(R)-N-(tert-butoxycarbonyl)-2-amino-3-propyl-N-methoxy-N-methylpropionamide | 169448-54-8

• 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: (R)-N-(tert-butoxycarbonyl)-2-amino-3-propyl-N-methoxy-N-methylpropionamide
• 英文别名: N-methoxy-N-methyl 2(R)-tert-butoxycarbonylaminohexanamide；tert-butyl N-[(2R)-1-[methoxy(methyl)amino]-1-oxohexan-2-yl]carbamate
• CAS: 169448-54-8
• 化学式: C₁₃H₂₆N₂O₄
• 分子量: 274.36
• InChiKey: PNYOAOWVAVVYRK-SNVBAGLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  19
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-N-(tert-butoxycarbonyl)-2-amino-3-propyl-N-methoxy-N-methylpropionamide 在 potassium hydrogen sulphate 作用下， 生成 2(R)-tert-butoxycarbonylaminohexanal
  参考文献：
  名称：

  Inhibitors of farnesyl-protein transferase

  摘要：

  本发明涉及抑制法尼基-蛋白转移酶（FTase）和致癌基因蛋白Ras的法尼酰化的化合物。该发明进一步涉及含有本发明化合物的化疗组合物以及抑制法尼基-蛋白转移酶和致癌基因蛋白Ras的方法。式A的化合物代表了本发明的化合物：##STR1##

  公开号：

  US05736539A1
• 作为产物：
  描述：

  二甲羟胺盐酸盐 、 叔丁氧羰酰基D-正亮氨酸 在 N-甲基吗啉 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 5.58h， 以90%的产率得到(R)-N-(tert-butoxycarbonyl)-2-amino-3-propyl-N-methoxy-N-methylpropionamide
  参考文献：
  名称：

  Synthesis of New (−)-Bestatin-Based Inhibitor Libraries Reveals a Novel Binding Mode in the S1 Pocket of the Essential Malaria M1 Metalloaminopeptidase

  摘要：

  The malarial PfA-M1 metalloaminopeptidase is considered a putative drug target. The natural product dipeptide mimetic, bestatin, is a potent inhibitor of PfA-M1. Herein we present a new, efficient, and high-yielding protocol for the synthesis of bestatin derivatives from natural and unnatural N-Boc-D-amino acids. A diverse library of bestatin derivatives was synthesized with variants at the side chain of either the alpha-hydroxy-beta-amino acid (P1) or the adjacent natural a-amino add (P1'). Surprisingly, we found that extended aromatic side chains at the P1 position resulted in potent inhibition against PfA-M1. To understand these data, we determined the X-ray cocrystal structures of PfA-M1 with two derivatives having either a Tyr(OMe) 15 or Tyr(OBz1) 16 at the 131 position and observed substantial inhibitor-induced rearrangement of the primary loop within the PEA-M1 pocket that interacts with the PI side chain. Our data provide important insights for the rational design of more potent and selective inhibitors of this enzyme that may eventually lead to new therapies for malaria.

  DOI：

  10.1021/jm101227t
• 作为试剂：
  描述：

  N-Boc-L-正亮氨酸 、 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 1-羟基苯并三唑 、 N,N-二甲基甲酰胺 在 (R)-N-(tert-butoxycarbonyl)-2-amino-3-propyl-N-methoxy-N-methylpropionamide 、 crude product 、 silica gel 、 乙酸乙酯 、 正己烷 作用下， 以 三乙胺 为溶剂， 生成 (R)-N-(tert-butoxycarbonyl)-2-amino-3-propyl-N-methoxy-N-methylpropionamide
  参考文献：
  名称：

  Inhibitors of farnesyl-protein transferase

  摘要：

  本发明涉及抑制法尼酰蛋白转移酶（FTase）和致癌基因蛋白Ras的法尼酰化的化合物。本发明还涉及包含本发明化合物的化疗组合物以及抑制法尼酰蛋白转移酶和致癌基因蛋白Ras的方法。式A的化合物代表本发明的化合物：##STR1##

  公开号：

  US05736539A1

文献信息

• INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
  申请人：MERCK & CO. INC.

  公开号：EP0703905A1

  公开（公告）日：1996-04-03
• US5736539A
  申请人：——

  公开号：US5736539A

  公开（公告）日：1998-04-07
• [EN] INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE<br/>[FR] INHIBITEURS DE FARNESYLE-PROTEINE TRANSFERASE
  申请人：MERCK & CO., INC.

  公开号：WO1995000497A1

  公开（公告）日：1995-01-05

  (EN) The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.(FR) L'invention concerne des composés inhibiteurs de farnésyle-protéine transférase (Ftase) et la farnésylation de la protéine d'oncogène Ras. L'invention concerne en outre des compositions chimiothérapiques contenant les composés de l'invention, des procédés d'inhibition de farnesyle-protéine transférase et la farnésylation de la protéine d'oncogène Ras.
• Inhibitors of farnesyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US05736539A1

  公开（公告）日：1998-04-07

  The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. The compounds of formula A are representative of the compounds of the present invention: ##STR1##

  本发明涉及抑制法尼基-蛋白转移酶（FTase）和致癌基因蛋白Ras的法尼酰化的化合物。该发明进一步涉及含有本发明化合物的化疗组合物以及抑制法尼基-蛋白转移酶和致癌基因蛋白Ras的方法。式A的化合物代表了本发明的化合物：##STR1##
• Synthesis of New (−)-Bestatin-Based Inhibitor Libraries Reveals a Novel Binding Mode in the S1 Pocket of the Essential Malaria M1 Metalloaminopeptidase
  作者：Geetha Velmourougane、Michael B. Harbut、Seema Dalal、Sheena McGowan、Christine A. Oellig、Nataline Meinhardt、James C. Whisstock、Michael Klemba、Doron C. Greenbaum

  DOI：10.1021/jm101227t

  日期：2011.3.24

  The malarial PfA-M1 metalloaminopeptidase is considered a putative drug target. The natural product dipeptide mimetic, bestatin, is a potent inhibitor of PfA-M1. Herein we present a new, efficient, and high-yielding protocol for the synthesis of bestatin derivatives from natural and unnatural N-Boc-D-amino acids. A diverse library of bestatin derivatives was synthesized with variants at the side chain of either the alpha-hydroxy-beta-amino acid (P1) or the adjacent natural a-amino add (P1'). Surprisingly, we found that extended aromatic side chains at the P1 position resulted in potent inhibition against PfA-M1. To understand these data, we determined the X-ray cocrystal structures of PfA-M1 with two derivatives having either a Tyr(OMe) 15 or Tyr(OBz1) 16 at the 131 position and observed substantial inhibitor-induced rearrangement of the primary loop within the PEA-M1 pocket that interacts with the PI side chain. Our data provide important insights for the rational design of more potent and selective inhibitors of this enzyme that may eventually lead to new therapies for malaria.