(S)-5-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-6-oxo-7-((2,4,6-trimethylbenzoyl)oxy)heptan-1-ammonium trifluoroacetate

• 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: (S)-5-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-6-oxo-7-((2,4,6-trimethylbenzoyl)oxy)heptan-1-ammonium trifluoroacetate
• 英文别名: (S)-7-Amino-3-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-2-oxoheptyl 2,4,6-trimethylbenzoate 2,2,2-trifluoroacetate；[(3S)-7-amino-2-oxo-3-[[(2S)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoyl]amino]heptyl] 2,4,6-trimethylbenzoate;2,2,2-trifluoroacetic acid
• 化学式: C₂HF₃O₂*C₃₄H₄₁N₃O₆
• 分子量: 701.74
• InChiKey: PSVOORHGOPOUNV-OCPPCWRMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.12
• 重原子数：
  50
• 可旋转键数：
  17
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  174
• 氢给体数：
  4
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  3-叠氮丙酸 、 (S)-5-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-6-oxo-7-((2,4,6-trimethylbenzoyl)oxy)heptan-1-ammonium trifluoroacetate 在 氯甲酸异丁酯 作用下， 以47%的产率得到
  参考文献：
  名称：

  用于生物医学应用的聚酯树突状支架的合成。

  摘要：

  使用定义明确的聚（2,2-双（羟甲基）丙酸）树状聚合物骨架，一系列G1至G3树突在炔烃的外围进行官能化，以通过铜催化炔烃-叠氮化物环加成反应实现“点击”官能化（CuAAC）。生成的树突在核心处用二聚烯丙基胺（DPA）进一步功能化，从而能够在分子成像应用中用99m Tc进行放射性标记。使用叠氮化物官能化的三乙二醇单甲醚（TEG-N 3）可实现有效的CuAAC偶联。在用99m Tc进行放射性标记之前，已成功在G1和G2树状聚合物上完成了从DPA配体中去除铜的操作。G3树状大分子的放射性标记是通过[CuDPA] 2+的金属转移来完成的Tm为99m Tc的配体，进一步证明了合成策略在制备树突显像剂中的可行性。随后探讨了用于组织蛋白酶B靶向的酰氧基甲基酮（AOMK）衍生物的后续连接。尽管显示了连接多个AOMK配体的能力，但AOMK-树状聚合物结合物不能与组织蛋白酶B结合，这可能归因于树状聚合物外围的空间位阻。

  DOI：

  10.1002/mabi.201600154
• 作为产物：
  描述：

  2,4,6-三甲基苯甲酸 在 potassium fluoride 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 (S)-5-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-6-oxo-7-((2,4,6-trimethylbenzoyl)oxy)heptan-1-ammonium trifluoroacetate
  参考文献：
  名称：

  达到目标的时间延长：利用半胱氨酸组织蛋白酶抑制剂来增强受体靶向药物的肿瘤保留能力†

  摘要：

  我们报告了利用不可逆的半胱氨酸组织蛋白酶抑制剂作为捕获剂以增加受体靶向药物的肿瘤停留时间的策略。掺入这些半胱氨酸组织蛋白酶捕获剂的靶向构建体能够与细胞内半胱氨酸组织蛋白酶形成高分子量加合物，从而在肿瘤组织中实现优异的保留。

  DOI：

  10.1039/c8cc05982a

文献信息

• Synthesis and Evaluation of Radioiodinated Acyloxymethyl Ketones as Activity-Based Probes for Cathepsin B
  作者：Patricia E. Edem、Shannon Czorny、John F. Valliant

  DOI：10.1021/jm501357r

  日期：2014.11.26

  Dipeptidyl (acyloxy)methyl ketones (AOMKs) were functionalized with different iodine-containing prosthetic groups to generate a library of candidate cathepsin B probes. Compound 23a, (S)-20-[(S)-2-[(benzyloxy)carbonyl]amino}-3-phenylpropanamido]-1-(4-iodophenyl)-1,14,21-trioxo-5,8,11-trioxa-2,15-diazadocosan-22-yl 2,4,6-trimethylbenzoate, was identified as a potential lead through in vitro screening, having a K-i = 181 +/- 9 nM and demonstrating the ability to effectively label active cathepsin B in vitro. Its less potent analogue 11a, (S)-3-[(S)-2-[(benzyloxy)carbonyl]amino}-3-phenylpropanamido]-7-[6-(4-iodobenzamido)hexanamido]-2-oxoheptyl 2,4,6-trimethylbenzoate, was also tested as a comparison. Biodistribution studies of the iodine-125-labeled compounds in MDA-MB-231 mouse xenografts exhibited tumor uptake of 0.58% +/- 0.06% injected dose per gram (ID/g) for [I-125]11a and 1.12% +/- 0.08% ID/g for [I-125]23a at 30 min. The tumor-to-blood ratios reached 1.2 for [I-125]23a and 1.6 for [I-125]11a after 23 h. The more hydrophilic [I-125]23a showed an improved clearance profile with a superior tumor-to-muscle ratio of 7.0 compared to 3.4 for [I-125]11a at 23 h. Iodinated AOMK ligands are suitable in vitro probes for cathepsin B and hold promise as a platform to develop molecular imaging probes.
• WO2019/147338
  申请人：——

