di-tert-butyl 2,3,4,5-tetrafluorobenzoyl-L-glutamate | 298211-20-8

• 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 2,3,4,5-tetrafluorobenzoyl-L-glutamate
• 英文别名: di-tert-butyl (2,3,4,5-tetrafluorobenzoyl)-L-glutamate；ditert-butyl (2S)-2-[(2,3,4,5-tetrafluorobenzoyl)amino]pentanedioate
• CAS: 298211-20-8
• 化学式: C₂₀H₂₅F₄NO₅
• 分子量: 435.416
• InChiKey: MIRXWQPKKLLWAP-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  30
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  81.7
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  di-tert-butyl 2,3,4,5-tetrafluorobenzoyl-L-glutamate 在 4-二甲氨基吡啶 、 三乙胺 、 三氟乙酸 、 lithium bromide 作用下， 以 二氯甲烷 、 N,N-二甲基乙酰胺 、 丙酮 为溶剂， 反应 150.0h， 生成 {4-[bis(2-bromoethyl)amino]-2,3,5-trifluorobenzoyl}-L-glutamic acid
  参考文献：
  名称：

  Novel Fluorinated Prodrugs for Activation by Carboxypeptidase G2 Showing Good in Vivo Antitumor Activity in Gene-Directed Enzyme Prodrug Therapy

  摘要：

  Sixteen novel polyfluorinated benzoic acid mustards have been synthesized for use in gene-directed enzyme prodrug therapy (GDEPT). Eight of these were benzoic acid L-glutamate mustards for evaluation as prodrugs and the other eight were the active drugs formed by the action of the bacterial enzyme carboxypeptidase G2 (CPG2). All of the di- and trifluorinated prodrugs were efficiently cleaved by the enzyme. In contrast, the tetrafluorinated prodrugs were found to be competitive inhibitors of CPG2, the first such inhibitors to have been described. The di- and trifluorinated prodrugs were differentially cytotoxic to human breast carcinoma cells (MDA MB 361) expressing CPG2, compared to control cells that did not express the enzyme. The difluorinated prodrug {4-[bis(2-bromoethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid and its iodoethylamino analogue were effective substrates for the enzyme and showed excellent therapeutic activity in CPG2-expressing MDA MB 361 xenografts, either curing or greatly inhibiting tumor growth and extending the life of the animals.

  DOI：

  10.1021/jm0502182
• 作为产物：
  描述：

  L-谷氨酸二叔丁酯盐酸盐 、 四氟苯甲酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以98%的产率得到di-tert-butyl 2,3,4,5-tetrafluorobenzoyl-L-glutamate
  参考文献：
  名称：

  Novel Fluorinated Prodrugs for Activation by Carboxypeptidase G2 Showing Good in Vivo Antitumor Activity in Gene-Directed Enzyme Prodrug Therapy

  摘要：

  Sixteen novel polyfluorinated benzoic acid mustards have been synthesized for use in gene-directed enzyme prodrug therapy (GDEPT). Eight of these were benzoic acid L-glutamate mustards for evaluation as prodrugs and the other eight were the active drugs formed by the action of the bacterial enzyme carboxypeptidase G2 (CPG2). All of the di- and trifluorinated prodrugs were efficiently cleaved by the enzyme. In contrast, the tetrafluorinated prodrugs were found to be competitive inhibitors of CPG2, the first such inhibitors to have been described. The di- and trifluorinated prodrugs were differentially cytotoxic to human breast carcinoma cells (MDA MB 361) expressing CPG2, compared to control cells that did not express the enzyme. The difluorinated prodrug {4-[bis(2-bromoethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid and its iodoethylamino analogue were effective substrates for the enzyme and showed excellent therapeutic activity in CPG2-expressing MDA MB 361 xenografts, either curing or greatly inhibiting tumor growth and extending the life of the animals.

  DOI：

  10.1021/jm0502182

文献信息

• Nitrogen mustard compounds and prodrugs therefor
  申请人：Springer Caroline J.

