Cbz-Phe-Ala-CH2Br | 115186-22-6

• 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: Cbz-Phe-Ala-CH2Br
• 英文别名: Z-Phe-Ala-CH2Br；Z-L-phenylalanyl-L-alanyl bromomethyl ketone；benzyl N-[(2S)-1-[[(2S)-4-bromo-3-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate
• CAS: 115186-22-6
• 化学式: C₂₁H₂₃BrN₂O₄
• 分子量: 447.329
• InChiKey: ZNYHIRBYIYJNCL-YJBOKZPZSA-N

物化性质

• 沸点：
  660.8±55.0 °C(Predicted)
• 密度：
  1.364±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  28
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  84.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Cbz-Phe-Ala-CH2Br 、 三甲基乙酸 在 potassium fluoride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  New inhibitors of cysteine proteinases. Peptidyl acyloxymethyl ketones and the quiescent nucleofuge strategy

  摘要：

  DOI：

  10.1021/ja00221a062
• 作为产物：
  描述：

  Z-苯丙氨酰-丙氨酰-重氮基甲基甲酮 在 氢溴酸 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 0.02h， 生成 Cbz-Phe-Ala-CH2Br
  参考文献：
  名称：

  Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases

  摘要：

  Dipeptidyl (acyloxy) methyl ketones (AOMKs) have been identified as mechanism-based inhibitors of certain cysteine proteases. These compounds are also inhibitors of the integral membrane proteins Rce1p and Ste24p, which are proteases that independently mediate a cleavage step associated with the maturation of certain isoprenylated proteins. The enzymatic mechanism of Rce1p is ill-defined, whereas Ste24p is a zinc metalloprotease. Rce1p is required for the proper processing of the oncoprotein Ras and is viewed as a potential target for cancer therapy. In this study, we synthesized a small library of dipeptidyl AOMKs to investigate the structural elements that contribute to the inhibitor properties of this class of molecules toward Rce1p and Ste24p. The compounds were evaluated using a fluorescence-based in vitro proteolysis assay. The most potent dipeptidyl AOMKs contained an arginine residue and the identity of the benzoate group strongly influenced potency. A 'warhead' free AOMK inhibited Rce1p and Ste24p. The data suggest that the dipeptidyl AOMKs are not mechanism-based inhibitors of Rce1p and Ste24p and corroborate the hypothesis that Rce1p is not a cysteine protease. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.07.041

文献信息

• Peptidyl Epoxides:  Novel Selective Inactivators of Cysteine Proteases¹
  作者：Amnon Albeck、Shulamit Fluss、Rachel Persky

  DOI：10.1021/ja954261y

  日期：1996.1.1

  Peptidyl epoxides were designed as selective pseudo-mechanism-based inactivators of cysteine proteases. Both threo- and erythro-peptidyl epoxides were synthesized and tested as potential inactivators of serine proteases (chymotrypsin, subtilisin, and elastase) and of cysteine proteases (papain, cathepsin B, and clostripain). Four tripeptidyl epoxides (Cbz-Gly-Leu-Phe-epoxide, Cbz-Ala-Ala-Phe-epoxide, Cbz-Gly-Leu-Ala-epoxide, and Cbz-Ala-Ala-Ala-epoxide), bearing amino acid sequences similar to those of good substrates or known inhibitors of the serine proteases, were tested in this study. Neither the threo- nor the erythro-peptidyl epoxides exhibited any inhibitory activity toward the serine proteases, even at high concentration and long incubation time. Nor did the threo-peptidyl epoxides inhibit the cysteine proteases. On the other hand, the erythro-peptidyl epoxides were time- and concentration-dependent inactivators of the cysteine proteases. Furthermore, stereoselectivity toward the natural L-amino acid at the P-1 position was also exhibited upon inhibition of papain. In order to demonstrate selectivity within the cysteine protease family, two other erythro-peptidyl epoxides (Cbz-Phe-Ala-epoxide and Cbz-Phe-O-Bn-Tnr-epoxide) were synthesized and tested as inhibitors of the three cysteine proteases. These new peptidyl epoxides exhibited selective inactivation of cysteine proteases, with second-order rate constants (k(i)/K-i) ranging over 4 orders of magnitude (0.04-330 M(-1) s(-1)). Thus, this new family of highly selective cysteine protease inhibitors offers mechanistic implications and may have useful applications.
• Aspartyl .alpha.-((Diphenylphosphinyl)oxy)methyl Ketones as Novel Inhibitors of Interleukin-1.beta. Converting Enzyme. Utility of the Diphenylphosphinic Acid Leaving Group for the Inhibition of Cysteine Proteases
  作者：Roland E. Dolle、Jasbir Singh、David Whipple、I. Kelly Osifo、Gary Speier、Todd L. Graybill、Jill S. Gregory、Alex L. Harris、Carla T. Helaszek

