(2S)-3-(4-bisethoxyphosphono)phenyl-2-(tert-butoxycarbonyl)amino-2-methyl-N-((1S)-1-{N-[(2S)-2-(naphthylmethyl)pent-4-enyl]carbamoyl}-2-carbamoylethyl)propylamide | 847934-54-7

• 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: (2S)-3-(4-bisethoxyphosphono)phenyl-2-(tert-butoxycarbonyl)amino-2-methyl-N-((1S)-1-{N-[(2S)-2-(naphthylmethyl)pent-4-enyl]carbamoyl}-2-carbamoylethyl)propylamide
• 英文别名: tert-butyl N-[(2S)-1-[[(2S)-4-amino-1-[[(2S)-2-(naphthalen-1-ylmethyl)pent-4-enyl]amino]-1,4-dioxobutan-2-yl]amino]-3-(4-diethoxyphosphorylphenyl)-2-methyl-1-oxopropan-2-yl]carbamate
• CAS: 847934-54-7
• 化学式: C₃₉H₅₃N₄O₈P
• 分子量: 736.846
• InChiKey: LKTKQFXOJXEWGP-UBFXLBCASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  52
• 可旋转键数：
  21
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  175
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2S)-3-(4-bisethoxyphosphono)phenyl-2-(tert-butoxycarbonyl)amino-2-methyl-N-((1S)-1-{N-[(2S)-2-(naphthylmethyl)pent-4-enyl]carbamoyl}-2-carbamoylethyl)propylamide 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 碘代三甲硅烷 、 茴香硫醚 、 苯甲醚 、 N,N-二异丙基乙胺 、 fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 30.0h， 生成 2-[(1S,5S,9R,13S)-3,12,15-triaza-13-(4-phosphono)phenylmethyl-9-(4-phosphonomethyl)phenyl-13-methyl-5-naphthylmethyl-2,11,14-trioxocyclopentadec-7-enyl]acetamide
  参考文献：
  名称：

  Design and Synthesis of Conformationally Constrained Grb2 SH2 Domain Binding Peptides Employing α-Methylphenylalanyl Based Phosphotyrosyl Mimetics

  摘要：

  Previous work has shown that incorporation of either I-aminocyclohexanecarboxylic acid (Ac(6)c) or alpha-methyl-p-phosphonophenylalanine ((alpha-Me)Ppp) in the phosphotyrosyl (pTyr) C-proximal position (pY + 1 residue) of Grb2 SH2 domain binding peptides confers high affinity. The tetralin-based (S)-2-amino-6-phosphonotetralin-2-carboxylic acid (Atc(6-(POH2)-H-3)) simultaneously presents structural features of both (a-Me)Ppp and Ac(6)c residues. The current study compares the affinity of this tetralin hybrid Atc(6-PO3H2) versus Ac(6)c and (alpha-Me)Ppp residues when incorporated into the pY + I position of a high-affinity Grb2 SH2 domain binding tripeptide platform. The highest binding affinity (K-D = 14.8 nM) was exhibited by the (alpha-Me)Ppp-containing parent, with the corresponding Ac(6)c-containing peptide being nearly 2-fold less potent (K-D = 23.8 nM). The lower KD value was attributable primarily to a 50% increase in off-rate. Replacement of the Ac(6)c residue with the tetralin-based hybrid resulted in a further 4-fold decrease in binding affnity (K-D = 97.8 nM), which was the result of a further 6-fold increase in off-rate, offset by an approximate 45% increase in on-rate. Therefore, by incorporation of the key structural components found in (alpha-Me)Ppp into the Ac(6)c residue, the tetralin hybrid does enhance binding on-rate. However, net binding affinity is decreased due to an associated increase in binding off-rate. Alternatively, global conformational constraint of an ((alpha-Me)Ppp-containing peptide by beta-macrocyclization did result in pronounced elevation of binding affinity, which was achieved primarily through a decrease in the binding off-rate. Mathematical fitting using a simple model that assumed a single binding site yielded an effective KD of 2.28 nM. However this did not closely approximate the data obtained. Rather, use of a complex model that assumed two binding sites resulted in a very close fit of data and provided KD values of 97 pM and 72 nM for the separate sites, respectively. Therefore, although local conformational constraint in the pY + 1 residue proved to be deleterious, global conformational constraint through beta-macrocyclization achieved higher affinity. Similar beta-macrocyclization may potentially be extended to SH2 domain systems other than Grb2, where bend geometries are required.

  DOI：

  10.1021/jm0492709
• 作为产物：
  描述：

  (S)-2-amino-N¹-((S)-2-(naphthalen-1-ylmethyl)pent-4-en-1-yl)succinamide 、 (2S)-2-(tert-butyloxycarbonyl)amino-3-(4-diethylphosphono)phenylpropionic acid 在 N,N-二异丙基乙胺 、 fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以38%的产率得到(2S)-3-(4-bisethoxyphosphono)phenyl-2-(tert-butoxycarbonyl)amino-2-methyl-N-((1S)-1-{N-[(2S)-2-(naphthylmethyl)pent-4-enyl]carbamoyl}-2-carbamoylethyl)propylamide
  参考文献：
  名称：

  Design and Synthesis of Conformationally Constrained Grb2 SH2 Domain Binding Peptides Employing α-Methylphenylalanyl Based Phosphotyrosyl Mimetics

  摘要：

  Previous work has shown that incorporation of either I-aminocyclohexanecarboxylic acid (Ac(6)c) or alpha-methyl-p-phosphonophenylalanine ((alpha-Me)Ppp) in the phosphotyrosyl (pTyr) C-proximal position (pY + 1 residue) of Grb2 SH2 domain binding peptides confers high affinity. The tetralin-based (S)-2-amino-6-phosphonotetralin-2-carboxylic acid (Atc(6-(POH2)-H-3)) simultaneously presents structural features of both (a-Me)Ppp and Ac(6)c residues. The current study compares the affinity of this tetralin hybrid Atc(6-PO3H2) versus Ac(6)c and (alpha-Me)Ppp residues when incorporated into the pY + I position of a high-affinity Grb2 SH2 domain binding tripeptide platform. The highest binding affinity (K-D = 14.8 nM) was exhibited by the (alpha-Me)Ppp-containing parent, with the corresponding Ac(6)c-containing peptide being nearly 2-fold less potent (K-D = 23.8 nM). The lower KD value was attributable primarily to a 50% increase in off-rate. Replacement of the Ac(6)c residue with the tetralin-based hybrid resulted in a further 4-fold decrease in binding affnity (K-D = 97.8 nM), which was the result of a further 6-fold increase in off-rate, offset by an approximate 45% increase in on-rate. Therefore, by incorporation of the key structural components found in (alpha-Me)Ppp into the Ac(6)c residue, the tetralin hybrid does enhance binding on-rate. However, net binding affinity is decreased due to an associated increase in binding off-rate. Alternatively, global conformational constraint of an ((alpha-Me)Ppp-containing peptide by beta-macrocyclization did result in pronounced elevation of binding affinity, which was achieved primarily through a decrease in the binding off-rate. Mathematical fitting using a simple model that assumed a single binding site yielded an effective KD of 2.28 nM. However this did not closely approximate the data obtained. Rather, use of a complex model that assumed two binding sites resulted in a very close fit of data and provided KD values of 97 pM and 72 nM for the separate sites, respectively. Therefore, although local conformational constraint in the pY + 1 residue proved to be deleterious, global conformational constraint through beta-macrocyclization achieved higher affinity. Similar beta-macrocyclization may potentially be extended to SH2 domain systems other than Grb2, where bend geometries are required.

  DOI：

  10.1021/jm0492709