  公开号：US06852755B1

  公开（公告）日：2005-02-08

  This invention pertains to nitrogen mustard compounds (Formula (II)) and prodrugs therefor (Formula (I)), methods for their preparation, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, in therapy and treatment, for example, of cancer, wherein: R 1 and R 2 are independently —Cl, —Br, —I, —OSO 2 CH 3 , or —OSO 2 Ph; R 1a , R 2a , R 1b , and R 2b are independently —H, a C 1-4 alkyl group, or a C 1-4 haloalkyl group; R 3 is —F, —Cl, —Br, —I, —OCHF 2 , —C≡CH, —OCF 3 , —CH 3 , —CF 3 , —SF 5 , —SCF 3 , or —CF 2 CF 3 ; R 4 is —H or as defined for R 3− , R 5 is —H or —F; R 7 is —H, —C(CH 3 ) 3 , or —CH 2 —CH—CH 2 ; Z is —CH 2 —T—W; T is —CH 2 —, —O—, —S—, —(S═O)—, or —(SO 2 )—; W is one of: (1) —COOH; (2)—(C═O)OR 8 ; (3) —(C═O)NR 9 R 9 ; (4) —SO 2 NHR 10− , (5) SO 2 OR 11 ; (6)—PO 3 R 11 R 11 ; (7) a tetrazol-5-yl group; (8) —CONH—SO 2 R 12 ; and, (9)-M-Het.

  本发明涉及氮芥化合物(公式(II))及其前药(公式(I))，其制备方法，含有这种化合物的制药组合物，以及这种化合物和组合物在体内外治疗癌症等方面的应用，其中：R1和R2分别为—Cl、—Br、—I、—OSO2CH3或—OSO2Ph；R1a、R2a、R1b和R2b分别为—H、C1-4烷基或C1-4卤代烷基；R3为—F、—Cl、—Br、—I、—OCHF2、—C≡CH、—OCF3、—CH3、—CF3、—SF5、—SCF3或—CF2CF3；R4为—H或如R3所定义的；R5为—H或—F；R7为—H、—C(CH3)3或—CH2—CH—CH2；Z为—CH2—T—W；T为—CH2—、—O—、—S—、—(S═O)—或—(SO2)—；W为以下之一：(1) —COOH；(2) —(C═O)OR8；(3) —(C═O)NR9R9；(4) —SO2NHR10−，(5) SO2OR11；(6) —PO3R11R11；(7) 五元杂环基；(8) —CONH—SO2R12；以及(9)-M-Het。
• NITROGEN MUSTARD COMPOUNDS AND PRODRUGS THEREFOR
  申请人：CANCER RESEARCH TECHNOLOGY LIMITED

  公开号：EP1165493B1

  公开（公告）日：2005-01-19
• Novel Fluorinated Prodrugs for Activation by Carboxypeptidase G2 Showing Good in Vivo Antitumor Activity in Gene-Directed Enzyme Prodrug Therapy
  作者：Lawrence C. Davies、Frank Friedlos、Douglas Hedley、Jan Martin、Lesley M. Ogilvie、Ian J. Scanlon、Caroline J. Springer

  DOI：10.1021/jm0502182

  日期：2005.8.1

  Sixteen novel polyfluorinated benzoic acid mustards have been synthesized for use in gene-directed enzyme prodrug therapy (GDEPT). Eight of these were benzoic acid L-glutamate mustards for evaluation as prodrugs and the other eight were the active drugs formed by the action of the bacterial enzyme carboxypeptidase G2 (CPG2). All of the di- and trifluorinated prodrugs were efficiently cleaved by the enzyme. In contrast, the tetrafluorinated prodrugs were found to be competitive inhibitors of CPG2, the first such inhibitors to have been described. The di- and trifluorinated prodrugs were differentially cytotoxic to human breast carcinoma cells (MDA MB 361) expressing CPG2, compared to control cells that did not express the enzyme. The difluorinated prodrug 4-[bis(2-bromoethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid and its iodoethylamino analogue were effective substrates for the enzyme and showed excellent therapeutic activity in CPG2-expressing MDA MB 361 xenografts, either curing or greatly inhibiting tumor growth and extending the life of the animals.