di-tert-butyl 4-{N-[4'-bis(2''-bromoethyl)aminophenyl]-N-methylcarbamoyloxymethyl}phenyloxycarbonyl-L-glutamate | 528836-63-7

• 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
• 英文名称: di-tert-butyl 4-{N-[4'-bis(2''-bromoethyl)aminophenyl]-N-methylcarbamoyloxymethyl}phenyloxycarbonyl-L-glutamate
• 英文别名: ditert-butyl (2S)-2-[[4-[[[4-[bis(2-bromoethyl)amino]phenyl]-methylcarbamoyl]oxymethyl]phenoxy]carbonylamino]pentanedioate
• CAS: 528836-63-7
• 化学式: C₃₃H₄₅Br₂N₃O₈
• 分子量: 771.544
• InChiKey: WREBHHQGIOGBST-MHZLTWQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  46
• 可旋转键数：
  20
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  di-tert-butyl 4-{N-[4'-bis(2''-bromoethyl)aminophenyl]-N-methylcarbamoyloxymethyl}phenyloxycarbonyl-L-glutamate 在 甲酸 作用下， 以85.3%的产率得到(S)-2-{4-[({4-[Bis-(2-bromo-ethyl)-amino]-phenyl}-methyl-carbamoyloxy)-methyl]-phenoxycarbonylamino}-pentanedioic acid
  参考文献：
  名称：

  Self-Immolative Nitrogen Mustards Prodrugs Cleavable by Carboxypeptidase G2 (CPG2) Showing Large Cytotoxicity Differentials in GDEPT

  摘要：

  Nineteen novel potential self-immolative prodrugs and their corresponding drugs have been synthesized for gene-directed enzyme prodrug therapy (GDEPT) with carboxypeptidase G2 (CPG2) as the activating enzyme. The compounds are derived from o- and p-amino and p-methylamino aniline nitrogen mustards. Their aqueous stability, kinetics of drug release by CPG2, and cytotoxicity in the colon carcinoma cell line WiDr, expressing either surface-tethered CPG2 (stCPG2(Q)3) or control beta-galactosidase, are assessed. The effect of various structural features on stability, kinetics of activation, and biological activity is discussed. The p-methylamino prodrugs are the most stable compounds from this series, with the largest cytotoxicity differentials between CPG2-expressing and nonexpressing cells. The most potent compounds in all series are prodrugs of bis-iodo nitrogen mustards. 4-{N-[4'-Bis(2"-iodoethyl)aminophenyll-N'-methylcarbamoyloxymethyl}phenylcarbamoyl-L-glutamic acid, compound 39b, is 124-fold more cytotoxic to WiDr cells expressing CPG2 than to cells expressing beta-galactosidase. An additional six compounds show better cytotoxicity differential than the published N-{4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl}-L-glutamic acid (CMDA) prodrug.

  DOI：

  10.1021/jm020462i
• 作为产物：
  描述：

  di-tert-butyl N-<(4-<<4-nitrophenoxycarbonyloxy>methyl>phenoxy)carbonyl>-L-glutamate 在 4-二甲氨基吡啶 、 triethylamine trihydrofluoride 、 三乙胺 、 lithium bromide 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基乙酰胺 为溶剂， 生成 di-tert-butyl 4-{N-[4'-bis(2''-bromoethyl)aminophenyl]-N-methylcarbamoyloxymethyl}phenyloxycarbonyl-L-glutamate
  参考文献：
  名称：

  Self-Immolative Nitrogen Mustards Prodrugs Cleavable by Carboxypeptidase G2 (CPG2) Showing Large Cytotoxicity Differentials in GDEPT

  摘要：

  Nineteen novel potential self-immolative prodrugs and their corresponding drugs have been synthesized for gene-directed enzyme prodrug therapy (GDEPT) with carboxypeptidase G2 (CPG2) as the activating enzyme. The compounds are derived from o- and p-amino and p-methylamino aniline nitrogen mustards. Their aqueous stability, kinetics of drug release by CPG2, and cytotoxicity in the colon carcinoma cell line WiDr, expressing either surface-tethered CPG2 (stCPG2(Q)3) or control beta-galactosidase, are assessed. The effect of various structural features on stability, kinetics of activation, and biological activity is discussed. The p-methylamino prodrugs are the most stable compounds from this series, with the largest cytotoxicity differentials between CPG2-expressing and nonexpressing cells. The most potent compounds in all series are prodrugs of bis-iodo nitrogen mustards. 4-{N-[4'-Bis(2"-iodoethyl)aminophenyll-N'-methylcarbamoyloxymethyl}phenylcarbamoyl-L-glutamic acid, compound 39b, is 124-fold more cytotoxic to WiDr cells expressing CPG2 than to cells expressing beta-galactosidase. An additional six compounds show better cytotoxicity differential than the published N-{4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl}-L-glutamic acid (CMDA) prodrug.

  DOI：

  10.1021/jm020462i

文献信息

• Self-Immolative Nitrogen Mustards Prodrugs Cleavable by Carboxypeptidase G2 (CPG2) Showing Large Cytotoxicity Differentials in GDEPT
  作者：Dan Niculescu-Duvaz、Ion Niculescu-Duvaz、Frank Friedlos、Jan Martin、Panos Lehouritis、Richard Marais、Caroline J. Springer

  DOI：10.1021/jm020462i

  日期：2003.4.1

  Nineteen novel potential self-immolative prodrugs and their corresponding drugs have been synthesized for gene-directed enzyme prodrug therapy (GDEPT) with carboxypeptidase G2 (CPG2) as the activating enzyme. The compounds are derived from o- and p-amino and p-methylamino aniline nitrogen mustards. Their aqueous stability, kinetics of drug release by CPG2, and cytotoxicity in the colon carcinoma cell line WiDr, expressing either surface-tethered CPG2 (stCPG2(Q)3) or control beta-galactosidase, are assessed. The effect of various structural features on stability, kinetics of activation, and biological activity is discussed. The p-methylamino prodrugs are the most stable compounds from this series, with the largest cytotoxicity differentials between CPG2-expressing and nonexpressing cells. The most potent compounds in all series are prodrugs of bis-iodo nitrogen mustards. 4-N-[4'-Bis(2"-iodoethyl)aminophenyll-N'-methylcarbamoyloxymethyl}phenylcarbamoyl-L-glutamic acid, compound 39b, is 124-fold more cytotoxic to WiDr cells expressing CPG2 than to cells expressing beta-galactosidase. An additional six compounds show better cytotoxicity differential than the published N-4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl}-L-glutamic acid (CMDA) prodrug.