甲基-L-亮氨酸甲酯 | 35026-08-5

• 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
• 中文名称: 甲基-L-亮氨酸甲酯
• 英文名称: N-methyl-L-leucine methyl ester
• 英文别名: N-methylleucine ester；N-methyl-L-leucinate；H-MeLeu-OMe；L-N-(Me)Leu-OMe；N-Me-L-Leu-OMe；H-NMe-Leu-OMe；methyl (2S)-4-methyl-2-(methylamino)pentanoate
• CAS: 35026-08-5
• 化学式: C₈H₁₇NO₂
• mdl: MFCD20661241
• 分子量: 159.228
• InChiKey: NYXMJFGTJZTHPT-ZETCQYMHSA-N

物化性质

• 沸点：
  190.7±23.0 °C(Predicted)
• 密度：
  0.917±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  11
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.875
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  甲基-L-亮氨酸甲酯 在 3-(二乙氧基邻酰氧基)-1,2,3-苯并三嗪-4-酮 盐酸 、 lithium hydroxide 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 苯甲醚 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 生成 cyclo[Leu-N(Me)Leu-Val-Leu-Phe]
  参考文献：
  名称：

  Synthesis of Second-Generation Sansalvamide A Derivatives: Novel Templates as Potential Antitumor Agents

  摘要：

  We report the synthesis of 34 second-generation Sansalvamide A derivatives. San A derivatives have unique anticancer properties and target multiple cancers, including colon, pancreatic, breast, prostate, and melanoma. As novel templates, the derivatives described herein explore the role of stereochemistry, amide bond geometry, transannular hydrogen bonding, and polarity on antitumor potency. Testing the chemotherapeutic activity of these derivatives against multiple cancer cell lines will provide clear structural motifs and identify conformational space that is important for cytotoxicity. The 34 compounds presented are divided into six series, where five series involve the insertion of D-amino acids in conjunction with four structural features at each of the five positions of the macrocycle. The sixth series involves comparison between all L- and all D-amino acid derivatives with N-methyls placed at each position around the macrocyclic core. The four structural features explored in conjunction with D-amino acids include N-methyl amino acids, aromatic amino acids, polar amino acids, and hydrophobic alkyl amino acids.

  DOI：

  10.1021/jo061830j
• 作为产物：
  描述：

  L-亮氨酸甲酯盐酸盐 在 吡啶 、 sodium methylate 、 巯基乙酸 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 、 乙腈 为溶剂， 生成 甲基-L-亮氨酸甲酯
  参考文献：
  名称：

  Di Gioia, Maria Luisa; Leggio, Antonella; Le Pera, Adolfo, Journal of Organic Chemistry, 2003, vol. 68, # 19, p. 7416 - 7421

  摘要：

  DOI：

文献信息

• Synthesis and Biological Activity of Peptides Related to Eledoisin. II. Hexapeptide Amides Containing<i>N</i>-Methylamino Acids
  作者：Hiroshi Sugano、Ko Higaki、Muneji Miyoshi

  DOI：10.1246/bcsj.46.231

  日期：1973.1

  Eledoisin-like hexapeptides were synthesized in order to obtain longer-lasting hypotensive analogs. A part of the amino acid of the standard pep tide, H–Lys–Phe–Ile–Gly–Leu–Met–NH2 (1), was replaced by N-methylamino acid. It was found, in these syntheses, that when the C-terminal amino acid of a carboxy component was an N-methylamino acid, a system of dicyclohexylcarbodiimide plus 1-hydroxybenzotriazole was a useful coupling agent. With regard to the hypotensive effect in rabbits, H–Lys–Phe–Melle–Gly–Leu–Met–NH2 (2) and H–Lys–Phe–Ile–Gly–Melle–Met–NH2 (6) show much less activity; H–Lys–MePhe–Ile–Gly–Leu–Met–NH2 (3) and H–Lys–MePhe–Ile–Gly–MeLeu–Met–NH2 (7) show a substantial activity, though weaker than the standard one. On the other hand, H–Lys–Phe–Ile–Gly–MeLeu–Met–NH2 (5) and H–Lys–Phe–Ile–Sar–Leu–Met–NH2(4) show a higher activity than 1. These results indicate that, in some cases, the replacement of an amide bond by an N-methylamide bond without any change in the side chain of amino acid would have an important influence on the activity. The duration of the action of N-methypeptildes synthesized was unexpectedly of the same order of magnitude as that of 1.

