(2S)-2-[[(2S)-2-acetamido-3-(1-tritylimidazol-4-yl)propanoyl]amino]-N-[(1S,2R)-1-benzyl-2-hydroxy-3-[[(3S,6S)-6-isopropyl-4,7-dioxo-12-oxa-5,8-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-3-yl]amino]-3-oxo-propyl]-3-methyl-butanamide | 454423-73-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (2S)-2-[[(2S)-2-acetamido-3-(1-tritylimidazol-4-yl)propanoyl]amino]-N-[(1S,2R)-1-benzyl-2-hydroxy-3-[[(3S,6S)-6-isopropyl-4,7-dioxo-12-oxa-5,8-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-3-yl]amino]-3-oxo-propyl]-3-methyl-butanamide
• 英文别名: (2S)-2-[[(2S)-2-acetamido-3-(1-tritylimidazol-4-yl)propanoyl]amino]-N-[(2S,3R)-4-[[(8S,11S)-7,10-dioxo-8-propan-2-yl-2-oxa-6,9-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-11-yl]amino]-3-hydroxy-4-oxo-1-phenylbutan-2-yl]-3-methylbutanamide
• CAS: 454423-73-5
• 化学式: C₅₉H₆₈N₈O₈
• 分子量: 1017.24
• InChiKey: VJQDNUUFVYCSMC-SDPHCHFUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  75
• 可旋转键数：
  18
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  222
• 氢给体数：
  7
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2S)-2-[[(2S)-2-acetamido-3-(1-tritylimidazol-4-yl)propanoyl]amino]-N-[(1S,2R)-1-benzyl-2-hydroxy-3-[[(3S,6S)-6-isopropyl-4,7-dioxo-12-oxa-5,8-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-3-yl]amino]-3-oxo-propyl]-3-methyl-butanamide 在 三氟乙酸 作用下， 以 水 为溶剂， 反应 1.0h， 以97%的产率得到(2S)-2-[[(2S)-2-acetamido-3-(1H-imidazol-4-yl)propanoyl]amino]-N-[(1S,2R)-1-benzyl-2-hydroxy-3-[[(3S,6S)-6-isopropyl-4,7-dioxo-12-oxa-5,8-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-3-yl]amino]-3-oxo-propyl]-3-methyl-butanamide
  参考文献：
  名称：

  Design and synthesis of broad-Based mono- and bi- cyclic inhibitors of FIV and HIV proteases

  摘要：

  Based on the substrate transition state and our strategy to tackle the problem of drug resistance, a series of HIV/FIV protease (HIV/FIV PR) monocyclic inhibitors incorporating a 15- or 17-membered macrocycle with an equivalent P3 or P3' group and a unique unnatural amino acid, (2R, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid, have been designed and synthesized. In addition, based on the structure of TL3 with small P3/P3' group, we have synthesized two conformationally restricted bicyclic inhibitors containing the macrocycle, which mimic the P1/P1'-P3/P3' tripeptide [Phe-Val-Ala] of TL3. We have found that the contribution of the macrocycle in our monocyclic inhibitors is important to the overall activity, but the ring size does not affect the activity to a significant extent. Several inhibitors that were developed in this work, exhibit low nanomolar inhibitory activity against the wild-type HIV/FIV PR and found to be highly effective against some drug-resistant as well as TL3-resistant mutants of HIV PRs. Compound 15, in particular, is the most effective cyclic inhibitor in hand to inhibit FIV replication in tissue culture at a concentration of 1.0 mug/mL (1.2 muM). (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00054-3
• 作为产物：
  描述：

  (2R,3S)-N-(tert-butoxycarbonyl)-3-amino-2-hydroxy-4-phenylbutanoic acid methyl ester 在 盐酸 、 lithium hydroxide 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 (2S)-2-[[(2S)-2-acetamido-3-(1-tritylimidazol-4-yl)propanoyl]amino]-N-[(1S,2R)-1-benzyl-2-hydroxy-3-[[(3S,6S)-6-isopropyl-4,7-dioxo-12-oxa-5,8-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-3-yl]amino]-3-oxo-propyl]-3-methyl-butanamide
  参考文献：
  名称：

  Design and synthesis of broad-Based mono- and bi- cyclic inhibitors of FIV and HIV proteases

  摘要：

  Based on the substrate transition state and our strategy to tackle the problem of drug resistance, a series of HIV/FIV protease (HIV/FIV PR) monocyclic inhibitors incorporating a 15- or 17-membered macrocycle with an equivalent P3 or P3' group and a unique unnatural amino acid, (2R, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid, have been designed and synthesized. In addition, based on the structure of TL3 with small P3/P3' group, we have synthesized two conformationally restricted bicyclic inhibitors containing the macrocycle, which mimic the P1/P1'-P3/P3' tripeptide [Phe-Val-Ala] of TL3. We have found that the contribution of the macrocycle in our monocyclic inhibitors is important to the overall activity, but the ring size does not affect the activity to a significant extent. Several inhibitors that were developed in this work, exhibit low nanomolar inhibitory activity against the wild-type HIV/FIV PR and found to be highly effective against some drug-resistant as well as TL3-resistant mutants of HIV PRs. Compound 15, in particular, is the most effective cyclic inhibitor in hand to inhibit FIV replication in tissue culture at a concentration of 1.0 mug/mL (1.2 muM). (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00054-3

文献信息

• Design and synthesis of broad-Based mono- and bi- cyclic inhibitors of FIV and HIV proteases
  作者：Chi Ching Mak、Ashraf Brik、Danica L Lerner、John H Elder、Garrett M Morris、Arthur J Olson、Chi-Huey Wong

  DOI：10.1016/s0968-0896(03)00054-3

  日期：2003.5

  Based on the substrate transition state and our strategy to tackle the problem of drug resistance, a series of HIV/FIV protease (HIV/FIV PR) monocyclic inhibitors incorporating a 15- or 17-membered macrocycle with an equivalent P3 or P3' group and a unique unnatural amino acid, (2R, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid, have been designed and synthesized. In addition, based on the structure of TL3 with small P3/P3' group, we have synthesized two conformationally restricted bicyclic inhibitors containing the macrocycle, which mimic the P1/P1'-P3/P3' tripeptide [Phe-Val-Ala] of TL3. We have found that the contribution of the macrocycle in our monocyclic inhibitors is important to the overall activity, but the ring size does not affect the activity to a significant extent. Several inhibitors that were developed in this work, exhibit low nanomolar inhibitory activity against the wild-type HIV/FIV PR and found to be highly effective against some drug-resistant as well as TL3-resistant mutants of HIV PRs. Compound 15, in particular, is the most effective cyclic inhibitor in hand to inhibit FIV replication in tissue culture at a concentration of 1.0 mug/mL (1.2 muM). (C) 2003 Elsevier Science Ltd. All rights reserved.