tert-butyl (3R)-3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-carbonyl]-6-phenylhexanoate | 161725-15-1

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: tert-butyl (3R)-3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-carbonyl]-6-phenylhexanoate
• CAS: 161725-15-1
• 化学式: C₂₇H₃₃NO₅
• 分子量: 451.563
• InChiKey: OSAWOIUQTBPNBY-PKTZIBPZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  33
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl (3R)-3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-carbonyl]-6-phenylhexanoate 在 lithium hydroxide 、 双氧水 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium nitrite 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 tert-butyl (3R)-3-[[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]-6-phenylhexanoate
  参考文献：
  名称：

  Inhibition of Membrane-Type 1 Matrix Metalloproteinase by Hydroxamate Inhibitors:  An Examination of the Subsite Pocket

  摘要：

  The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (Delta MT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an a-branched alkyl group is critical for the binding toward Delta MT1, while the introduction of a bulky group at the a-position of hydroxamic acid seems to diminish the activity against Delta MT1. Summation of the data on the sensitivity of Delta MT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of Delta MT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against Delta MT1 over MMP-1, but no selectivity between Delta MT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.

  DOI：

  10.1021/jm970404a
• 作为产物：
  描述：

  5-苯基戊酰氯 在 正丁基锂 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 0.42h， 生成 tert-butyl (3R)-3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidine-3-carbonyl]-6-phenylhexanoate
  参考文献：
  名称：

  Inhibition of Membrane-Type 1 Matrix Metalloproteinase by Hydroxamate Inhibitors:  An Examination of the Subsite Pocket

  摘要：

  The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (Delta MT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an a-branched alkyl group is critical for the binding toward Delta MT1, while the introduction of a bulky group at the a-position of hydroxamic acid seems to diminish the activity against Delta MT1. Summation of the data on the sensitivity of Delta MT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of Delta MT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against Delta MT1 over MMP-1, but no selectivity between Delta MT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.

  DOI：

  10.1021/jm970404a

文献信息

• Synthesis and SAR of succinamide peptidomimetic inhibitors of cathepsin S
  作者：Arnab K. Chatterjee、Hong Liu、David C. Tully、Jianhua Guo、Robert Epple、Ross Russo、Jennifer Williams、Michael Roberts、Tove Tuntland、Jonathan Chang、Perry Gordon、Thomas Hollenbeck、Christine Tumanut、Jun Li、Jennifer L. Harris

  DOI：10.1016/j.bmcl.2007.02.049

  日期：2007.5

  Peptidic, non-covalent inhibitors of lysosomal cysteine protease cathepsin S (1 and 2) were investigated due to low oral bioavailability, leading to an improved series of peptidomimetic inhibitors. Utilizing phenyl succinamides as the P2 residue increased the oral exposure of this lead series of compounds, while retaining selective inhibition of the cathepsin S isoform. Concurrent investigation of

  由于口服生物利用度低，研究了溶酶体半胱氨酸蛋白酶组织蛋白酶S（1和2）的肽类非共价抑制剂，从而产生了一系列拟肽抑制剂。使用苯基琥珀酰亚胺作为P2残基可增加该先导系列化合物的口腔暴露，同时保留对组织蛋白酶S亚型的选择性抑制作用。对P1和P2亚位点的同时研究导致发现了几种有效的和选择性的组织蛋白酶S抑制剂，这些酶由于消除了饱和脂肪族P2残基而具有良好的药代动力学特性。
• Inhibition of Membrane-Type 1 Matrix Metalloproteinase by Hydroxamate Inhibitors:  An Examination of the Subsite Pocket
  作者：Minoru Yamamoto、Hideki Tsujishita、Noriyuki Hori、Yuichi Ohishi、Shintaro Inoue、Shoji Ikeda、Yasunori Okada

  DOI：10.1021/jm970404a

  日期：1998.4.1

  The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (Delta MT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an a-branched alkyl group is critical for the binding toward Delta MT1, while the introduction of a bulky group at the a-position of hydroxamic acid seems to diminish the activity against Delta MT1. Summation of the data on the sensitivity of Delta MT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of Delta MT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against Delta MT1 over MMP-1, but no selectivity between Delta MT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.