Z-Ile-H | 149357-59-5

• 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: Z-Ile-H
• 英文别名: Cbz-isoleucinal；Cbz-L-Ile-H；(S,S)-N-Cbz-isoleucinal；Z-L-Ile-H；(2S,3S)-3-methyl-1-oxopentane-2-benzylcarbamate；(S)-N-Cbz-isoleucinal；Z-isoleucine；Z-Ile；benzyl N-[(2S,3S)-3-methyl-1-oxopentan-2-yl]carbamate
• CAS: 149357-59-5
• 化学式: C₁₄H₁₉NO₃
• 分子量: 249.31
• InChiKey: VJCXBFMFEZXGDB-WCQYABFASA-N

物化性质

• 沸点：
  380.3±35.0 °C(Predicted)
• 密度：
  1.076±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  18
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  Z-Ile-H 在 palladium on activated charcoal lithium hydroxide 、 氢气 、 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 98.0h， 生成
  参考文献：
  名称：

  Design of a Potent Combined Pseudopeptide Endothelin-A/Endothelin-B Receptor Antagonist, Ac-dBhg¹⁶-Leu-Asp-Ile-[NMe]Ile-Trp²¹ (PD 156252):  Examination of Its Pharmacokinetic and Spectral Properties

  摘要：

  The endothelins (ETs) are a family of bicyclic 21-amino acid peptides that are potent and prolonged vasoconstrictors. It has been shown that highly potent combined ETA/ETB receptor antagonists can be developed from the C-terminal hexapeptide of ET (His(16)-Leu(17)-Asp(18)-Ile(19)-Ile(20)-Trp(21)), such as Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 142893) and Ac-DBhg(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 145065). However, these compounds are relatively unstable to enzymatic proteolysis as determined in an in vitro rat intestinal perfusate assay. This instability is thought to be due to carboxypeptidase activity. In fact, incubation of PD 145065 with carboxypeptidase inhibitors greatly increased its half-life in rat intestinal perfusate. By performing a reduced amide bond and N-methyl amino acid scan, it was discovered that N-methylation of Ile(20) resulted in a compound (Ac-DBhg(16)-Leu-Asp-Ile-[NMe]Ile-Trp(21), PD 156252) that retained full receptor affinity at both endothelin receptor subtypes along with enhanced proteolytic stability and cellular permeability. Interestingly, N-methylation of this bond allows the cis configuration to be readily accessible which greatly alters the preferred structure of the entire molecule and may be responsible for the observed enhanced metabolic stability.

  DOI：

  10.1021/jm970161m
• 作为产物：
  描述：

  benzyl ((2S,3S)-1-(methoxy(methyl)amino)-3-methyl-1-oxopentan-2-yl)carbamate 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 生成 Z-Ile-H
  参考文献：
  名称：

  Design of a Potent Combined Pseudopeptide Endothelin-A/Endothelin-B Receptor Antagonist, Ac-dBhg¹⁶-Leu-Asp-Ile-[NMe]Ile-Trp²¹ (PD 156252):  Examination of Its Pharmacokinetic and Spectral Properties

  摘要：

  The endothelins (ETs) are a family of bicyclic 21-amino acid peptides that are potent and prolonged vasoconstrictors. It has been shown that highly potent combined ETA/ETB receptor antagonists can be developed from the C-terminal hexapeptide of ET (His(16)-Leu(17)-Asp(18)-Ile(19)-Ile(20)-Trp(21)), such as Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 142893) and Ac-DBhg(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 145065). However, these compounds are relatively unstable to enzymatic proteolysis as determined in an in vitro rat intestinal perfusate assay. This instability is thought to be due to carboxypeptidase activity. In fact, incubation of PD 145065 with carboxypeptidase inhibitors greatly increased its half-life in rat intestinal perfusate. By performing a reduced amide bond and N-methyl amino acid scan, it was discovered that N-methylation of Ile(20) resulted in a compound (Ac-DBhg(16)-Leu-Asp-Ile-[NMe]Ile-Trp(21), PD 156252) that retained full receptor affinity at both endothelin receptor subtypes along with enhanced proteolytic stability and cellular permeability. Interestingly, N-methylation of this bond allows the cis configuration to be readily accessible which greatly alters the preferred structure of the entire molecule and may be responsible for the observed enhanced metabolic stability.

  DOI：

  10.1021/jm970161m

文献信息

• CYTOTOXIC PEPTIDES AND ANTIBODY DRUG CONJUGATES THEREOF
  申请人：PFIZER INC.

  公开号：US20130129753A1

  公开（公告）日：2013-05-23

  The present invention is directed to cytotoxic pentapeptides, to antibody drug conjugates thereof, and to methods for using the same to treat cancer.

