(2S,3S,5R,6S)-2-(methoxycarbonyl)-6-(2-nitro-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate | 148580-01-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2S,3S,5R,6S)-2-(methoxycarbonyl)-6-(2-nitro-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate
• 英文别名: (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(2-nitro-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate；(2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-[2-nitro-4-(4-nitro-phenoxycarbonyloxymethyl)-phenoxy]-tetrahydro-pyran-2-carboxylic acid methyl ester；methyl (2S,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-[2-nitro-4-[(4-nitrophenoxy)carbonyloxymethyl]phenoxy]oxane-2-carboxylate
• CAS: 148580-01-2
• 化学式: C₂₇H₂₆N₂O₁₇
• 分子量: 650.507
• InChiKey: PFVWGUQXFZWIJM-IIDPJMFPSA-N

物化性质

• 沸点：
  745.1±60.0 °C(Predicted)
• 密度：
  1.50±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  46
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  251
• 氢给体数：
  0
• 氢受体数：
  17

反应信息

• 作为反应物：
  描述：

  (2S,3S,5R,6S)-2-(methoxycarbonyl)-6-(2-nitro-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate 在 聚合甲醛 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 (2S,3R,4S,5S,6S)-2-(4-(((((2-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-10-(3-fluorophenyl)-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)methyl)(ethyl)carbamoyl)oxy)methyl)-2-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  参考文献：
  名称：

  [EN] PHENYL MALEIMIDE LINKER AGENTS
  [FR] LIEURS À BASE DE PHÉNYL MALÉIMIDE

  摘要：

  本发明公开了可用作连接剂-负载化合物的化合物。这些化合物具有如下结构 (I)，作为其立体异构体、对映体或同系物或其混合物；或其药学上可接受的盐、溶液或原药，其中 X1、X2、X3、X4、X5、R4a 和 R4b 如本文所定义。还提供了与结构(I)化合物和靶向分子或其结合片段的共轭物有关的其它化合物、共轭物、制备方法、药物组合物和治疗方法。

  公开号：

  WO2023173121A1
• 作为产物：
  描述：

  4-羟基-3-硝基苯甲醛 在 吡啶 、 sodium tetrahydroborate 、 silver(l) oxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 20.5h， 生成 (2S,3S,5R,6S)-2-(methoxycarbonyl)-6-(2-nitro-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  参考文献：
  名称：

  肿瘤微环境中靶向β-葡萄糖醛酸酶的auristatins-葡萄糖醛酸苷缀合物的设计、合成

  摘要：

  在本研究中，合成了针对肿瘤微环境中的β-葡萄糖醛酸酶的Auristatins-葡萄糖醛酸苷缀合物，并对其稳定性、auristatins的释放和抗肿瘤活性进行了评估。缀合物20和21在磷酸盐缓冲液和牛血清溶液中表现出显着的稳定性，并且在针对 β-葡萄糖醛酸酶预处理和未处理的癌细胞的体外抗增殖活性之间具有优异的选择性（IC 50  = 5.7 nM ∼ 9.7 nM，IC 50 (-Enz) > 1μM）。此外，缀合物20在 HCT-116 异种移植小鼠模型中显示出有效的抗肿瘤功效，且不会引起副作用。

  DOI：

  10.1016/j.bmcl.2023.129493

文献信息

• The Methylene Alkoxy Carbamate Self-Immolative Unit: Utilization for the Targeted Delivery of Alcohol-Containing Payloads with Antibody-Drug Conjugates
  作者：Robert V. Kolakowski、Karl T. Haelsig、Kim K. Emmerton、Chris I. Leiske、Jamie B. Miyamoto、Julia H. Cochran、Robert P. Lyon、Peter D. Senter、Scott C. Jeffrey

  DOI：10.1002/anie.201601506

  日期：2016.7.4

  A strategy for the conjugation of alcohol‐containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self‐immolative unit. A series of MAC β‐glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution‐dependent manner. All the MAC model compounds

