Fmoc-Ala-GlyΨ(PO2Bn-N)Pro-Phe-p-CMA | 460053-81-0

• 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: Fmoc-Ala-GlyΨ(PO2Bn-N)Pro-Phe-p-CMA
• 英文别名: 2-[4-[[(2S)-2-[[(2S)-1-[[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoyl]amino]methyl-phenylmethoxyphosphoryl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoyl]amino]phenyl]acetic acid
• CAS: 460053-81-0
• 化学式: C₄₈H₅₀N₅O₉P
• 分子量: 871.927
• InChiKey: UFVNETGHSAPMRW-LGUHACNTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  63
• 可旋转键数：
  19
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  193
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  Fmoc-Ala-GlyΨ(PO2Bn-N)Pro-Phe-p-CMA 在 10percent Pd/C 氢气 、 碳酸氢钠 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、400.01 kPa 条件下， 反应 5.0h， 生成 Ac-Ala-GlyΨ(PO2H-N)Pro-Phe-4-carboxymethylaniline
  参考文献：
  名称：

  Synthesis and Evaluation of Glyψ(PO₂R-N)Pro-Containing Pseudopeptides as Novel Inhibitors of the Human Cyclophilin hCyp-18

  摘要：

  The human cyclophilin hCyp-18, an abundant peptidyl-prolyl cis-trans isomerase (PPIase) implicated in protein folding, controls the infection of CD4(+) T-cells by HIV-1, the pathologic agent of AIDS. Therefore, hCyp-18 is an interesting target for the development of novel anti-HIV-1 therapeutics. We focused on the design of transition-state analogue inhibitors of the PPIase activity of cyclophilin. Most experimental results reported in the literature suggest that hCyp-18 catalyzes the pyramidalization of the nitrogen of pyrrolidine via an H-bond network which results in the deconjugation of the amino acyl-prolyl peptide bond. We proposed the Glypsi(PO2R1-N)Pro motif (R = alkyl or H) as a selective transition-state analogue inhibitor of cyclophilin. This motif was inserted in Suc-Ala-Ala-Pro-Phe-pNA, a peptide substrate of hCyp18. The pseudopeptide Suc-Ala-Glypsi(PO2Et-N)Pro-Phe-pNA 1b bound to hCyp-18 (K-d = 20 +/- 5 muM) and was able to selectively inhibit its PPIase activity(IC50 =15 +/- muM) but not hFKBP-12, another important PPIase. Deprotection of the phosphonamidate moiety resulted in a complete lack of inhibition. We previously demonstrated that reduction of the Phe-pNA moiety caused a quantitative reduction of the affinity; however, Suc-Ala-Glypsi(PO2Et-N)Pro-Phepsi(CH2-NH)pNA 7b still bound and inhibited hCyp-18, suggesting that the Glypsi(PO2Et-N)Pro motif plays the major role in the binding to cyclophilin. Consequently, we propose compound 1b as being a novel transition-state mimic inhibitor of hCyp-18.

  DOI：

  10.1021/jm020865i
• 作为产物：
  描述：

  dibenzyl phthalimidomethylphosphonate 在 五氯化磷 、 肼 作用下， 以 四氢呋喃 、 四氯化碳 为溶剂， 反应 7.0h， 生成 Fmoc-Ala-GlyΨ(PO2Bn-N)Pro-Phe-p-CMA
  参考文献：
  名称：

  Synthesis and Evaluation of Glyψ(PO₂R-N)Pro-Containing Pseudopeptides as Novel Inhibitors of the Human Cyclophilin hCyp-18

  摘要：

  The human cyclophilin hCyp-18, an abundant peptidyl-prolyl cis-trans isomerase (PPIase) implicated in protein folding, controls the infection of CD4(+) T-cells by HIV-1, the pathologic agent of AIDS. Therefore, hCyp-18 is an interesting target for the development of novel anti-HIV-1 therapeutics. We focused on the design of transition-state analogue inhibitors of the PPIase activity of cyclophilin. Most experimental results reported in the literature suggest that hCyp-18 catalyzes the pyramidalization of the nitrogen of pyrrolidine via an H-bond network which results in the deconjugation of the amino acyl-prolyl peptide bond. We proposed the Glypsi(PO2R1-N)Pro motif (R = alkyl or H) as a selective transition-state analogue inhibitor of cyclophilin. This motif was inserted in Suc-Ala-Ala-Pro-Phe-pNA, a peptide substrate of hCyp18. The pseudopeptide Suc-Ala-Glypsi(PO2Et-N)Pro-Phe-pNA 1b bound to hCyp-18 (K-d = 20 +/- 5 muM) and was able to selectively inhibit its PPIase activity(IC50 =15 +/- muM) but not hFKBP-12, another important PPIase. Deprotection of the phosphonamidate moiety resulted in a complete lack of inhibition. We previously demonstrated that reduction of the Phe-pNA moiety caused a quantitative reduction of the affinity; however, Suc-Ala-Glypsi(PO2Et-N)Pro-Phepsi(CH2-NH)pNA 7b still bound and inhibited hCyp-18, suggesting that the Glypsi(PO2Et-N)Pro motif plays the major role in the binding to cyclophilin. Consequently, we propose compound 1b as being a novel transition-state mimic inhibitor of hCyp-18.

  DOI：

  10.1021/jm020865i