酚羟基糖苷（2）是在丙酮或丙酮水溶液中，在碳酸钾的存在下，与乙酰化的 α-溴糖反应，然后进行脱保护而得到的。单磷酸盐（3p）和硫酸盐（4a 和 4b）的有机铵盐对体内的 L1210 具有显著的活性。
• Chu, Xiao-Yan; Kato, Yukio; Niinuma, Kayoko, Journal of Pharmacology and Experimental Therapeutics, 1997, vol. 281, # 1, p. 304 - 314
  作者：Chu, Xiao-Yan、Kato, Yukio、Niinuma, Kayoko、Sudo, Ken-Ichi、Hakusui, Hideo、Sugiyama, Yuichi

  DOI：——

  日期：——