tri-tert-butyl 2,2',2"-(10-(2-((6-(3-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)-5-iodobenzamido)hexyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate | 1411600-03-7

• 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: tri-tert-butyl 2,2',2"-(10-(2-((6-(3-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)-5-iodobenzamido)hexyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate
• CAS: 1411600-03-7
• 化学式: C₄₆H₇₂IN₇O₁₂
• 分子量: 1042.02
• InChiKey: JLKXBZXEVHPUKG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.17
• 重原子数：
  66.0
• 可旋转键数：
  18.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  213.74
• 氢给体数：
  2.0
• 氢受体数：
  16.0

反应信息

• 作为反应物：
  描述：

  tri-tert-butyl 2,2',2"-(10-(2-((6-(3-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)-5-iodobenzamido)hexyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate 在 三氟乙酸 作用下， 反应 1.0h， 以86%的产率得到2,2',2"-(10-(2-((6-(3-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)-5-iodobenzamido)hexyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid
  参考文献：
  名称：

  SIB-DOTA: A trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies

  摘要：

  A major drawback of internalizing monoclonal antibodies (mAbs) radioiodinated with direct electrophilic approaches is that tumor retention of radioactivity is compromised by the rapid washout of iodo-tyrosine, the primary labeled catabolite for mAbs labeled via this strategy. In our continuing efforts to develop more versatile residualizing labels that could overcome this problem, we have designed SIB-DOTA, a prosthetic labeling template that combines the features of the prototypical, dehalogenation-resistant N-succinimidyl 3-iodobenzoate (SIB) with DOTA, a useful macrocyclic chelator for labeling with radiometals. Herein we describe the synthesis of the unlabeled standard of this prosthetic moiety, its protected tin precursor, and radioiodinated SIB-DOTA. An anti-EGFRvIII-reactive mAb, L8A4 was radiolabeled with [I-131]SIB-DOTA in 27.1 +/- 6.2% (n = 2) conjugation yields and its targeting properties to the same mAb labeled with [I-125]SGMIB both in vitro and in vivo using U87MG.Delta EGFR cells and xenografts were compared. In vitro paired-label internalization assays showed that the intracellular radioactivity from [I-131]SIB-DOTA-L8A4 was 21.4 +/- 0.5% and 26.2 +/- 1.1% of initially bound radioactivity at 16 and 24 h, respectively. In comparison, these values for [I-125]SGMIB-L8A4 were 16.7 +/- 0.5% and 14.9 +/- 1.1%. Similarly, the SIB-DOTA prosthetic group provided better tumor targeting in vivo than SGMIB over 8 d period. These results suggest that SIB-DOTA warrants further evaluation as a residualizing agent for labeling internalizing mAbs including those targeted to EGFRvIII. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.10.025
• 作为产物：
  描述：

  5-碘间苯二甲酸 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 16.0h， 生成 tri-tert-butyl 2,2',2"-(10-(2-((6-(3-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)-5-iodobenzamido)hexyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate
  参考文献：
  名称：

  SIB-DOTA: A trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies

  摘要：

  A major drawback of internalizing monoclonal antibodies (mAbs) radioiodinated with direct electrophilic approaches is that tumor retention of radioactivity is compromised by the rapid washout of iodo-tyrosine, the primary labeled catabolite for mAbs labeled via this strategy. In our continuing efforts to develop more versatile residualizing labels that could overcome this problem, we have designed SIB-DOTA, a prosthetic labeling template that combines the features of the prototypical, dehalogenation-resistant N-succinimidyl 3-iodobenzoate (SIB) with DOTA, a useful macrocyclic chelator for labeling with radiometals. Herein we describe the synthesis of the unlabeled standard of this prosthetic moiety, its protected tin precursor, and radioiodinated SIB-DOTA. An anti-EGFRvIII-reactive mAb, L8A4 was radiolabeled with [I-131]SIB-DOTA in 27.1 +/- 6.2% (n = 2) conjugation yields and its targeting properties to the same mAb labeled with [I-125]SGMIB both in vitro and in vivo using U87MG.Delta EGFR cells and xenografts were compared. In vitro paired-label internalization assays showed that the intracellular radioactivity from [I-131]SIB-DOTA-L8A4 was 21.4 +/- 0.5% and 26.2 +/- 1.1% of initially bound radioactivity at 16 and 24 h, respectively. In comparison, these values for [I-125]SGMIB-L8A4 were 16.7 +/- 0.5% and 14.9 +/- 1.1%. Similarly, the SIB-DOTA prosthetic group provided better tumor targeting in vivo than SGMIB over 8 d period. These results suggest that SIB-DOTA warrants further evaluation as a residualizing agent for labeling internalizing mAbs including those targeted to EGFRvIII. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.10.025