N-(4-N-Boc-aminobenzoyl)-methionine methyl ester | 180863-61-0

• 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: N-(4-N-Boc-aminobenzoyl)-methionine methyl ester
• 英文别名: N-BOC-4-aminobenzoyl methionine methyl ester；N-(1(S)-carbomethoxy-3-methylthiopropyl)-4-(t-butyloxycarbonyl)aminobenzamide；methyl (2S)-2-[[4-[(2-methylpropan-2-yl)oxycarbonylamino]benzoyl]amino]-4-methylsulfanylbutanoate
• CAS: 180863-61-0
• 化学式: C₁₈H₂₆N₂O₅S
• 分子量: 382.481
• InChiKey: KOWNOPHOLRLGGJ-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  26
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(4-N-Boc-aminobenzoyl)-methionine methyl ester 在 盐酸 、 sodium cyanoborohydride 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 16.5h， 生成 N-[4-[N-[2(R)-(tert-butoxycarbonyl)amino-3-(triphenylmethyl)thio]propyl]-aminobenzoyl]-methionine methyl ester
  参考文献：
  名称：

  Probing the hydrophobic pocket of farnesyltransferase: aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors

  摘要：

  Cysteine farnesylation at the carboxylate terminal tetrapeptide CAAX of Ras protein is catalyzed by farnesyltransferase. This lipid modification is necessary for regulatory function of both normal and oncogenic Ras. The high frequency of Ras mutation in human cancers has prompted an intensive study on finding ways of controlling oncogenic Ras function. Inhibition of farnesyltransferase is among the most sought after targets for cancer chemotherapy. We report here the design, synthesis and biological characterization of a series of peptidomimetics as farnesyltransferase inhibitors. These compounds are extremely potent towards farnesyltransferase with IC50 values ranging from subnanomolar to low nanomolar concentrations. They have a high selectivity for farnesyltransferase over the closely related geranylgeranyltransferase-I. Structure-activity relationship studies demonstrated that a properly positioned hydrophobic group significantly enhanced inhibition potency, reflecting an improved complementarity to the large hydrophobic pocket in the CAAX binding site. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00252-7
• 作为产物：
  描述：

  N-BOC-4-氨基苯甲酸 、 L-蛋氨酸甲酯盐酸盐 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以86%的产率得到N-(4-N-Boc-aminobenzoyl)-methionine methyl ester
  参考文献：
  名称：

  Probing the hydrophobic pocket of farnesyltransferase: aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors

  摘要：

  Cysteine farnesylation at the carboxylate terminal tetrapeptide CAAX of Ras protein is catalyzed by farnesyltransferase. This lipid modification is necessary for regulatory function of both normal and oncogenic Ras. The high frequency of Ras mutation in human cancers has prompted an intensive study on finding ways of controlling oncogenic Ras function. Inhibition of farnesyltransferase is among the most sought after targets for cancer chemotherapy. We report here the design, synthesis and biological characterization of a series of peptidomimetics as farnesyltransferase inhibitors. These compounds are extremely potent towards farnesyltransferase with IC50 values ranging from subnanomolar to low nanomolar concentrations. They have a high selectivity for farnesyltransferase over the closely related geranylgeranyltransferase-I. Structure-activity relationship studies demonstrated that a properly positioned hydrophobic group significantly enhanced inhibition potency, reflecting an improved complementarity to the large hydrophobic pocket in the CAAX binding site. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00252-7
• 作为试剂：
  描述：

  DL-蛋氨酸甲酯盐酸盐 、 三乙胺 、 Boc-4-氨基-3-甲基苯甲酸 在 1-羟基苯并三唑 作用下， 以 N-(4-N-Boc-aminobenzoyl)-methionine methyl ester 为溶剂， 以2.61 g (85.7%)的产率得到N-Boc-4-amino-3-methylbenzoyl methionine methyl ester
  参考文献：
  名称：

  Inhibitors of farnesyltransferase

  摘要：

  公式为C.beta.X的肽类模拟物，其中C代表半胱氨酸，X代表任何自然存在的氨基酸，.beta.代表疏水间隔物，尤其是2-苯基-4-氨基苯甲酸。这些化合物是p2lras法尼基转移酶的有效抑制剂，可以阻断Ras依赖的致癌信号传导，并在动物模型中有效抑制人类肿瘤生长。还披露了通过功能化肽和肽类模拟物的末端氨基和羧基团制备的前药。这些功能化衍生物表现出增加的细胞摄取。还披露了其他结构修饰。

  公开号：

  US05834434A1

文献信息

• Inhibitors of prenyl transferases
  申请人：Univeristy of Pittsburgh

  公开号：US05965539A1

  公开（公告）日：1999-10-12

  Compounds which inhibit prenyl transferases, particularly farnysyltransferase and geranylgeranyl transferase I, processes for preparing the compounds, pharmaceutical compositions containing the compounds, and methods of use.

