依维莫司杂质DCP | 147438-27-5

• 物质功能分类: 分析化学 - 对照品
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 依维莫司杂质DCP
• 英文名称: seco-rapamycin
• 英文别名: Seco Rapamycin；(2S)-1-[2-[(2R,3R,6S)-2-hydroxy-6-[(2S,3E,5E,7E,9S,11R,13R,14R,15E,17R,19E,21R)-14-hydroxy-22-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-2,13-dimethoxy-3,9,11,15,17,21-hexamethyl-12,18-dioxodocosa-3,5,7,15,19-pentaenyl]-3-methyloxan-2-yl]-2-oxoacetyl]piperidine-2-carboxylic acid
• CAS: 147438-27-5
• 化学式: C₅₁H₇₉NO₁₃
• 分子量: 914.187
• InChiKey: ZAVMPSVOEQNVCP-FWSQOCJKSA-N

物化性质

• 沸点：
  965.7±75.0 °C(Predicted)
• 密度：
  1.17±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  7.6
• 重原子数：
  65
• 可旋转键数：
  24
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  206
• 氢给体数：
  4
• 氢受体数：
  13

制备方法与用途

生物活性

Seco Rapamycin (Secorapamycin A) 是 Rapamycin 的开环代谢物。Seco-Rapamycin 几乎不影响 mTOR 功能。

体外研究

Disposition of Seco Rapamycin in Human Tissue Homogenates and Caco-2 Cell Monolayers. To determine whether Seco Rapamycin (D2) can be metabolized to dihydro Sirolimus (M2), 20μM Seco Rapamycin is incubated with human liver, jejunal mucosal, and Caco-2 homogenates. All of these homogenates produced M2 in an NADPH-dependent manner. Ketoconazole, at a high concentration (100μM), has no effect on the formation of M2 in any of the homogenates examined. To determine whether Seco Rapamycin can be metabolized to M2 in intact cells, 20μM Seco Rapamycin is added to Caco-2 cell monolayers. When applied to the apical compartment, little Seco Rapamycin is detected in the basolateral compartment and in the cellular fraction after 4 h. In addition, little M2 is detected. LY335979 has little effect on the distribution of Seco Rapamycin after an apical dose, although M2 became detectable in the apical compartment. In contrast, when Seco Rapamycin is applied to the basolateral compartment, both Seco Rapamycin and M2 are readily detected in the apical compartment; LY335679 decreases the flux of Seco Rapamycin to the apical compartment and increases the amount of M2 in both apical and basolateral compartments.

反应信息

• 作为反应物：
  描述：

  依维莫司杂质DCP 在 N-甲基吗啉 、 1-羟基苯并三唑 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 (2S)-N-[2-(cyclohexen-1-yl)ethyl]-1-[2-[(2R,3R,6S)-6-[(2S,3E,5E,7E,9S,11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxotrideca-3,5,7-trienyl]-2-hydroxy-3-methyloxan-2-yl]-2-oxoacetyl]piperidine-2-carboxamide
  参考文献：
  名称：

  Synthesis of secorapamycin esters and amides

  摘要：

  Secorapamycin acid has been converted to a variety of functionalized esters and amides. Sequential retroaldol/realdol reaction of a secorapamycin amide provided a truncated analog.

  DOI：

  10.1016/s0040-4039(00)76509-9
• 作为产物：
  描述：

  雷帕霉素 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 为溶剂， 反应 6.0h， 生成 依维莫司杂质DCP
  参考文献：
  名称：

  分子内离子氢键稳定开环雷帕霉素降解产物的酰胺键旋转异构体

  摘要：

  雷帕霉素 (1) 是一种大环内酯类免疫抑制剂，在生理相关条件下会降解为开环酸产物 2 和 3。在这项工作中分离和研究了不饱和产物 (3)。与在溶液中其酰胺主要呈反式构象的 1 不同，3 在二甲基亚砜 (DMSO) 中具有大约 1:1 的顺式和反式构象。在有机碱如三乙胺的存在下，顺式旋转异构体的量显着增加。详细的 NMR 结果表明，顺式旋转异构体通过羧酸根阴离子与作为九元环系统一部分的叔醇的分子内离子氢键稳定。这种氢键在有机介质中得到进一步表征，反式-顺式旋转异构体平衡用于估计几种溶剂中的相对键强度。由顺式旋转异构体中的离子氢键产生的额外稳定性被确定为 DMSO-d6 中 1.4 kcal mol-1、CD3CN 中 2.0 kcal mol-1 和 CD3OD 中 1.1 kcal mol-1。版权所有 © 2004 John Wiley & Sons, Ltd.

  DOI：

  10.1002/mrc.1501

文献信息

• Studies on the chemistry of rapamycin: Novel transformations under Lewis-acid catalysis
  作者：Juan I. Luengo、Arda L. Konialian、Dennis A. Holt

  DOI：10.1016/s0040-4039(00)77473-9

  日期：1993.2

  The reactivity of rapamycin under mild Lewis-acid catalysis has been investigated. The molecule has been found to be extremely sensitive to basic reagents due to carboxylate elimination beta to the C24 ketone. However, transformations normally effected under basic conditions, such as C-13-C-14 benzilic acid rearrangement Of C28-C30 retroaldol, can be achieved on rapamycin itself by catalysis with ZnCl2 in the appropriate solvent. These are novel transformations that circumvent the protection or masking of reactive functional groups and allow efficient degradation of the molecule for synthetic and biological studies.
• Degradation of rapamycin: Synthesis of a rapamycin derived fragment containing the tricarbonyl and triene sectors
  作者：Daniel Yohannes、Cheryl D. Myers、Samuel J. Danishefsky

  DOI：10.1016/s0040-4039(00)60349-0

  日期：1993.3

  A degradation of rapamycin involving retro-Michael and retro-aldol steps retrieves the entire C1-C27 subunit.
• Ring expanded rapamycin derivatives
  作者：Jerauld S. Skotnicki、Robert M. Kearney

  DOI：10.1016/s0040-4039(00)76510-5

  日期：1994.1

  Two ring expanded rapamycin derivatives were synthesized from secorapamycin acid via sequential conjugate addition and high dilution macrolactone (lactam) formation.
• MACROLIDE INHIBITORS OF mTOR
  申请人：Zhang Chengzhi

  公开号：US20150361120A1

  公开（公告）日：2015-12-17

  The present invention relates to new macrolide inhibitors of mTOR, pharmaceutical compositions thereof, and methods of use thereof.
• [EN] MACROLIDE INHIBITORS OF MTOR<br/>[FR] MACROLIDES INHIBITEURS DE MTOR
  申请人：AUSPEX PHARMACEUTICAL INC

  公开号：WO2011123524A2

  公开（公告）日：2011-10-06

  The present invention relates to new macrolide inhibitors of mTOR, pharmaceutical compositions thereof, and methods of use thereof (Formula I).