  为获得更持久降压效果的模拟物，合成了促咽激素样六肽。将标准肽H-Lys-Phe-Ile-Gly-Leu-Met-NH2（1）中的部分氨基酸替换为N-甲基氨基酸。在这些合成中，发现当羧基部分C末端氨基酸为N-甲基氨基酸时，二环己基碳二亚胺加1-羟基苯并三唑是一种有用的偶联剂。关于对兔子的降压效果，H-Lys-Phe-Melle-Gly-Leu-Met-NH2（2）和H-Lys-Phe-Ile-Gly-Melle-Met-NH2（6）的活性大大降低；H-Lys-MePhe-Ile-Gly-Leu-Met-NH2（3）和H-Lys-MePhe-Ile-Gly-MeLeu-Met-NH2（7）显示出相当的活性，尽管弱于标准肽。另一方面，H-Lys-Phe-Ile-Gly-MeLeu-Met-NH2（5）和H-Lys-Phe-Ile-Sar-Leu-Met-NH2（4）的活性高于1。这些结果表明，在某些情况下，将酰胺键替换为N-甲基酰胺键而不改变氨基酸侧链会对活性产生重要影响。合成的N-甲基肽的作用持续时间与1相当。
• [EN] PEPTIDOMIMETIC N5-METHYL-N2-(NONANOYL-L-LEUCYL)-L-GLUTAMINATE DERIVATIVES, TRIAZASPIRO[4.14]NONADECANE DERIVATIVES AND SIMILAR COMPOUNDS AS INHIBITORS OF NOROVIRUS AND CORONAVIRUS REPLICATION<br/>[FR] DÉRIVÉS DE N5-MÉTHYL-N2-(NONANOYL-L-LEUCYL)-L-GLUTAMINATE PEPTIDOMIMÉTIQUES, DÉRIVÉS DE TRIAZASPIRO[4.14]NONADÉCANE ET COMPOSÉS SIMILAIRES UTILISÉS EN TANT QU'INHIBITEURS DE RÉPLICATION DE NOROVIRUS ET DE CORONAVIRUS
  申请人：COCRYSTAL PHARMA INC

  公开号：WO2021188620A1

  公开（公告）日：2021-09-23

  Peptidomimetic N5-methyl-N2-(nonanoyl-L-leucyl)-L-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds for use in methods of inhibiting the replication of noroviruses and coronaviruses in a biological sample or patient, for use in reducing the amount of noroviruses or coronaviruses in a biological sample or patient, and for use in treating norovirus and coronavirus in a patient, comprising administering to said biological sample or patient a safe and effective amount of a compound represented by formulae I or II, or a pharmaceutically acceptable salt thereof. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. page 99 to page 271; examples 1 to 3; compounds A1 to A104 and Bl to B66; tables A to E).

  肽拟态N5-甲基-N2-(壬酰基-L-亮氨酰基)-L-谷氨酸衍生物，三唑螺[4.14]十九烷衍生物以及类似化合物用于抑制生物样本或患者中诺如病毒和冠状病毒的复制，用于减少生物样本或患者中诺如病毒或冠状病毒的数量，以及用于治疗患者中的诺如病毒和冠状病毒，包括向所述生物样本或患者施用由公式I或II表示的化合物的安全有效量，或其药用可接受盐。本描述公开了典型化合物的合成和特性，以及其药理数据（例如，第99页至第271页；例1至例3；化合物A1至A104和B1至B66；表A至表E）。
• Preparation and Evaluation at the Delta Opioid Receptor of a Series of Linear Leu-Enkephalin Analogues Obtained by Systematic Replacement of the Amides
  作者：Kristina Rochon、Arnaud Proteau-Gagné、Philippe Bourassa、Jean-François Nadon、Jérome Côté、Véronique Bournival、Fernand Gobeil、Brigitte Guérin、Yves L. Dory、Louis Gendron

  DOI：10.1021/cn4000583

  日期：2013.8.21

  receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogues were also measured. Our results revealed that the last amide bond can be successfully replaced by either an ester or an N-methyl amide bond without significantly decreasing the biological activity of the corresponding analogues when compared to Leu-enkephalin. The peptidomimetics with an N-methyl amide function between

