di-tert-butyl 1,1'-(5-amino-1,3-phenylene)(14S,14'S)-bis(1,12-dioxo-14-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-5,8-dioxa-2,11-diazapentadecan-15-oate) | 1236075-36-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 生物素及其衍生物
• 英文名称: di-tert-butyl 1,1'-(5-amino-1,3-phenylene)(14S,14'S)-bis(1,12-dioxo-14-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-5,8-dioxa-2,11-diazapentadecan-15-oate)
• CAS: 1236075-36-7
• 化学式: C₅₆H₈₉N₁₁O₁₆S₂
• 分子量: 1236.52
• InChiKey: RXEDRYQBPFQWRB-MDZADTIFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.91
• 重原子数：
  85.0
• 可旋转键数：
  38.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  372.4
• 氢给体数：
  11.0
• 氢受体数：
  19.0

反应信息

• 作为反应物：
  描述：

  di-tert-butyl 1,1'-(5-amino-1,3-phenylene)(14S,14'S)-bis(1,12-dioxo-14-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-5,8-dioxa-2,11-diazapentadecan-15-oate) 、 N,N'-硫羰基二咪唑 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 di-tert-butyl 1,1'-(5-isothiocyanato-1,3-phenylene)(14S,14'S)-bis(1,12-dioxo-14-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-5,8-dioxa-2,11-diazapentadecan-15-oate)
  参考文献：
  名称：

  Design and Synthesis of Bis-Biotin-Containing Reagents for Applications Utilizing Monoclonal Antibody-Based Pretargeting Systems with Streptavidin Mutants

  摘要：

  Previous studies have shown that pretargeting protocols, using cancer-targeting fusion proteins, composed of 4 anti-CD20 single chain Fv (scFv) fragments and streptavidin (scFv(4)-SAv), followed by a biotinylated dendrimeric N-acetyl-galactosamine blood clearing agent (CA), 1, then a radiolabeled DOTA-biotin derivative (a monobiotin), 3a, can provide effective therapy for lymphoma xenografts in mouse models. A shortcoming in this pretargeting system is that endogenous biotin may affect its efficacy in patients. To circumvent this potential problem, we investigated a pretargeting system that employs anti-CD20 scFv(4)-SAv mutant fusion proteins with radioiodinated bis-biotin derivatives. With that combination of reagents, good localization of the radiolabel to lymphoma tumor xenografts was obtained in the presence of endogenous biotin. However, the blood clearance reagents employed in the studies were ineffective, resulting in abnormally high levels of radioactivity in other tissues. Thus, in the present investigation a bis-biotin-trigalactose blood clearance reagent, 2, was designed, synthesized, and evaluated in vivo. Additionally, another DOTA-biotin derivative (a bis-biotin), 4a, was designed and synthesized, such that radiometals (e.g., In-111, Y-90, Lu-177) could be used in the pretargeting protocols employing scFv(4)-SAv mutant fusion proteins. Studies in mice demonstrated that the CA 2 was more effective than CA 1 at removing [I-125]scFv(4)-SAv-S45A mutant fusion proteins from blood. Another in vivo study compared tumor targeting and normal tissue concentrations of the new reagents (2 and [In-111]4b) with standard reagents (1 and [In-111]3b) used in pretargeting protocols. The study showed that lymphoma xenografts could be targeted in the presence of endogenous biotin when anti-CD20 fusion potent containing SAv mutants (scFv(4)-SAv-S45A or scFv(4)-SAv-Y43A) were employed in combination with CA 2 and [In-111]4b). Importantly, normal tissue concentrations of [In-111]4b were similar to those obtained using the standard reagents (1 and [In-111]3b), except that the blood and liver concentrations were slightly higher with the new reagents. While the reasons for the higher blood and liver concentrations are unknown, the differences in the galactose structures of the clearance agents 1 and 2 may play a role.

  DOI：

  10.1021/bc100030q
• 作为产物：
  描述：

  (S)-4-(tert-butoxy)-4-oxo-3-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)butanoic acid 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 生成 di-tert-butyl 1,1'-(5-amino-1,3-phenylene)(14S,14'S)-bis(1,12-dioxo-14-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-5,8-dioxa-2,11-diazapentadecan-15-oate)
  参考文献：
  名称：

  Design and Synthesis of Bis-Biotin-Containing Reagents for Applications Utilizing Monoclonal Antibody-Based Pretargeting Systems with Streptavidin Mutants

  摘要：

  Previous studies have shown that pretargeting protocols, using cancer-targeting fusion proteins, composed of 4 anti-CD20 single chain Fv (scFv) fragments and streptavidin (scFv(4)-SAv), followed by a biotinylated dendrimeric N-acetyl-galactosamine blood clearing agent (CA), 1, then a radiolabeled DOTA-biotin derivative (a monobiotin), 3a, can provide effective therapy for lymphoma xenografts in mouse models. A shortcoming in this pretargeting system is that endogenous biotin may affect its efficacy in patients. To circumvent this potential problem, we investigated a pretargeting system that employs anti-CD20 scFv(4)-SAv mutant fusion proteins with radioiodinated bis-biotin derivatives. With that combination of reagents, good localization of the radiolabel to lymphoma tumor xenografts was obtained in the presence of endogenous biotin. However, the blood clearance reagents employed in the studies were ineffective, resulting in abnormally high levels of radioactivity in other tissues. Thus, in the present investigation a bis-biotin-trigalactose blood clearance reagent, 2, was designed, synthesized, and evaluated in vivo. Additionally, another DOTA-biotin derivative (a bis-biotin), 4a, was designed and synthesized, such that radiometals (e.g., In-111, Y-90, Lu-177) could be used in the pretargeting protocols employing scFv(4)-SAv mutant fusion proteins. Studies in mice demonstrated that the CA 2 was more effective than CA 1 at removing [I-125]scFv(4)-SAv-S45A mutant fusion proteins from blood. Another in vivo study compared tumor targeting and normal tissue concentrations of the new reagents (2 and [In-111]4b) with standard reagents (1 and [In-111]3b) used in pretargeting protocols. The study showed that lymphoma xenografts could be targeted in the presence of endogenous biotin when anti-CD20 fusion potent containing SAv mutants (scFv(4)-SAv-S45A or scFv(4)-SAv-Y43A) were employed in combination with CA 2 and [In-111]4b). Importantly, normal tissue concentrations of [In-111]4b were similar to those obtained using the standard reagents (1 and [In-111]3b), except that the blood and liver concentrations were slightly higher with the new reagents. While the reasons for the higher blood and liver concentrations are unknown, the differences in the galactose structures of the clearance agents 1 and 2 may play a role.

  DOI：

  10.1021/bc100030q