pyrrolidine-1,2-dicarboxylic acid (2S)-2-[(1S,3S,5S)-1-tert-butyl-6-carboxy-5-(2,2,2-trichloroethoxycarbonyloxy)-3,6-dimethylhept-1-yl]ester 1-(9H-fluoren-9-ylmethyl)ester | 1585181-12-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: pyrrolidine-1,2-dicarboxylic acid (2S)-2-[(1S,3S,5S)-1-tert-butyl-6-carboxy-5-(2,2,2-trichloroethoxycarbonyloxy)-3,6-dimethylhept-1-yl]ester 1-(9H-fluoren-9-ylmethyl)ester
• 英文别名: pyrrolidine-1,2-dicarboxylic acid (2S)-2-[(1S,5S)-1-tert-butyl-6-carboxy-5-(2,2,2-trichloroethoxycarbonyloxy)-3,6-dimethylhept-1-yl]ester 1-(9H-fluoren-9-ylmethyl)ester
• CAS: 1585181-12-9
• 化学式: C₃₇H₄₆Cl₃NO₉
• 分子量: 755.133
• InChiKey: IZMQZUOQVUEDPA-REICUKPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.78
• 重原子数：
  50.0
• 可旋转键数：
  12.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  128.67
• 氢给体数：
  1.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  pyrrolidine-1,2-dicarboxylic acid (2S)-2-[(1S,3S,5S)-1-tert-butyl-6-carboxy-5-(2,2,2-trichloroethoxycarbonyloxy)-3,6-dimethylhept-1-yl]ester 1-(9H-fluoren-9-ylmethyl)ester 在 盐酸 、 四(三苯基膦)钯 、 ammonium acetate 、 四氯化钛 、 N,N-二异丙基乙胺 、 ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) 、 N-甲基苯胺 、 锌 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 1,2-二氯乙烷 为溶剂， 反应 6.5h， 生成
  参考文献：
  名称：

  Improved Total Synthesis and Biological Evaluation of Potent Apratoxin S4 Based Anticancer Agents with Differential Stability and Further Enhanced Activity

  摘要：

  Apratoxins are cytotoxic natural products originally isolated from marine cyanobacteria that act by preventing cotranslational translocation early in the secretory pathway to downregulate receptor levels and inhibit growth factor secretion, leading to potent antiproliferative activity. Through rational design and total synthesis of an apratoxin A/ E hybrid, apratoxin S4 (1a), we have previously improved the antitumor activity and tolerability in vivo. Compound la and newly designed analogues apratoxins S7-S9 (1b-d), with various degrees of methylation at C34 (1b,c) or epimeric configuration at C30 (1d), were efficiently synthesized utilizing improved procedures. Optimizations have been applied to the synthesis of key intermediate aldehyde 7 and further include the application of Leighton's silanes and modifications of Kelly's methods to induce thiazoline ring formation in other crucial steps of the apratoxin synthesis. Apratoxin S9 (1d) exhibited increased activity with subnanomolar potency. Apratoxin S8 (lc) lacks the propensity to be deactivated by dehydration and showed efficacy in a human HCT116 xenograft mouse model.

  DOI：

  10.1021/jm4019965
• 作为产物：
  描述：

  methyl (3S,5S,7S)-3-hydroxy-7-(4-methoxybenzyloxy)-2,2,5,8,8-pentamethylnonanoate 在 吡啶 、 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 2,4,6-三氯苯甲酰氯 、 水 、 potassium carbonate 、 N,N-二异丙基乙胺 、 N-甲基苯胺 、 2,3-二氯-5,6-二氰基-1,4-苯醌 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 二甲基亚砜 、 甲苯 为溶剂， 反应 8.34h， 生成 pyrrolidine-1,2-dicarboxylic acid (2S)-2-[(1S,3S,5S)-1-tert-butyl-6-carboxy-5-(2,2,2-trichloroethoxycarbonyloxy)-3,6-dimethylhept-1-yl]ester 1-(9H-fluoren-9-ylmethyl)ester
  参考文献：
  名称：

  [EN] MACROCYCLIC THERAPEUTIC AGENTS, METHODS OF MANUFACTURE, AND METHODS OF TREATMENT
  [FR] AGENTS THÉRAPEUTIQUES MACROCYCLIQUES, DES MÉTHODES DE FABRICATION, ET MÉTHODES DE TRAITEMENT

  摘要：

  本发明描述了具有治疗活性的大环化合物，以及治疗自身免疫疾病、炎症、癌症、肿瘤和与细胞增殖有关的疾病的机制和方法。

  公开号：

  WO2015127161A1

文献信息

• Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors
  作者：Weijing Cai、Qi-Yin Chen、Long H. Dang、Hendrik Luesch

  DOI：10.1021/acsmedchemlett.7b00192

  日期：2017.10.12

  Renal, hepatocellular, and neuroendocrine carcinomas are known as highly vascularized tumors. Although vascular endothelial growth factor A (VEGF-A)-targeted therapies have shown efficacy in the treatment of these cancers, drug resistance is a major concern and might be mediated by interleukin 6 (IL-6). Furthermore, upon antiangiogenic drug exposure, tumor cells may adapt to survive in a vascular-independent manner. Apratoxins are potent marine-derived cytotoxic in vivo -active agents, preventing cotranslational translocation in the secretory pathway, and show promise to overcome resistance by targeting angiogenesis and tumor growth simultaneously. We designed and synthesized a novel apratoxin analogue, apratoxin S10, with a balanced potency and stability as well as synthetic accessibility and scalability. We showed that apratoxin S10 potently inhibits both angiogenesis in vitro and growth of cancer cells from vascularized tumors. Apratoxin S10 down -regulated vascular endothelial growth factor receptor 2 (VEGFR2) on endothelial cells and blocked the secretion of VEGF-A and IL-6 from cancer cells. It inhibited cancer cell growth through down -regulation of multiple receptor tyrosine kinases (RTKs) and compares favorably to currently approved RTK inhibitors in both angiogenesis and cancer cell growth.