  使用经典有机化学和固相肽合成 (SPPS) 制备亮氨酸脑啡肽类似物，其中酰胺键被酯或N-甲基酰胺键顺序和系统地取代。使用竞争结合、ERK1/2 磷酸化、受体内化和收缩性测定来表征肽模拟物，以评估它们对 delta 阿片受体 (DOPr) 的药理学特征。还测量了活性类似物的亲脂性(LogD 7.4 )和血浆稳定性。我们的结果表明，最后一个酰胺键可以被酯或N成功取代与亮氨酸脑啡肽相比，-甲基酰胺键不会显着降低相应类似物的生物活性。发现在残基 Phe 和 Leu 之间具有N-甲基酰胺功能的肽模拟物比 Leu-脑啡肽更亲脂且更稳定。本研究的结果进一步表明，亮氨酸脑啡肽的第四个酰胺的氢键供体性质对其对 DOPr 的生物活性并不重要。我们的结果表明，用等排功能系统地替换酰胺键代表了一种设计和合成具有增强稳定性的新型肽类似物的有效方法。我们的研究结果进一步表明，这种策略也可用于研究酰胺键的生物学作用。
• Synthesis of sansalvamide A peptidomimetics: triazole, oxazole, thiazole, and pseudoproline containing compounds
  作者：Melinda R. Davis、Erinprit K. Singh、Hendra Wahyudi、Leslie D. Alexander、Joseph B. Kunicki、Lidia A. Nazarova、Kelly A. Fairweather、Andrew M. Giltrap、Katrina A. Jolliffe、Shelli R. McAlpine

  DOI：10.1016/j.tet.2011.11.089

  日期：2012.1

  heterocycles (triazoles, oxazoles, thiazoles, or pseudoprolines) along the macrocyclic backbone. The syntheses of these derivatives employ several approaches that can be applied to convert a macrocyclic peptide into its peptidomimetic counterpart. These approaches include peptide modifications to generate the alkyne and azide for click chemistry, a serine conversion into an oxazole, a Hantzsch reaction

  与用肽类似物观察到的相比，基于肽模拟物的大环化合物通常具有改进的药代动力学特性。描述了基于活性 sansalvamide A 结构的 13 种拟肽衍生物的合成，其中这些类似物沿大环骨架包含杂环（三唑、恶唑、噻唑或假脯氨酸）。这些衍生物的合成采用了几种可用于将大环肽转化为其拟肽对应物的方法。这些方法包括肽修饰以生成用于点击化学的炔烃和叠氮化物、丝氨酸转化为恶唑、Hantzsch 反应生成噻唑以及保护苏氨酸生成假脯氨酸衍生物。此外，我们展示了两种不同的拟肽部分，三唑和噻唑，
• Toward the Synthesis and Improved Biopotential of an N-methylated Analog of a Proline-Rich Cyclic Tetrapeptide from Marine Bacteria
  作者：Rajiv Dahiya、Suresh Kumar、Sukhbir Khokra、Sheeba Gupta、Vijaykumar Sutariya、Deepak Bhatia、Ajay Sharma、Shamjeet Singh、Sandeep Maharaj

  DOI：10.3390/md16090305

  日期：——

  tetrapeptide fragment under alkaline conditions. The structure of the synthesized cyclooligopeptide was confirmed using quantitative elemental analysis, FTIR (Fourier-transform infrared spectroscopy), ¹H NMR (Nuclear magnetic resonance spectroscopy), 13C NMR, and mass spectrometry. From the bioactivity results, it was clear that the newly synthesized proline-rich tetracyclopeptide exhibited better anthelmintic

  通过偶联去保护的二肽片段Boc-1-脯氨酰-1N-甲基亮氨酸-OH和1-脯氨酰-1N-甲基苯丙氨酸-OMe，合成了源自海洋细菌的天然富含脯氨酸的四环肽的N-甲基化类似物。以N,N'-二环己基碳二亚胺(DCC)和1-乙基-3-(3-二甲氨基丙基)碳二亚胺(EDC·HCl)为偶联剂，三乙胺(TEA)或N-甲基吗啉(NMM)为偶联剂，完成偶联反应。碱在外消旋抑制剂存在下。随后线性四肽片段在碱性条件下环化。使用定量元素分析、FTIR（傅里叶变换红外光谱）、1H NMR（核磁共振光谱）、13C NMR 和质谱法确认了合成的环寡肽的结构。从生物活性结果来看，新合成的富含脯氨酸的四环肽在浓度为 2 mg/mL 时对康卡巨藻、Pontoscotex corethruses 和 Eudrilus eugeniae 表现出更好的驱虫潜力，并且对致病性皮肤癣菌、毛癣菌和须癣菌具有更好的抗真菌活性。与非甲基化四环肽相比，奥杜氏小孢子菌浓度为