  公开号：——

  公开（公告）日：——
• In vivo Inhibition of Cathepsin B by Peptidyl (Acyloxy)methyl Ketones
  作者：Bonnie M. Wagner、Roger A. Smith、Peter J. Coles、Leslie J. Copp、Michael J. Ernest、Allen Krantz

  DOI：10.1021/jm00038a012

  日期：1994.6

  Peptidyl (acyloxy)methyl ketones, previously established as potent irreversible inhibitors of the cysteine proteinase cathepsin B in vitro, were investigated and optimized for their inhibitory activity in vivo. Incorporation of polar or charged functional groups in the inhibitor structure afforded effective cathepsin B inhibition, following dosing to rats. The most effective inhibitor, Z-Phe-Lys-CH2OCO-(2,4,6-Me(3))Ph (8), was found to give ED(50) values of 18 mg/kg po (orally) and 5.0 mg/kg ip (intraperitoneally) at 4-5 h postdose, and 2.4 mg/kg sc (subcutaneously) at 24 h postdose, for liver cathepsin B inhibition (measured ex vivo). The subcutaneous route of administration of (acyloxy)methyl ketone 8 also provided potent cathepsin B inhibition in certain peripheral tissues (e.g., ED(50) 1.0 mg/kg for skeletal muscle, 0.1 mg/kg for heart). These investigations demonstrate that peptidyl (acyloxy)methyl ketones such as 8 have promise as tools for the characterization of in vivo biochemical processes and as therapeutic agents.
• Synthesis of Polyester Dendritic Scaffolds for Biomedical Applications
  作者：Lukas P. Sadowski、Patricia E. Edem、John F. Valliant、Alex Adronov

  DOI：10.1002/mabi.201600154

  日期：2016.10

  Using a well‐defined poly(2,2‐bis(hydroxymethyl)propanoic acid) dendrimer scaffold, a series of G1 to G3 dendrons is functionalized at the periphery with alkynes to enable “Click” functionalization via the copper‐catalyzed alkyne–azide cycloaddition (CuAAC). The resulting dendrons are further functionalized at the core with a dipicolylamine (DPA) moiety to enable radiolabeling with 99mTc for molecular

  使用定义明确的聚（2,2-双（羟甲基）丙酸）树状聚合物骨架，一系列G1至G3树突在炔烃的外围进行官能化，以通过铜催化炔烃-叠氮化物环加成反应实现“点击”官能化（CuAAC）。生成的树突在核心处用二聚烯丙基胺（DPA）进一步功能化，从而能够在分子成像应用中用99m Tc进行放射性标记。使用叠氮化物官能化的三乙二醇单甲醚（TEG-N 3）可实现有效的CuAAC偶联。在用99m Tc进行放射性标记之前，已成功在G1和G2树状聚合物上完成了从DPA配体中去除铜的操作。G3树状大分子的放射性标记是通过[CuDPA] 2+的金属转移来完成的Tm为99m Tc的配体，进一步证明了合成策略在制备树突显像剂中的可行性。随后探讨了用于组织蛋白酶B靶向的酰氧基甲基酮（AOMK）衍生物的后续连接。尽管显示了连接多个AOMK配体的能力，但AOMK-树状聚合物结合物不能与组织蛋白酶B结合，这可能归因于树状聚合物外围的空间位阻。
• Increasing time on target: utilization of inhibitors of cysteine cathepsins to enhance the tumor retention of receptor-targeted agents
  作者：Wei Fan、Wenting Zhang、Sameer Alshehri、Jered C. Garrison

  DOI：10.1039/c8cc05982a

  日期：——

  report a strategy of utilizing irreversible cysteine cathepsin inhibitor as trapping agent to increase the tumor residence time of receptor-targeted agents. The targeted constructs incorporating these cysteine cathepsin trapping agents were able to form high molecular weight adducts with intracellular cysteine cathepsins, thus achieving superior retention in tumor tissues.

  我们报告了利用不可逆的半胱氨酸组织蛋白酶抑制剂作为捕获剂以增加受体靶向药物的肿瘤停留时间的策略。掺入这些半胱氨酸组织蛋白酶捕获剂的靶向构建体能够与细胞内半胱氨酸组织蛋白酶形成高分子量加合物，从而在肿瘤组织中实现优异的保留。