[(R),(R,S),(S)]-(1-benzyloxycarbonylamino-2-phenylethyl)-{2-[1-carbamoyl-2-(1H-indol-3-yl)ethylcarbamoyl]-3-(2-isopropylphenylsulfanyl)propyl}phosphinic acid

• 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: [(R),(R,S),(S)]-(1-benzyloxycarbonylamino-2-phenylethyl)-{2-[1-carbamoyl-2-(1H-indol-3-yl)ethylcarbamoyl]-3-(2-isopropylphenylsulfanyl)propyl}phosphinic acid
• 英文别名: [3-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-oxo-2-[(2-propan-2-ylphenyl)sulfanylmethyl]propyl]-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphinic acid
• 化学式: C₄₀H₄₅N₄O₆PS
• 分子量: 740.86
• InChiKey: WAWDPHZIPOKGOU-IOMCEKGVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  52
• 可旋转键数：
  18
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  189
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  (R)-2-[(1-benzyloxycarbonylamino-2-phenylethyl)hydroxyphosphinoylmethyl]acrylic acid tert-butyl ester 在 sodium ethanolate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 反应 7.0h， 生成 [(R),(R,S),(S)]-(1-benzyloxycarbonylamino-2-phenylethyl)-{2-[1-carbamoyl-2-(1H-indol-3-yl)ethylcarbamoyl]-3-(2-isopropylphenylsulfanyl)propyl}phosphinic acid
  参考文献：
  名称：

  Evaluation of P₁'-Diversified Phosphinic Peptides Leads to the Development of Highly Selective Inhibitors of MMP-11

  摘要：

  Phosphinic peptides were previously reported to be potent inhibitors of several matrixins (MMPs). To identify more selective inhibitors of MMP-11, a matrixin overexpressed in breast cancer, a series of phosphinic pseudopeptides bearing a variety of P-1'-side chains has been synthesized, by parallel diversification of a phosphinic template. The potencies of these compounds were evaluated against a set of seven MMPs (MMP-2, MMP-7, MMP-8, MMP-9, MMP-11, MMP-13, and MMP-14). The chemical strategy applied led to the identification of several phosphinic inhibitors displaying high selectivity toward MMP-11. One of the most selective inhibitors of MMP-11 in this series, compound 22, exhibits a K-i value of 0.23 PM toward MMP-11, while its potency toward the other MMPs tested is 2 orders of magnitude lower. This remarkable selectivity may rely on interactions of the P-1'-side chain atoms of these inhibitors with residues located at the entrance of the S-1'-cavity of MMP-11. The design of inhibitors able to interact with residues located at the entrance of MMPs' S-1'-cavity might represent an alternative strategy to identify selective inhibitors that will fully differentiate one MMP among the others.

  DOI：

  10.1021/jm0308491

文献信息

• Evaluation of P₁'-Diversified Phosphinic Peptides Leads to the Development of Highly Selective Inhibitors of MMP-11
  作者：Magdalini Matziari、Fabrice Beau、Philippe Cuniasse、Vincent Dive、Athanasios Yiotakis

  DOI：10.1021/jm0308491

  日期：2004.1.1

  Phosphinic peptides were previously reported to be potent inhibitors of several matrixins (MMPs). To identify more selective inhibitors of MMP-11, a matrixin overexpressed in breast cancer, a series of phosphinic pseudopeptides bearing a variety of P-1'-side chains has been synthesized, by parallel diversification of a phosphinic template. The potencies of these compounds were evaluated against a set of seven MMPs (MMP-2, MMP-7, MMP-8, MMP-9, MMP-11, MMP-13, and MMP-14). The chemical strategy applied led to the identification of several phosphinic inhibitors displaying high selectivity toward MMP-11. One of the most selective inhibitors of MMP-11 in this series, compound 22, exhibits a K-i value of 0.23 PM toward MMP-11, while its potency toward the other MMPs tested is 2 orders of magnitude lower. This remarkable selectivity may rely on interactions of the P-1'-side chain atoms of these inhibitors with residues located at the entrance of the S-1'-cavity of MMP-11. The design of inhibitors able to interact with residues located at the entrance of MMPs' S-1'-cavity might represent an alternative strategy to identify selective inhibitors that will fully differentiate one MMP among the others.