  抑制戊二烯基转移酶，特别是戊二烯基转移酶和戊二烯基转移酶I的化合物，制备这些化合物的方法，含有这些化合物的药物组合物，以及使用方法。
• [EN] INHIBITORS OF PRENYL TRANSFERASES<br/>[FR] INHIBITEURS DES PRENYLE TRANSFERASES
  申请人：UNIVERSITY OF PITTSBURGH

  公开号：WO1996021456A1

  公开（公告）日：1996-07-18

  (EN) Compounds which inhibit prenyl transferases, particularly farnysyltransferase and geranylgeranyl transferase I, processes for preparing the compounds, pharmaceutical compositions containing the compounds, and methods of use.(FR) L'invention a pour objet des composés inhibiteurs des prényle transférases, particulièrement, des farnysyltransférases et des géranylgéranyle transférases I. L'invention traite également de procédés de préparations de ces composés, de compositions pharmaceutiques contenant ces composés et de leurs procédés d'utilisation.

  (EN) 抑制戊二烯转移酶，尤其是戊二烯基转移酶和戊二烯基转移酶I的化合物，制备这些化合物的方法，包含这些化合物的制药组合物以及使用方法。 (FR) 本发明涉及抑制戊二烯转移酶的化合物，尤其是戊二烯基转移酶和戊二烯基转移酶I的化合物，制备这些化合物的方法，包含这些化合物的制药组合物以及使用方法。
• Prodrugs of inhibitors of farnesyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US05534537A1

  公开（公告）日：1996-07-09

  The present invention comprises peptidomimetic compounds which comprise a suitably substituted aminoalkylbenzamide moiety. The instant compounds inhibit the farnesyl protein transferase enzyme and the farnesylation of certain proteins. Furthermore, the instant farnesyl protein transferase inhibitors differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

  本发明包括肽类似物化合物，其包括适当取代的氨基烷基苯甲酰胺基团。这些化合物抑制法尼烯基蛋白转移酶和某些蛋白的法尼烯化。此外，这些法尼烯基蛋白转移酶抑制剂与以前描述的抑制剂不同，因为它们没有巯基。缺乏巯基在改善动物的药代动力学行为、预防巯基依赖性化学反应（如快速自氧化和与内源性巯基形成二硫键）以及降低全身毒性方面具有独特的优势。此外，本发明还包括含有这些法尼烯基转移酶抑制剂的化疗组合物和其生产方法。
• Benzamide-containing inhibitors of farnesyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US05578629A1

  公开（公告）日：1996-11-26

  The present invention comprises peptidomimetic compounds which comprise a suitably substituted aminoalkylbenzamide moiety. The instant compounds inhibit the farnesyl protein transferase enzyme and the farnesylation of certain proteins. Furthermore, the instant farnesyl protein transferase inhibitors differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

  本发明涉及一种包含适当取代的氨基烷基苯甲酰胺基团的肽类似物化合物。这些化合物能够抑制法尼酰基蛋白转移酶和某些蛋白质的法尼酰化。此外，这些法尼酰基蛋白转移酶抑制剂与以前描述的法尼酰基蛋白转移酶抑制剂不同，因为它们不具有巯基。缺乏巯基提供了独特的优势，可以改善动物的药代动力学行为，防止巯基依赖性化学反应，如快速自氧化和与内源性巯基形成二硫键，以及减少系统毒性。此外，本发明还包括含有这些法尼酰转移酶抑制剂的化疗组合物和其生产方法。
• INHIBITORS OF PRENYL TRANSFERASES
  申请人：UNIVERSITY OF PITTSBURGH

  公开号：EP0794789A1

  公开（公告）日：1997-09-17