  本发明涉及细胞毒性五肽，其抗体药物偶联物，以及使用它们治疗癌症的方法。
• Efficient Access to Enantiopure γ⁴-Amino Acids with Proteinogenic Side-Chains and Structural Investigation of γ⁴-Asn and γ⁴-Ser in Hybrid Peptide Helices
  作者：Sandip V. Jadhav、Rajkumar Misra、Sumeet K. Singh、Hosahudya N. Gopi

  DOI：10.1002/chem.201302732

  日期：2013.11.25

  to fold into ordered helical structures. As amino acid side‐chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of γ4‐residues with functional proteinogenic side‐chains and their structural analysis in hybrid‐peptide sequences. Here, the efficient and enantiopure synthesis of various N‐ and C‐terminal free‐γ4‐residues

  由α-和β-氨基酸组成的杂合肽最近已成为一类新型的肽折叠剂。相比较而言，γ的组成γ-和混合γ-肽4 -氨基酸比其β-对应物少的研究。然而，最近的研究表明，γ 4 -氨基酸有较高的倾向折叠成有序的螺旋结构。作为氨基酸侧链的官能团起到生物上下文中的关键作用，本研究的目的是调查γ的有效合成4 -残基与官能蛋白原侧链和在混合的肽序列的结构分析。在这里，各种N-末端和C-末端游离-γ的有效和对映体纯合成4-残基，从苄基酯（COOBzl）起始Ñ -Cbz保护的（ë）- α，报道β不饱和γ氨基通过在单锅催化氢化多个氢解和双键还原酸。8未受保护的γ的结晶构象，4 -氨基酸（γ 4 -Val，γ 4 -Leu，γ 4 -Ile，γ 4 -Thr（O吨丁基），γ 4 -Tyr，γ 4 -Asp（O吨卜），γ 4 -Glu（O吨丁基），和γ-AIB）显示，这些氨基酸通过一个螺旋利于笨拙沿着中心Ç构象γ  Ç β键。来研究γ行为4
• Aminoalkyl-Substituted α-Methylene-γ-butyrolactones from α-Amino Acids Using an Indium-Mediated Barbier Allyl Addition
  作者：Steffen Steurer、Joachim Podlech

  DOI：10.1002/(sici)1099-0690(199907)1999:7<1551::aid-ejoc1551>3.0.co;2-8

  日期：1999.7

  The indium-mediated reaction of Z-protected α-amino aldehydes 1–6 with 2-(bromomethyl)acrylates 8/9 in aqueous solvents has been investigated. The preference for the formation of syn-configured homoallyl alcohols 10–16 (diastereoselectivities ranging from 2:1 to 32:1, yields 68–93%) may be explained by a chelate-controlled reaction. No racemization occurred during the preparation and transformation

  Z-保护的α氨基醛的铟-介导的反应1 - 6与2-（溴甲基）丙烯酸酯8 / 9在水性溶剂中进行了研究。可以通过螯合物控制的反应来解释偏爱形成顺式配置的烯丙基醇10 – 16（非对映选择性范围为2：1至32：1，收率68–93％）。在氨基醛的制备和转化过程中未发生外消旋作用。酸催化的酯化反应（在Et 2 O中为H 2 SO 4）导致α-亚甲基-γ-丁内酯17 – 22产率从89％到97％不等。通过五个X射线晶体学分析和NMR谱图的比较，确定了所有非对映异构体的构型。
• A new method to synthesize .ALPHA.-aminoaldehydes.
  作者：AKIRA ITO、RIEKO TAKAHASHI、YOSHIHIKO BABA

  DOI：10.1248/cpb.23.3081

  日期：——

  Benzyloxycarbonyl (Cbz)-amino acid esters were reduced to the corresponding α-aminoaldehydes with diisobutylaluminum hydride. Comparison of specific rotation of the Cbz-aminoalcohols, which were derived from the aldehydes by sodium borohydride reduction, with that of the optically pure material showed that chromatography on a silica gel caused marked racemization in the Cbz-α-aminoaldehyde through keto-enol tautomerism. Cbz-S-Bzl-cysteinal was liable to racemize to a great extent. On the other hand, little racemization occurred in Cbz-NG-nitroargininal. This fact might be accounted for the characteristic cyclic carbinolamine structure of the argininal derivative. The semicarbazones prepared from the crude Cbz-α-aminoaldehydes could be reproduced to the initial aldehydes without racemization. These semicarbazones might be used as good starting materials in peptide aldehyde synthesis.

  苄氧羰基（Cbz）氨基酸酯通过二异丁基铝氢化物还原为相应的α-氨基醛。通过钠硼氢化物还原得到的Cbz-氨基醇的特定旋转与光学纯材料的比较表明，在硅胶上进行色谱分离会显著导致Cbz-α-氨基醛的变旋现象，这是通过酮-烯醇的互变异构造成的。Cbz-S-Bzl-半胱氨酸易于显著变旋。另一方面，Cbz-NG-硝基精氨酸醛的变旋现象很少。这一事实可能与精氨酸衍生物特有的环状卡宾醇胺结构有关。由粗制Cbz-α-氨基醛制备的半卡宾酮可以不发生变旋地再生成为初始的醛。这些半卡宾酮可能作为肽醛合成的良好起始材料。
• A Second-Generation Cycloaddition Route to 5-Substituted 3-Acyltetramic Acids
  作者：Raymond C. F. Jones、Claire E. Dawson、Mary J. O'Mahony

  DOI：10.1055/s-1999-3091

  日期：——

  The 1,3-dipolar cycloaddition of α-aminonitrile oxides, formed from α-amino-acids, to enamines of β-ketoesters affords 3-(1-aminoalkyl)isoxazole-4-carboxylic esters that are converted via pyrrolo[3,4-c]isoxazol-4-ones into 5-substituted 3-acetyltetramic acids.

  α-氨基腈氧化物与β-酮酯的寡肽烯烃发生1,3-偶极环加成反应，生成3-(1-氨基烷基)异噁唑-4-羧酸酯，随后通过吡咯并[3,4-c]异噁唑-4-酮转化为5-取代的3-乙酰基四氨酸。