Dab(Boc)-Thr(tBu)-Dab(Boc)-cyclo[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)-Dab(Boc)-Thr(tBu)] | 1416048-27-5

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: Dab(Boc)-Thr(tBu)-Dab(Boc)-cyclo[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)-Dab(Boc)-Thr(tBu)]
• 英文别名: H-Dab(Boc)(Boc)-Thr(tBu)-Dap(Boc)(Boc)-Dab(1)-Dab(Boc)(Boc)-D-Phe-Leu-Dab(Boc)(Boc)-Dab(Boc)(Boc)-Thr(tBu)-(1)；tert-butyl N-[(3S)-3-amino-4-[[(2S,3R)-1-[[(2S)-1-[[(3S,6S,9S,12S,15R,18S,21S)-15-benzyl-6,9,18-tris[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]-3-[(1R)-1-[(2-methylpropan-2-yl)oxy]ethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]-3-[(2-methylpropan-2-yl)oxycarbonylamino]-1-oxopropan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxobutan-2-yl]amino]-4-oxobutyl]carbamate
• CAS: 1416048-27-5
• 化学式: C₇₉H₁₃₆N₁₆O₂₂
• 分子量: 1662.04
• InChiKey: QXWNCXLMBLOFSQ-OBWMOOJCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  117
• 可旋转键数：
  40
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  527
• 氢给体数：
  16
• 氢受体数：
  23

反应信息

• 作为反应物：
  描述：

  Dab(Boc)-Thr(tBu)-Dab(Boc)-cyclo[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)-Dab(Boc)-Thr(tBu)] 、 4-苯基苯甲酸 在 N-甲基吗啉 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  Discovery of Dap-3 Polymyxin Analogues for the Treatment of Multidrug-Resistant Gram-Negative Nosocomial Infections

  摘要：

  We report novel polymyxin analogues with improved antibacterial in vitro potency against polymprin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa. In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.

  DOI：

  10.1021/jm400416u
• 作为产物：
  描述：

  在 ammonium hydroxide 、 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 15.0 ℃ 、111.46 kPa 条件下， 反应 96.0h， 生成 Dab(Boc)-Thr(tBu)-Dab(Boc)-cyclo[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)-Dab(Boc)-Thr(tBu)]
  参考文献：
  名称：

  Discovery of Dap-3 Polymyxin Analogues for the Treatment of Multidrug-Resistant Gram-Negative Nosocomial Infections

  摘要：

  We report novel polymyxin analogues with improved antibacterial in vitro potency against polymprin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa. In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.

  DOI：

  10.1021/jm400416u

文献信息

• Discovery of Dap-3 Polymyxin Analogues for the Treatment of Multidrug-Resistant Gram-Negative Nosocomial Infections
  作者：Thomas V. Magee、Matthew F. Brown、Jeremy T. Starr、David C. Ackley、Joseph A. Abramite、Jiri Aubrecht、Andrew Butler、Jared L. Crandon、Fadia Dib-Hajj、Mark E. Flanagan、Karl Granskog、Joel R. Hardink、Michael D. Huband、Rebecca Irvine、Michael Kuhn、Karen L. Leach、Bryan Li、Jian Lin、David R. Luke、Shawn H. MacVane、Alita A. Miller、Sandra McCurdy、James M. McKim、David P. Nicolau、Thuy-Trinh Nguyen、Mark C. Noe、John P. O’Donnell、Scott B. Seibel、Yue Shen、Antonia F. Stepan、Andrew P. Tomaras、Paul C. Wilga、Li Zhang、Jinfeng Xu、Jinshan Michael Chen

  DOI：10.1021/jm400416u

  日期：2013.6.27

  We report novel polymyxin analogues with improved antibacterial in vitro potency against polymprin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa. In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.