{1-[(R/S)-hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-(S)-methyl]-3-methylbutyl}carbamic acid tert-butyl ester | 660847-45-0

• 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: {1-[(R/S)-hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-(S)-methyl]-3-methylbutyl}carbamic acid tert-butyl ester
• 英文别名: {1-[hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)methyl]-3-methylbutyl}carbamic acid tert-butyl ester；tert-butyl N-[(2S)-1-hydroxy-4-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)pentan-2-yl]carbamate
• CAS: 660847-45-0
• 化学式: C₁₉H₂₇N₃O₄
• 分子量: 361.441
• InChiKey: ATXUWRHAIXGOFG-MLCCFXAWSA-N

物化性质

• 密度：
  1.141±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  97.5
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  {1-[(R/S)-hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-(S)-methyl]-3-methylbutyl}carbamic acid tert-butyl ester 在 N-甲基吗啉 、 盐酸 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 7.0h， 生成 2-(S)-amino-N-{1(R/S)-[hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-(S)-methyl]-3-methylbutyl}-3-methoxypropionamide hydrochloride
  参考文献：
  名称：

  Optimization of Subsite Binding to the β5 Subunit of the Human 20S Proteasome Using Vinyl Sulfones and 2-Keto-1,3,4-oxadiazoles:  Syntheses and Cellular Properties of Potent, Selective Proteasome Inhibitors

  摘要：

  Beginning with the peptide sequence Cbz-Ile-Glu(OtBu)-Ala-Leu found in PSI (3), a series of vinyl sulfones (VS) were synthesized for evaluation as inhibitors of the chymotrypsin-like activity of the 20S proteasome. Variations at the key P3 position confirmed the importance of a long side chain capped with a hydrophobic group for optimal potency, consistent with a model of binding to the S3 subsite. The tert-butyl glutamic ester initially used at P3 gave plasma unstable, insoluble compounds and was replaced with the better isostere, N-beta-neopentyl asparagine. The inhibitors were shortened by replacing the N-terminal Cbz-isoleucine with a p-tosyl group without loss of potency. Small L-amino acids were used at P2, where D-substitution was not tolerated. The resulting optimized P4-P3-P2 sequence was grafted onto a novel proteasome inhibitor warhead, 2-keto-1,3,4-oxadiazoles (KOD), to produce reversible, subnanomolar proteasome inhibitors that were 1000-fold selective versus cathepsin B (CatB), cathepsin S (CatS), and trypsin-like as well as PGPH-like proteasome activity. A number of compounds in both the VS and the KOD series exhibited growth inhibitory effects against the human prostate cancer cell line PC3 at submicromolar concentrations.

  DOI：

  10.1021/jm058289o
• 作为产物：
  描述：

  2-苯基-1,3,4-噁二唑 、 2-甲基-2-丙基[(2S)-4-甲基-1-氧代-2-戊烷基]氨基甲酸酯 在 正丁基锂 、 magnesium bromide 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 3.5h， 以70%的产率得到{1-[(R/S)-hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-(S)-methyl]-3-methylbutyl}carbamic acid tert-butyl ester
  参考文献：
  名称：

  Optimization of Subsite Binding to the β5 Subunit of the Human 20S Proteasome Using Vinyl Sulfones and 2-Keto-1,3,4-oxadiazoles:  Syntheses and Cellular Properties of Potent, Selective Proteasome Inhibitors

  摘要：

  Beginning with the peptide sequence Cbz-Ile-Glu(OtBu)-Ala-Leu found in PSI (3), a series of vinyl sulfones (VS) were synthesized for evaluation as inhibitors of the chymotrypsin-like activity of the 20S proteasome. Variations at the key P3 position confirmed the importance of a long side chain capped with a hydrophobic group for optimal potency, consistent with a model of binding to the S3 subsite. The tert-butyl glutamic ester initially used at P3 gave plasma unstable, insoluble compounds and was replaced with the better isostere, N-beta-neopentyl asparagine. The inhibitors were shortened by replacing the N-terminal Cbz-isoleucine with a p-tosyl group without loss of potency. Small L-amino acids were used at P2, where D-substitution was not tolerated. The resulting optimized P4-P3-P2 sequence was grafted onto a novel proteasome inhibitor warhead, 2-keto-1,3,4-oxadiazoles (KOD), to produce reversible, subnanomolar proteasome inhibitors that were 1000-fold selective versus cathepsin B (CatB), cathepsin S (CatS), and trypsin-like as well as PGPH-like proteasome activity. A number of compounds in both the VS and the KOD series exhibited growth inhibitory effects against the human prostate cancer cell line PC3 at submicromolar concentrations.

  DOI：

  10.1021/jm058289o

文献信息

• [EN] PROTEASOME INHIBITORS : PEPTIDE DERIVATIVES HAVING C-TERMINAL HETEROARYL GROUPS<br/>[FR] INHIBITEURS DU PROTEASOME : DERIVES PEPTIDIQUES COMPRENANT DES GROUPES HETEROARYLE C-TERMINAUX
  申请人：AXYS PHARMACEUTICALS

  公开号：WO2004014882A3

  公开（公告）日：2004-08-05
• Optimization of Subsite Binding to the β5 Subunit of the Human 20S Proteasome Using Vinyl Sulfones and 2-Keto-1,3,4-oxadiazoles:  Syntheses and Cellular Properties of Potent, Selective Proteasome Inhibitors
  作者：Robert M. Rydzewski、Leland Burrill、Rohan Mendonca、James T. Palmer、Mark Rice、Ram Tahilramani、Kathryn E. Bass、Ling Leung、Erik Gjerstad、James W. Janc、Lin Pan

  DOI：10.1021/jm058289o

  日期：2006.5.1

  Beginning with the peptide sequence Cbz-Ile-Glu(OtBu)-Ala-Leu found in PSI (3), a series of vinyl sulfones (VS) were synthesized for evaluation as inhibitors of the chymotrypsin-like activity of the 20S proteasome. Variations at the key P3 position confirmed the importance of a long side chain capped with a hydrophobic group for optimal potency, consistent with a model of binding to the S3 subsite. The tert-butyl glutamic ester initially used at P3 gave plasma unstable, insoluble compounds and was replaced with the better isostere, N-beta-neopentyl asparagine. The inhibitors were shortened by replacing the N-terminal Cbz-isoleucine with a p-tosyl group without loss of potency. Small L-amino acids were used at P2, where D-substitution was not tolerated. The resulting optimized P4-P3-P2 sequence was grafted onto a novel proteasome inhibitor warhead, 2-keto-1,3,4-oxadiazoles (KOD), to produce reversible, subnanomolar proteasome inhibitors that were 1000-fold selective versus cathepsin B (CatB), cathepsin S (CatS), and trypsin-like as well as PGPH-like proteasome activity. A number of compounds in both the VS and the KOD series exhibited growth inhibitory effects against the human prostate cancer cell line PC3 at submicromolar concentrations.