cryptophycin 55 | 186256-69-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: cryptophycin 55
• 英文别名: (3S,10R,13E,16S)-16-[(2R,3R,4S)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6,6-dimethyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone
• CAS: 186256-69-9
• 化学式: C₃₆H₄₆Cl₂N₂O₈
• 分子量: 705.676
• InChiKey: MXZDFWPOJAPNJL-VIVUCZJBSA-N

物化性质

• 沸点：
  906.1±65.0 °C(Predicted)
• 密度：
  1.175±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  48
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  140
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  cryptophycin 55 在 potassium carbonate 作用下， 以 水 、 乙腈 为溶剂， 反应 4.0h， 以77.3%的产率得到cryptophycin 52
  参考文献：
  名称：

  Cryptophycin-55/52 based antibody-drug conjugates: Synthesis, efficacy, and mode of action studies

  摘要：

  Cryptophycin-52 (CR52), a tubulin inhibitor, exhibits promising antitumor activity in vitro (picomolar level) and in mouse xenograft models. However, the narrow therapeutic window in clinical trials limits its further development. Antibody-drug conjugate (ADC), formed by coupling cytotoxic compound (payload) to an antibody via a linker, can deliver drug to tumor locations in a targeted manner by antibody, enhancing the therapeutic effects and reducing toxic and side effects. In this study, we aim to explore the possibility of CR52-based ADC for tumor targeted therapy. Due to the lack of a coupling site in CR52, its prodrug cryptophycin-55 (CR55) containing a free hydroxyl was synthesized and conjugated to the model antibody trastuzumab (anti-HER2 antibody drug approved by FDA for breast cancer therapy) via the linkers based on Mc-NHS and Mc-Val-Cit-PAB-PNP. The average drug-to-antibody ratios (DARs) of trastuzumab-CR55 conjugates (named T-L1-CR55, T-L2-CR55, and T-L3-CR55) were 3.50, 3.29, and 3.35, respectively. These conjugates exhibited potent cytotoxicity in HER2-positive tumor cell lines with IC50 values at low nanomolar levels (0.58-1.19 nM). Further, they displayed significant antitumor activities at the doses of 10 mg/kg in established ovarian cancer (SKOV3) and gastric cancer (NCI-N87) xenograft models without overt toxicities. Finally, the drug releases were analyzed and the results indicated that T-L3-CR55 was able to effectively release CR55 and further epoxidized to CR52, which may be responsible for its best performance in antitumor activities. In conclusion, our results demonstrated that these conjugates have the potential for tumor targeted therapy, which provides insights to further research the CR55/CR52-based ADC for tumor therapy. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112364
• 作为产物：
  描述：

  cryptophycin 52 在 盐酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 2.0h， 以43 mg的产率得到cryptophycin 55
  参考文献：
  名称：

  [EN] CRYPTOPHYCIN-BASED ANTIBODY-DRUG CONJUGATES WITH NOVEL SELF-IMMOLATIVE LINKERS
  [FR] CONJUGUÉS MÉDICAMENT-ANTICORPS À BASE DE CRYPTOPHYCINE AVEC NOUVEAUX LIEURS AUTO-IMMOLABLES

  摘要：

  本发明涉及抗体或肽药物结合物，其中一个或多个隐花链霉素衍生物（大环脱氨肽）通过一种自解离连接剂共价结合到一个或多个肿瘤相关抗原或细胞表面受体上。连接剂包含蛋白酶的裂解位点和能够形成二肽环的二肽单元。这些化合物可能在癌症的诊断或治疗方法以及其他疾病和紊乱，如免疫或感染性疾病中有用。

  公开号：

  WO2016146638A1

文献信息

• Cryptophycin compounds
  申请人：Eli Lilly and Company

  公开号：US06680311B1

  公开（公告）日：2004-01-20

  The present invention provides cryptophycin compounds of Formula I that are useful in the treatment of neoplasms.

  本发明提供了一种在肿瘤治疗中有用的Formula I的cryptophycin化合物。
• [EN] NOVEL CRYPTOPHYCIN COMPOUNDS AND CONJUGATES, THEIR PREPARATION AND THEIR THERAPEUTIC USE<br/>[FR] NOUVEAUX COMPOSÉS ET CONJUGUÉS DE CRYPTOPHYCINE, LEUR PRÉPARATION ET LEUR UTILISATION THÉRAPEUTIQUE
  申请人：SANOFI SA

  公开号：WO2017076998A1

  公开（公告）日：2017-05-11

  The present invention relates to cryptophycin compounds of formula (I). The invention also relates to cryptophycin payloads, to cryptophycin conjugates, to compositions containing them and to their therapeutic use, especially as anticancer agents. The invention also relates to the process for preparing these conjugates.

  本发明涉及公式（I）的隐藻素化合物。该发明还涉及隐藻素有效载荷、隐藻素偶联物、含有它们的组合物及其治疗用途，尤其是作为抗癌剂。该发明还涉及制备这些偶联物的过程。
• NOVEL CONJUGATES, PREPARATION THEREOF, AND THERAPEUTIC USE THEREOF
  申请人：BOUCHARD Hervé

  公开号：US20120225089A1

  公开（公告）日：2012-09-06

  Provided herein are cryptophycin conjugates and compositions containing them. Methods of making and using such compounds also are provided.

  本发明提供了隐藻素偶联物及其包含它们的组合物。还提供了制备和使用此类化合物的方法。
• Stereoselective process for producing intermediates of cryptophycins
  申请人：Eli Lilly and Company

  公开号：US06376230B1

  公开（公告）日：2002-04-23

  This invention provides processes for preparing intermediates useful for the preparation of cryptophycin compounds.

  该发明提供了制备用于制备隐花链霉素化合物的中间体的过程。
• Cryptophycin compounds and conjugates, their preparation and their therapeutic use
  申请人：SANOFI

  公开号：US10941139B2

  公开（公告）日：2021-03-09

  The present invention relates to cryptophycin compounds of formula (I). The invention also relates to cryptophycin payloads, to cryptophycin conjugates, to compositions containing them and to their therapeutic use, especially as anticancer agents. The invention also relates to the process for preparing these conjugates.

  本发明涉及式（I）的隐球霉素化合物。本发明还涉及隐球菌苷有效载荷、隐球菌苷共轭物、含有它们的组合物及其治疗用途，特别是作为抗癌剂。本发明还涉及制备这些共轭物的工艺。