Boc-Tyr-D-Ala-Gly-Phe-OH | 67582-10-9

• 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: Boc-Tyr-D-Ala-Gly-Phe-OH
• 英文别名: (2S)-2-[[2-[[(2R)-2-[[(2S)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoic acid
• CAS: 67582-10-9
• 化学式: C₂₈H₃₆N₄O₈
• 分子量: 556.616
• InChiKey: KIVXMSKOWUNKLJ-WTNAPCKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  40
• 可旋转键数：
  14
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  183
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  Boc-Tyr-D-Ala-Gly-Phe-OH 在 盐酸 、 氨 、 1-羟基苯并三唑 、 溶剂黄146 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 生成 (S)-2-[(S)-2-(2-{(R)-2-[(S)-2-Amino-3-(4-hydroxy-phenyl)-propionylamino]-propionylamino}-acetylamino)-3-phenyl-propionylamino]-4-methylsulfanyl-butyramide
  参考文献：
  名称：

  Audigier; Mazarguil; Gout, European Journal of Medicinal Chemistry, 1980, vol. 15, # 2, p. 173 - 177

  摘要：

  DOI：
• 作为产物：
  描述：

  N-(tert-butyloxycarbonyl)-L-tyrosyl-D-alanine 在 N-羟基丁二酰亚胺 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 Boc-Tyr-D-Ala-Gly-Phe-OH
  参考文献：
  名称：

  Hydrazone Linker as a Useful Tool for Preparing Chimeric Peptide/Nonpeptide Bifunctional Compounds

  摘要：

  The area of multitarget compounds, joining two pharmacophores within one molecule, is a vivid field of research in medicinal chemistry. Not only pharmacophoric elements are essential for the design and activity of such compounds, but the type and length of linkers used to connect them are also crucial. In the present contribution, we describe compound 1 in which a typical opioid peptide sequence is combined with a fragment characteristic for neurokinin-1 receptor (NKIR) antagonists through a hydrazone bridge. The compound has a high affinity for mu- and delta-opioid receptors (IC50=12.7 and 74.0 nM, respectively) and a weak affinity for the NK1R. Molecular modeling and structural considerations explain the observed activities. In in vivo test, intrathecal and intravenous administrations of 1 exhibited a strong analgesic effect, which indicates potential BBB penetration. This letter brings an exemplary application of the hydrazone linker for fast, facile, and successful preparation of chimeric compounds.

  DOI：

  10.1021/acsmedchemlett.6b00381

文献信息

• Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives
  作者：Srinivas Deekonda、Lauren Wugalter、David Rankin、Tally M. Largent-Milnes、Peg Davis、Yue Wang、Neemah M. Bassirirad、Josephine Lai、Vinod Kulkarni、Todd W. Vanderah、Frank Porreca、Victor J. Hruby

  DOI：10.1016/j.bmcl.2015.07.064

  日期：2015.10

  derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have

  我们描述了基于 4-苯胺哌啶衍生物与脑啡肽类似物缀合的新型二价配体的设计和合成。非肽类似物的设计采用含有 5-氨基取代的（四氢萘-2基）甲基的 4-苯胺哌啶衍生物进行探索，而非肽-肽配体则通过缀合脑啡肽类似物的 C 末端（H-Xxx-DAla）进行探索。 -Gly-Phe-OH) 与 4-苯胺基哌啶小分子衍生物的氨基连接，有或没有连接基。对这些新型二价配体在 μ 和 δ 阿片受体的生物活性进行了评估。它们对 μ 和 δ 阿片受体表现出非常好的亲和力，并在 MVD 和 GPI 测定中表现出有效的激动剂活性。其中，先导二价配体17分别对 μ 和 δ 阿片受体表现出优异的结合亲和力（0.1 nM 和 0.5 nM），并且发现在 MVD (56 ± 5.9 nM) 和 GPI (4.6 ± 1.9 nM) 中具有非常有效的激动剂活性）测定。在体内，先导二价配体17表现出与 4-苯胺哌啶衍生物相当的短作用持续时间（<15
• Antinociceptive and Cytotoxic Activity of Opioid Peptides with Hydrazone and Hydrazide Moieties at the C-Terminus
  作者：Jolanta Dyniewicz、Piotr F. J. Lipiński、Piotr Kosson、Marta Bochyńska-Czyż、Joanna Matalińska、Aleksandra Misicka

  DOI：10.3390/molecules25153429

  日期：——

  In the present contribution, we analyze the influence that C-terminal extension of short opioid peptide sequences by organic fragments has on receptor affinity, in vivo analgesic activity, and antimelanoma properties. The considered fragments were based on either N-acylhydrazone (NAH) or N′-acylhydrazide motifs combined with the 3,5-bis(trifluoromethyl)phenyl moiety. Eleven novel compounds were synthesized

