N^α-Boc-D-Trp(Nⁱⁿ-MeS)

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N^α-Boc-D-Trp(Nⁱⁿ-MeS)
• 英文别名: N^α-Boc-DTrp (Nⁱⁿ-MeS)；Boc-D-Trp(Bes(2,4,6-triMe))(Bes(2,4,6-triMe))-OH；(2R)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[1-(2,4,6-trimethylphenyl)sulfonylindol-3-yl]propanoic acid
• 化学式: C₂₅H₃₀N₂O₆S
• 分子量: 486.589
• InChiKey: FKFFMEHZWLQPKM-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  123
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-叔丁氧羰基-N'-甲苯磺酰基-L-精氨酸 、 NAlpha-BOC-Nε-FMOC-L-赖氨酸 、 Boc-D-苯丙氨酸 、 N^α-Boc-D-Trp(Nⁱⁿ-MeS) 、 alkaline earth salt of/the/ methylsulfuric acid 生成 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Lys)-NH2
  参考文献：
  名称：

  β-Methylation of the Phe⁷ and Trp⁹ Melanotropin Side Chain Pharmacophores Affects Ligand−Receptor Interactions and Prolonged Biological Activity

  摘要：

  Topographically modified melanotropin side chain pharmacophore residues Phe(7) and Trp(9) in a cyclic peptide template (Ac-Nle(4)-c[Asp-His-Xaa(7)-Arg-Yaa(9)-Lys]-NH2) and Phe(7) in a linear peptide template (Ac-Ser-Tyr-Ser-Nle(4)-Glu-His-Xaa(7)-Arg-Trp-Gly-Lys-Pro-Val-NH2) result in differences in potency and prolonged biological activity in the frog and lizard skin bioassays. These topographic modifications included the four isomers of beta-methylphenylalanine (beta-MePhe)(7) and beta-methyltryptophan (beta-MeTrp)(9) and the two isomers of 1,2,3,4-tetrahydro-beta-carboline (Tea)(9) Modifications in the cyclic template resulted in up to a 1000-fold difference in potency for the beta-MePhe(7) stereoisomeric peptides; up to a 476-fold difference in potency resulted for the beta-MeTrp(9) peptides, and about a 50-fold difference between the Tca(9)-containing peptides. Up to a 40-fold difference in potency resulted for the beta-MePhe(7)? stereoisomeric peptides using the linear template in these assays. The relative potency racing for modifications in the cyclic template of beta-MePhe(7) were 2R,3S > 2S,3S = 2S,3R 2 > 2R,3R in the frog assay and 2S,3R > 2R,3S > 2S,3S > 2R,3R in the lizard assay. The relative potencies for modifications in the cyclic template of beta-MeTrp(9) were 2R,3S > 2R,3R > 2S,3R > 2S,3R in the frog assay and 2S,3S = 2R,3R > 2R,3S > 2S,3R in the lizard assay. The relative potencies for modifications in the cyclic template of Tca(9) were DTca > LTca in both assays, Significant differences in prolonged (residual) activities were also observed for these modified peptides and were dependent upon stereochemistry of the beta-methyl amino acid, peptide template, and bioassay system. Furthermore, comparisons of beta-MeTrp(9) stereoisomeric peptides on the frog, lizard, and human MC1 receptors suggest that structure-activity relationships on both the classical frog and lizard skin bioassays do not necessarily predict corresponding SAR profiles for the human melanocortin receptors, indicating a remarkable species specificity of the MC1 receptor requirements.

  DOI：

  10.1021/jm970018t

文献信息

• Topographical modification of melanotropin peptide analogs with .beta.-methyltryptophan isomers at position 9 leads to differential potencies and prolonged biological activities
  作者：Carrie Haskell-Luevano、Lakmal W. Boteju、Hiroto Miwa、Chris Dickinson、Ira Gantz、Tadataka Yamada、Mac E. Hadley、Victor J. Hruby

