1-(9H-fluoren-9-ylmethyl) 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: 1-(9H-fluoren-9-ylmethyl) 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate
• 英文别名: 1-(9H-fluoren-9-ylmethyl)-2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate；ethyl (S)-N-Fmoc-pyroglutamate；(S)-1-((9H-Fluoren-9-yl)methyl) 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate；2-O-ethyl 1-O-(9H-fluoren-9-ylmethyl) (2S)-5-oxopyrrolidine-1,2-dicarboxylate
• 化学式: C₂₂H₂₁NO₅
• 分子量: 379.412
• InChiKey: SPOXFTFFXPHVFI-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(9H-fluoren-9-ylmethyl) 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate 在 哌啶 、 正丁基锂 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 0.2h， 生成 6-重氮-5-氧代-L-正亮氨酸
  参考文献：
  名称：

  Coutts, Ian G. C.; Saint, Robert E., Tetrahedron Letters, 1998, vol. 39, # 20, p. 3242 - 3246

  摘要：

  DOI：
• 作为产物：
  描述：

  L-焦谷氨酸 在 氯化亚砜 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 34.42h， 生成 1-(9H-fluoren-9-ylmethyl) 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate
  参考文献：
  名称：

  Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-l-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery

  摘要：

  DOI：

  10.1021/acs.jmedchem.3c01681

文献信息

• [EN] PRODRUGS OF GLUTAMINE ANALOGS<br/>[FR] PROMÉDICAMENTS D'ANALOGUES DE GLUTAMINE
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2017023774A9

  公开（公告）日：2017-11-23
• Chemical reactivity of 6-diazo-5-oxo-l-norleucine (DON) catalyzed by metalloporphyrins (Fe,Ru)
  作者：Paul Le Maux、Irène Nicolas、Soizic Chevance、Gérard Simonneaux

  DOI：10.1016/j.tet.2010.04.080

  日期：2010.6

  The transfer of the metallocarbene derived from N- and O-protected 6-diazo-5-oxo-L-norleucine (DON) catalyzed by metalloporphyrins undergoes dimerization, cyclopropanation. N-H and S-H insertion reactions, respectively. An efficient and direct synthesis of 5-oxo-L-pipecolic acid from DON is described from unprotected 6-diazo-5-oxo-L-norleucine. (C) 2010 Elsevier Ltd. All rights reserved.
• Discovery of 6-Diazo-5-oxo-<scp>l</scp>-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma
  作者：Rana Rais、Andrej Jančařík、Lukáš Tenora、Michael Nedelcovych、Jesse Alt、Judson Englert、Camilo Rojas、Anne Le、Amira Elgogary、Jessica Tan、Lenka Monincová、Kelly Pate、Robert Adams、Dana Ferraris、Jonathan Powell、Pavel Majer、Barbara S. Slusher

  DOI：10.1021/acs.jmedchem.6b01069

  日期：2016.9.22

  The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DONs therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DONs amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.
• Coutts; Saint; Saint, Synthesis, 2001, # 2, p. 247 - 250
  作者：Coutts、Saint、Saint、Chambers-Asman

  DOI：——

  日期：——
• PRODRUGS OF GLUTAMINE ANALOGS
  申请人：The Johns Hopkins University

  公开号：US20180222930A1

  公开（公告）日：2018-08-09

  The disclosure provides compounds having formula (I): and the pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2 ′, and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON). The disclosure also provides compounds having formula (I) for use in treating cancer.