O-Adamantyl P-(benzyloxycarbonylaminomethyl)-P-(ethyl 2-isobutylpropionate-3-yl)phosphinate | 253192-90-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: O-Adamantyl P-(benzyloxycarbonylaminomethyl)-P-(ethyl 2-isobutylpropionate-3-yl)phosphinate
• 英文别名: Ethyl 2-[[1-adamantyloxy(phenylmethoxycarbonylaminomethyl)phosphoryl]methyl]-4-methylpentanoate
• CAS: 253192-90-4
• 化学式: C₂₈H₄₂NO₆P
• 分子量: 519.618
• InChiKey: SOHRCLTZAWDUND-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  36
• 可旋转键数：
  14
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  90.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  O-Adamantyl P-(benzyloxycarbonylaminomethyl)-P-(ethyl 2-isobutylpropionate-3-yl)phosphinate 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 以88%的产率得到2-[(Adamantan-1-yloxy)-(benzyloxycarbonylamino-methyl)-phosphinoylmethyl]-4-methyl-pentanoic acid
  参考文献：
  名称：

  Functional examination of novel kisspeptin phosphinic peptides

  摘要：

  吻肽作用于其同源的 G 蛋白偶联受体--吻肽受体，在抑制癌细胞转移和调节生殖系统方面发挥着重要作用，因此对治疗干预具有重要意义。所有原生功能性人类吻肽（吻肽素-54、吻肽素-14 和吻肽素-13）的 C 端（45-54）都含有吻肽素-10 的 10 个氨基酸。然而，它们会被基质金属蛋白酶（MMPs）通过裂解甘氨酸51 和亮氨酸52 之间的肽键而迅速失活，这限制了它们的临床应用。开发抗 MMP 的吻肽类似物可提供更好的治疗效果。本研究设计并合成了两种吻肽（kisspeptin phosphinic peptides），评估了它们通过吻肽（kisspeptin）受体诱导ERK1/2磷酸化的能力及其对与癌症转移相关的MMP-2和MMP-9的抑制作用。结果表明，其中一种类似物--膦酰基吻肽素 R 异构体（PKPR）不仅具有吻肽素受体拮抗活性，还具有抑制 MMP-2 的活性，这表明 PKPR 可作为进一步开发用于治疗的吻肽素类似物的先导。

  DOI：

  10.1371/journal.pone.0195089
• 作为产物：
  描述：

  N-benzyloxycarbonylaminomethyl-H-phosphinic acid 在 草酰氯 、 sodium hydride 、 N,N-二甲基甲酰胺 、 六甲基二硅氮烷 作用下， 以 四氢呋喃 为溶剂， 反应 7.16h， 生成 O-Adamantyl P-(benzyloxycarbonylaminomethyl)-P-(ethyl 2-isobutylpropionate-3-yl)phosphinate
  参考文献：
  名称：

  Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach

  摘要：

  The solid-phase synthesis of an array of different pseudopeptides containing a phosphinic glycine-leucine moiety (-G Psi/{P(O)OH-CH2}L-)([1]) is described. The resulting pseudopeptides were shown to act as matrix metalloproteinase-9 (MMP-9) inhibitors. Starting from available materials, the protected amino acid isosters benzyloxy-carbonyl aminomethylphosphinic acid (glycine analogue) and ethyl alpha-isobutylacrylate (leucine analogue) were synthesized and coupled with the bis(trimethylsilyl)phosphonite. Protective group interchange yielded a protected phosphinic dipeptide building block 1 ready for use in solid-phase peptide synthesis, Solid-phase peptide synthesis was performed with 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry on a polyethylene glycol polyamide (PEGA) support and the coupling of 1 (1.5 equiv) was carried out with standard activation. The P-4-P-2 and P-2'-P-4' positions of the pseudopeptides were designed by analogy of the cleavage sequences of different natural extracellular matrix protein substrates with a synthetic peptide substrate of MMP-9. The crude peptides were obtained in high yield and purity as determined by RP-HPLC, and were characterized by electrospray mass spectrometry and amino acid analysis after purification. Enzyme kinetic investigations with MMP-9 of the purified peptide inhibitors showed Ki values in the range from mM to nM.