  DOI：10.1021/jm00023a012

  日期：1995.11

  We have introduced topographical constraints at the 9 position of a superpotent cyclic alpha-melanotropin analogue, Ac-Nle(4)-Asp(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Lys(10)-NH2, by incorporating a methyl group at the beta-carbon of Trp(9). These studies were performed on the Trp side chain pharmacophore to identify the bioactive topography of the indole moiety with melanocortin MC1 receptors. The four beta-MeTrp(9) isomers, in addition to the stereochemical controls L- and DTrp(9), were used to probe differential receptor molecular recognition of the tryptophan moiety in two bioassay systems. Approximately a 460-fold difference in potency was observed between the diastereoisomeric peptides in the frog skin bioassay, with only 33- and 10-fold efficacy differences observed in binding and intracellular cAMP accumulation, respectively, on the human melanocortin receptor, hMC1R. The relative orders of potencies in the frog skin bioassay were 2R,3S > 2S,3S = 2R,3R >> 2S,3R and for the hMC1R were 2S,3S > 2R,3R > 2R,3S >> 2S,3R. Of particular interest is the ability of these topographically constrained ligands to differentially affect prolonged biological activity. The 2R,3R diastereoisomeric peptide possessed superprolonged activity, whereas the 2S,3S peptide lacked any residual activity in the frog skin bioassay. However, on the melanocortin receptor, the 2S,3S diastereoisomeric peptide maintained slow dissociation rates (t(1/2) = 7 h), while the other diastereoisomeric peptides possessed dissociation t(1/2) rates of ca. 2 h. These data strongly implicate ligand-receptor interactions and kinetics as contributing to the observed prolonged biological activities and clearly illustrate topographical recognition differences between these two peripheral MC1 receptors involved in skin pigmentation. This study also demonstrates that topographical modifications of pharmacophore side chain residues, in addition to identifying preferential side chain orientation, can be a useful strategy for the design of peptides to increase the duration of biological activity, relative to the native ligand.
• β-Methylation of the Phe⁷ and Trp⁹ Melanotropin Side Chain Pharmacophores Affects Ligand−Receptor Interactions and Prolonged Biological Activity
  作者：Carrie Haskell-Luevano、Kate Toth、Lakmal Boteju、Constatin Job、Ana Maria de L. Castrucci、Mac E. Hadley、Victor J. Hruby

  DOI：10.1021/jm970018t

  日期：1997.8.1

  Topographically modified melanotropin side chain pharmacophore residues Phe(7) and Trp(9) in a cyclic peptide template (Ac-Nle(4)-c[Asp-His-Xaa(7)-Arg-Yaa(9)-Lys]-NH2) and Phe(7) in a linear peptide template (Ac-Ser-Tyr-Ser-Nle(4)-Glu-His-Xaa(7)-Arg-Trp-Gly-Lys-Pro-Val-NH2) result in differences in potency and prolonged biological activity in the frog and lizard skin bioassays. These topographic modifications included the four isomers of beta-methylphenylalanine (beta-MePhe)(7) and beta-methyltryptophan (beta-MeTrp)(9) and the two isomers of 1,2,3,4-tetrahydro-beta-carboline (Tea)(9) Modifications in the cyclic template resulted in up to a 1000-fold difference in potency for the beta-MePhe(7) stereoisomeric peptides; up to a 476-fold difference in potency resulted for the beta-MeTrp(9) peptides, and about a 50-fold difference between the Tca(9)-containing peptides. Up to a 40-fold difference in potency resulted for the beta-MePhe(7)? stereoisomeric peptides using the linear template in these assays. The relative potency racing for modifications in the cyclic template of beta-MePhe(7) were 2R,3S > 2S,3S = 2S,3R 2 > 2R,3R in the frog assay and 2S,3R > 2R,3S > 2S,3S > 2R,3R in the lizard assay. The relative potencies for modifications in the cyclic template of beta-MeTrp(9) were 2R,3S > 2R,3R > 2S,3R > 2S,3R in the frog assay and 2S,3S = 2R,3R > 2R,3S > 2S,3R in the lizard assay. The relative potencies for modifications in the cyclic template of Tca(9) were DTca > LTca in both assays, Significant differences in prolonged (residual) activities were also observed for these modified peptides and were dependent upon stereochemistry of the beta-methyl amino acid, peptide template, and bioassay system. Furthermore, comparisons of beta-MeTrp(9) stereoisomeric peptides on the frog, lizard, and human MC1 receptors suggest that structure-activity relationships on both the classical frog and lizard skin bioassays do not necessarily predict corresponding SAR profiles for the human melanocortin receptors, indicating a remarkable species specificity of the MC1 receptor requirements.