  已经开发出一种将含酒精的有效载荷与抗体结合的策略，该策略涉及亚甲基烷氧基氨基甲酸酯（MAC）自消灭单元。制备了一系列MACβ-葡糖醛酸苷模型构建体以评估稳定性和酶促释放，结果证明了在生理pH下以取代依赖性方式具有很高的稳定性。所有的MAC模型化合物都在β-葡萄糖醛酸苷酶的作用下有效地释放了醇类药物替代物。为了评估用于ADC的MAC技术，通过去甲麻黄碱醇掺入了有效的微管破坏剂auristatin E（AE）。MACβ-葡糖醛酸苷AE药物接头与抗CD30抗体cAC10和IgG对照抗体的结合在体外和体内均具有强大的免疫学特异性活性。
• Prodrugs of Anthracyclines for Use in Antibody-Directed Enzyme Prodrug Therapy
  作者：Jean-Claude Florent、Xia Dong、Gilbert Gaudel、Sofia Mitaku、Claude Monneret、Jean-Pierre Gesson、Jean-Claude Jacquesy、Martine Mondon、Brigitte Renoux、Solo Andrianomenjanahary、Sylvie Michel、Michel Koch、François Tillequin、Manfred Gerken、Joerg Czech、Rainer Straub、Klaus Bosslet

  DOI：10.1021/jm970589l

  日期：1998.9.1

  A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by

  报道了柔红霉素和阿霉素的一系列新前药，它们是抗体指导的酶前药治疗（ADEPT）的候选药物。这些化合物（25a，b，c和32a，b，c）经设计可在被β-葡萄糖醛酸苷酶激活后产生细胞毒性药物。如所期望的，在大肠杆菌β-葡糖醛酸糖苷酶以及从人β-葡糖醛酸糖苷酶和人源化CEA特异性结合区获得的融合蛋白进行酶促切割后，观察到活性药物的回收。这六种前药对鼠L1210细胞系的稳定性高，比阿霉素的细胞毒性低100倍以上。邻位取代的氨基甲酸苯酯25a，b，c比相应的对位取代的类似物更好地是β-葡萄糖醛酸苷酶的底物。
• Synthesis and β-Glucuronidase Mediated Cleavage of an Alcohol Prodrug Incorporating a Double Spacer Moiety
  作者：Sébastien Papot、Freddy Rivault、Isabelle Tranoy、Jean-Pierre Gesson

  DOI：10.1055/s-2002-19327

  日期：——

  An alcohol prodrug has been prepared by incorporation of two spacer groups between the trigger (glucuronic acid) and nitroveratryl alcohol, used as a model. Release of the latter has been observed after hydrolysis of the glycoside by β-glucuronidase. Such prodrugs may find application in ADEPT or PMT protocols in cancer chemotherapy.

  通过在触发剂（葡萄糖醛酸）和硝基藜芦醇（用作模型）之间加入两个间隔基团，制备了一种醇类原药。在δ-葡糖醛酸酶水解该苷之后，可以观察到后者的释放。这种原药可应用于癌症化疗中的 ADEPT 或 PMT 方案。
• Synthesis and cytotoxic activity of a glucuronylated prodrug of nornitrogen mustard
  作者：Sébastien Papot、Damien Combaud、Klaus Bosslet、Manfred Gerken、Jorg Czech、Jean-Pierre Gesson

  DOI：10.1016/s0960-894x(00)00353-x

  日期：2000.8

  A new glucuronlylated prodrug of nornitrogen mustard, incorporating the same spacer group as the doxorubicin prodrug HMR 1826, has been prepared. Upon exposure to E. coli beta-glucuronidase, fast hydrolysis occurs but a lower cytotoxicity against LoVo cancer cells is observed compared to the nornitrogen mustard alone. This is explained by cyclization of the intermediate carbamic acid to the inactive chloroethyl oxazolidinone. (C) 2000 Elsevier Science Ltd. All rights reserved.
• Synthesis and biological evaluation of glucuronide prodrugs of the histone deacetylase inhibitor CI-994 for application in selective cancer chemotherapy
  作者：Mickaël Thomas、Jonathan Clarhaut、Isabelle Tranoy-Opalinski、Jean-Pierre Gesson、Joëlle Roche、Sébastien Papot

  DOI：10.1016/j.bmc.2008.07.048

  日期：2008.9

  Two glucuronide prodrugs of the histone deacetylase inhibitor CI-994 were synthesized. These compounds were found to be soluble in aqueous media and stable under physiological conditions. The carbamoyl derivatisation of CI-994 significantly decreased its toxicity towards NCI-H661 lung cancer cells. Prodrug incubation with beta-glucuronidase in the culture media led efficiently to the release of the parent drug and thereby restoring its ability to decrease cell proliferation, to inhibit HDAC and to induce E-Cadherin expression. (C) 2008 Elsevier Ltd. All rights reserved.