  DOI：

  10.1002/(sici)1521-3765(19991001)5:10<2877::aid-chem2877>3.0.co;2-z

文献信息

• Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach
  作者：Jens Buchardt、Mercedes Ferreras、Christian Krog-Jensen、Jean-Marie Delaissé、Niels Tækker Foged、Morten Meldal

  DOI：10.1002/(sici)1521-3765(19991001)5:10<2877::aid-chem2877>3.0.co;2-z

  日期：1999.10.1

  The solid-phase synthesis of an array of different pseudopeptides containing a phosphinic glycine-leucine moiety (-G Psi/P(O)OH-CH2}L-)([1]) is described. The resulting pseudopeptides were shown to act as matrix metalloproteinase-9 (MMP-9) inhibitors. Starting from available materials, the protected amino acid isosters benzyloxy-carbonyl aminomethylphosphinic acid (glycine analogue) and ethyl alpha-isobutylacrylate (leucine analogue) were synthesized and coupled with the bis(trimethylsilyl)phosphonite. Protective group interchange yielded a protected phosphinic dipeptide building block 1 ready for use in solid-phase peptide synthesis, Solid-phase peptide synthesis was performed with 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry on a polyethylene glycol polyamide (PEGA) support and the coupling of 1 (1.5 equiv) was carried out with standard activation. The P-4-P-2 and P-2'-P-4' positions of the pseudopeptides were designed by analogy of the cleavage sequences of different natural extracellular matrix protein substrates with a synthetic peptide substrate of MMP-9. The crude peptides were obtained in high yield and purity as determined by RP-HPLC, and were characterized by electrospray mass spectrometry and amino acid analysis after purification. Enzyme kinetic investigations with MMP-9 of the purified peptide inhibitors showed Ki values in the range from mM to nM.
• Functional examination of novel kisspeptin phosphinic peptides
  作者：Xiaoyang Zhang、Magdalini Matziari、Yixin Xie、David Fernig、Rong Rong、Jia Meng、Zhi-Liang Lu

  DOI：10.1371/journal.pone.0195089

  日期：——

  Kisspeptins acting on their cognate G protein-coupled receptor, kisspeptin receptor, play important roles in the suppression of cancer cell metastasis and regulation of the reproductive system, and therefore are important for therapeutic intervention. All native functional human kisspeptins (kisspeptin-54, kisspsptin-14 and kisspeptin-13) share the 10 amino acids of kisspeptin-10 at their C-terminus (45–54). However, they are inactivated rapidly by matrix metalloproteinases (MMPs) through the cleavage of the peptide bond between glycine51 and leucine52, which limits their clinical applications. Development of MMP-resistant analogues of kisspeptins may provide better therapeutic outputs. In the present study, two kisspeptin phosphinic peptides were designed and synthesized, and their ability to induce phosphorylation of ERK1/2 through kisspeptin receptor and their inhibition on MMP-2 and MMP-9 whose activity correlates with cancer metastasis were assessed. The results showed that one analogue, phosphinic kisspeptin R isomer (PKPR), exhibited kisspeptin receptor-agonistic activity and also inhibitory activity on MMP-2, indicating that PKPR may serve as a lead for the further development of kisspeptin analogues for therapeutic purpose.

  吻肽作用于其同源的 G 蛋白偶联受体--吻肽受体，在抑制癌细胞转移和调节生殖系统方面发挥着重要作用，因此对治疗干预具有重要意义。所有原生功能性人类吻肽（吻肽素-54、吻肽素-14 和吻肽素-13）的 C 端（45-54）都含有吻肽素-10 的 10 个氨基酸。然而，它们会被基质金属蛋白酶（MMPs）通过裂解甘氨酸51 和亮氨酸52 之间的肽键而迅速失活，这限制了它们的临床应用。开发抗 MMP 的吻肽类似物可提供更好的治疗效果。本研究设计并合成了两种吻肽（kisspeptin phosphinic peptides），评估了它们通过吻肽（kisspeptin）受体诱导ERK1/2磷酸化的能力及其对与癌症转移相关的MMP-2和MMP-9的抑制作用。结果表明，其中一种类似物--膦酰基吻肽素 R 异构体（PKPR）不仅具有吻肽素受体拮抗活性，还具有抑制 MMP-2 的活性，这表明 PKPR 可作为进一步开发用于治疗的吻肽素类似物的先导。