  DOI：10.1021/jm00002a002

  日期：1995.1
• In vivo Inhibition of Cathepsin B by Peptidyl (Acyloxy)methyl Ketones
  作者：Bonnie M. Wagner、Roger A. Smith、Peter J. Coles、Leslie J. Copp、Michael J. Ernest、Allen Krantz

  DOI：10.1021/jm00038a012

  日期：1994.6

  Peptidyl (acyloxy)methyl ketones, previously established as potent irreversible inhibitors of the cysteine proteinase cathepsin B in vitro, were investigated and optimized for their inhibitory activity in vivo. Incorporation of polar or charged functional groups in the inhibitor structure afforded effective cathepsin B inhibition, following dosing to rats. The most effective inhibitor, Z-Phe-Lys-CH2OCO-(2,4,6-Me(3))Ph (8), was found to give ED(50) values of 18 mg/kg po (orally) and 5.0 mg/kg ip (intraperitoneally) at 4-5 h postdose, and 2.4 mg/kg sc (subcutaneously) at 24 h postdose, for liver cathepsin B inhibition (measured ex vivo). The subcutaneous route of administration of (acyloxy)methyl ketone 8 also provided potent cathepsin B inhibition in certain peripheral tissues (e.g., ED(50) 1.0 mg/kg for skeletal muscle, 0.1 mg/kg for heart). These investigations demonstrate that peptidyl (acyloxy)methyl ketones such as 8 have promise as tools for the characterization of in vivo biochemical processes and as therapeutic agents.
• Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases
  作者：Anne-Marie R. Dechert、James P. MacNamara、Sarah R. Breevoort、Emily R. Hildebrandt、Ned W. Hembree、Adam C. Rea、Duncan E. McLain、Stephen B. Porter、Walter K. Schmidt、Timothy M. Dore

  DOI：10.1016/j.bmc.2010.07.041

  日期：2010.9

  Dipeptidyl (acyloxy) methyl ketones (AOMKs) have been identified as mechanism-based inhibitors of certain cysteine proteases. These compounds are also inhibitors of the integral membrane proteins Rce1p and Ste24p, which are proteases that independently mediate a cleavage step associated with the maturation of certain isoprenylated proteins. The enzymatic mechanism of Rce1p is ill-defined, whereas Ste24p is a zinc metalloprotease. Rce1p is required for the proper processing of the oncoprotein Ras and is viewed as a potential target for cancer therapy. In this study, we synthesized a small library of dipeptidyl AOMKs to investigate the structural elements that contribute to the inhibitor properties of this class of molecules toward Rce1p and Ste24p. The compounds were evaluated using a fluorescence-based in vitro proteolysis assay. The most potent dipeptidyl AOMKs contained an arginine residue and the identity of the benzoate group strongly influenced potency. A 'warhead' free AOMK inhibited Rce1p and Ste24p. The data suggest that the dipeptidyl AOMKs are not mechanism-based inhibitors of Rce1p and Ste24p and corroborate the hypothesis that Rce1p is not a cysteine protease. (C) 2010 Elsevier Ltd. All rights reserved.
• New inhibitors of cysteine proteinases. Peptidyl acyloxymethyl ketones and the quiescent nucleofuge strategy
  作者：Roger A. Smith、Leslie J. Copp、Peter J. Coles、Henry W. Pauls、Valerie J. Robinson、Robin W. Spencer、Stephen B. Heard、Allen. Krantz

  DOI：10.1021/ja00221a062

  日期：1988.6