  在目前的贡献中，我们分析了有机片段对短阿片肽序列的 C 端延伸对受体亲和力、体内镇痛活性和抗黑色素瘤特性的影响。所考虑的片段基于与 3,5-双（三氟甲基）苯基部分结合的 N-酰基腙（NAH）或 N'-酰基酰肼基序。合成了 11 种新化合物并进行了生物学评价。所分析的化合物对 µ 阿片受体 (MOR) 的亲和力范围广泛，对 δ 阿片受体 (DOR) 的亲和力相当低，并且没有明显的神经激肽-1 受体结合。在四对中的三对中，基于 N-酰腙的衍生物比它们的 N'-酰肼对应物更好地结合 MOR。最好的新型衍生物具有与参考阿片类药物（例如吗啡和双啡肽）相似的低纳摩尔 MOR 结合亲和力。将获得的 MOR 亲和力的顺序与分子对接的结果进行比较。在体内，四种测试化合物被证明是相对强的镇痛剂。最后，基于 NAH 的类似物减少了细胞培养中黑色素瘤细胞的数量，而它们的 N'-酰肼对应物则不会。抗黑色素瘤特性与化合物的亲脂性大致相关。而他们的
• METHOD OF PRODUCING A NOVEL OPIOID PEPTIDE
  申请人：LIPKOWSKI Andrej

  公开号：US20120004180A1

  公开（公告）日：2012-01-05

  The use of opioid peptides of a novel structure is claimed which, in addition to a pharmacophore, additionally contain structural elements reactive with tachykinin receptors. Due to the synergistic reactivity of the opioid with an additional element, an increased analgesic activity is obtained facilitating protracted effective use due to decreased drug tolerance effects. The drugs may particularly be of use in the treatment of chronic pain as effective analgesics during inflammation caused by rheumatism, gout, neurodegenerative states, post-surgical and post-traumatic inflammations or ones induced by tumours.

  本发明声明了一种新结构的阿片肽的使用，除了具有药效团以外，还含有与速激肽受体反应的结构元素。由于阿片与附加元素的协同反应，获得了增强的镇痛活性，减少了药物耐受性效应，便于长期有效使用。该药物可特别用于治疗慢性疼痛，作为治疗风湿病、痛风、神经退行性疾病、手术后和创伤后炎症或肿瘤引起的炎症的有效镇痛剂。
• Enkephalin analogues with N-phenyl-N-(piperidin-2-ylmethyl)propionamide derivatives: Synthesis and biological evaluations
  作者：Srinivas Deekonda、Jacob Cole、Sydney Sunna、David Rankin、Tally M. Largent-Milnes、Peg Davis、Neemah M. BassiriRad、Josephine Lai、Todd W. Vanderah、Frank Porecca、Victor J. Hruby

  DOI：10.1016/j.bmcl.2015.10.081

  日期：2016.1

  displayed potent agonist activities as well. The replacement of Tyr with Dmt and introduction of a linker between the small molecule and enkephalin analogue resulted in highly potent ligands. Both series of ligands showed excellent binding affinities at both μ (0.6–0.9 nM) and δ (0.2–1.2 nM) opioid receptors respectively. Similarly, these bivalent ligands exhibited potent agonist activities in both MVD

  基于N-苯基-N- (哌啶-2-基甲基)丙酰胺的二价配体尚未被探索用于基于阿片类药物的配体的设计。设计并合成了两个系列的杂化分子，其带有N-苯基-N- (哌啶-2-基甲基)丙酰胺衍生的小分子，与带有和不带有连接子（β-丙氨酸）的脑啡肽类似物缀合。两个二价配体系列均在μ和δ阿片受体上表现出从纳摩尔到亚纳摩尔范围的显着结合亲和力，并且还表现出有效的激动剂活性。用 Dmt 取代 Tyr 并在小分子和脑啡肽类似物之间引入连接子，产生了高效的配体。两个系列的配体分别对 μ (0.6–0.9 nM) 和 δ (0.2–1.2 nM) 阿片受体表现出优异的结合亲和力。同样，这些二价配体在 MVD 和 GPI 测定中均表现出有效的激动剂活性。脊髓给药后，在未受伤的大鼠中评价配体17 的体内抗伤害活性。配体17在缓解急性疼痛方面没有显着效果。尽管体外结合亲和力高、体外活性适中，但对体内内在功效低的最可能的解
• Development of Novel Enkephalin Analogues that Have Enhanced Opioid Activities at Both μ and δ Opioid Receptors
  作者：Yeon Sun Lee、Ravil Petrov、Chad K. Park、Shou-wu Ma、Peg Davis、Josephine Lai、Frank Porreca、Ruben Vardanyan、Victor J. Hruby

  DOI：10.1021/jm061465o

  日期：2007.11.1

  Enkephalin analogues with a 4-anilidopiperidine scaffold have been designed and synthesized to achieve therapeutic benefit for the treatment of pain due to mixed mu and delta opioid agonist activities. Ligand 16, in which a Dmt-substituted enkephalin-like structure was linked to the N-phenyl-N-piperidin-4-yl propionamide moiety, showed very high binding affinities (0.4 nM) at mu and delta receptors with an increased hydrophobicity (aLogP = 2.96). This novel lead compound was found to have very potent agonist activities in MVD (1.8 nM) and GPI (8.5 nM) assays.