R-1-[2-(4-phenylamino-2-oxo-2H-pyridin-1-yl)acetamido]-3-methylbutylboronic acid | 1443646-29-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: R-1-[2-(4-phenylamino-2-oxo-2H-pyridin-1-yl)acetamido]-3-methylbutylboronic acid
• 英文别名: [(1R)-1-[[2-(4-anilino-2-oxopyridin-1-yl)acetyl]amino]-3-methylbutyl]boronic acid
• CAS: 1443646-29-4
• 化学式: C₁₈H₂₄BN₃O₄
• 分子量: 357.217
• InChiKey: LXDQJQYUHNTYAY-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.13
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  102
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,4-二氯吡啶 在 盐酸 、 tris-(dibenzylideneacetone)dipalladium(0) 、 palladium 10% on activated carbon 、 水 、 氢气 、 potassium hydride 、 sodium hydride 、 1-羟基苯并三唑 、 lithium hydroxide 、 sodium t-butanolate 、 2-二环己膦基-2'-(N,N-二甲胺)-联苯 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 49.58h， 生成 R-1-[2-(4-phenylamino-2-oxo-2H-pyridin-1-yl)acetamido]-3-methylbutylboronic acid
  参考文献：
  名称：

  Development of peptidomimetic boronates as proteasome inhibitors

  摘要：

  Proteasome inhibition has emerged over the past decade as an effective therapeutic approach for the treatment of hematologic malignancies. It is a multicatalytic complex, whose proteolytic activity relies in three types of subunits: chymotrypsin-like (beta 5), trypsin-like (beta 2) and caspase-like (beta 1). Most important for the development of effective antitumor agents is the inhibition of the beta 5 subunits. In this context, the dipeptide boronate bortezomib (Velcade (R)) represents the first proteasome inhibitor approved by the FDA and the lead compound in drug discovery. This paper describes the synthesis and biological evaluation of a series of conformationally constrained pseudopeptide boronates (1-3) structurally related to bortezomib. The synthesized compounds showed a promising inhibitory profile by blocking primarily the chymotrypsin-like activity of the proteasome with K-i values in submicromolar/micromolar range. These compounds also resulted quite selective since no significant inhibition was recorded in the test against bovine pancreatic alpha-chymotrypsin. The obtained results were rationalized by means of docking experiments based on a model of the crystal structure of bortezomib bound to the yeast 20S proteasome providing essential insights for further optimization of this class of inhibitors. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.032

文献信息

• Development of peptidomimetic boronates as proteasome inhibitors
  作者：Nicola Micale、Roberta Ettari、Antonio Lavecchia、Carmen Di Giovanni、Kety Scarbaci、Valeria Troiano、Silvana Grasso、Ettore Novellino、Tanja Schirmeister、Maria Zappalà

  DOI：10.1016/j.ejmech.2013.03.032

  日期：2013.6

  Proteasome inhibition has emerged over the past decade as an effective therapeutic approach for the treatment of hematologic malignancies. It is a multicatalytic complex, whose proteolytic activity relies in three types of subunits: chymotrypsin-like (beta 5), trypsin-like (beta 2) and caspase-like (beta 1). Most important for the development of effective antitumor agents is the inhibition of the beta 5 subunits. In this context, the dipeptide boronate bortezomib (Velcade (R)) represents the first proteasome inhibitor approved by the FDA and the lead compound in drug discovery. This paper describes the synthesis and biological evaluation of a series of conformationally constrained pseudopeptide boronates (1-3) structurally related to bortezomib. The synthesized compounds showed a promising inhibitory profile by blocking primarily the chymotrypsin-like activity of the proteasome with K-i values in submicromolar/micromolar range. These compounds also resulted quite selective since no significant inhibition was recorded in the test against bovine pancreatic alpha-chymotrypsin. The obtained results were rationalized by means of docking experiments based on a model of the crystal structure of bortezomib bound to the yeast 20S proteasome providing essential insights for further optimization of this class of inhibitors. (C) 2013 Elsevier Masson SAS. All rights reserved.