(2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-[4-(2,5-dioxo-pyrrolidin-1-yloxycarbonyloxymethyl)-2-nitro-phenoxy]-tetrahydro-pyran-2-carboxylic acid methyl ester | 148579-95-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-[4-(2,5-dioxo-pyrrolidin-1-yloxycarbonyloxymethyl)-2-nitro-phenoxy]-tetrahydro-pyran-2-carboxylic acid methyl ester
• CAS: 148579-95-7
• 化学式: C₂₅H₂₆N₂O₁₇
• 分子量: 626.485
• InChiKey: ODJVXCAYLZILNP-VZGLXOSZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.38
• 重原子数：
  44.0
• 可旋转键数：
  10.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  239.71
• 氢给体数：
  0.0
• 氢受体数：
  17.0

反应信息

• 作为反应物：
  描述：

  (2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-[4-(2,5-dioxo-pyrrolidin-1-yloxycarbonyloxymethyl)-2-nitro-phenoxy]-tetrahydro-pyran-2-carboxylic acid methyl ester 在 sodium methylate 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 34.5h， 生成 methyl N-[β-D-glucopyranuronate-3-nitrobenzyloxycarbonyl]glycine pentafluorophenyl ester
  参考文献：
  名称：

  Synthesis and Biological Activity of the Prodrug of Class I Major Histocompatibility Peptide GILGFVFTL Activated by β-Glucuronidase

  摘要：

  The first synthesis of a prodrug of HLA-A.2.1 associated antigenic influenza peptide 2a was accomplished. Two methods for synthesis of prodrugs of antigenic peptides activated by beta-glucuronidase and comprising a self-immolative 3-nitrobenzyloxycarbonyl moiety were investigated. Reaction of P-glucuronic acid glycoside of 4-hydroxy-3-nitrobenzyl alcohol (3) with N,N'-disuccinimidyl carbonate (DSC) followed by conjugation with AlaOMe, Gly, Thr, Phe-Leu, and Leu-Arg gave carbamates 4a-4f. Deacetylation of 4b and 4e with MeONa/MeOH gave beta-glucuronides 5b and 5e. Compound 5e was converted to P-glucuronic acid conjugate 6e by the action of pig liver esterase (PLE). Compound 6e is a substrate for beta-glucuronidase. Method of a direct introduction of the prodrug residue into antigenic nonapeptide GILGFVFTL (2b) failed. Alternately, glycine conjugate 5b was activated to pentafluorophenyl ester 10. Model coupling of 10 with Phe-Leu gave tripeptide conjugate ester 11a which was hydrolyzed by PLE to uronic acid 12. Condensation of 10 with octapeptide ILGFVFTL (9) gave prodrug precursor 11b. Octapeptide 9 was prepared by de novo synthesis using a racemization-free fragment coupling method. Ester hydrolysis with Ba(OH)(2)/MeOH gave the target prodrug 2a which is a substrate for beta-glucuronidase. Prodrug 2a does not bind to HLA-A2.1 of T2 human cells defective in major histocompatibility complex I (MHC I)-associated peptide processing. Addition of beta-glucuronidase restored the binding to the level observed with parent nonapeptide 2b although higher concentrations of prodrug 2a and enzyme were necessary.

  DOI：

  10.1021/jm010352w
• 作为产物：
  描述：

  D-glucurono-6,3-lactone 在 甲醇 、 sodium tetrahydroborate 、 sodium methylate 、 溴化钛(IV) 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 34.5h， 生成 (2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-[4-(2,5-dioxo-pyrrolidin-1-yloxycarbonyloxymethyl)-2-nitro-phenoxy]-tetrahydro-pyran-2-carboxylic acid methyl ester
  参考文献：
  名称：

  5-氨基乙酰丙酸对β-葡萄糖醛酸苷酶敏感的前药的设计，合成和体外评价，可用于乳腺癌细胞的光诊断

  摘要：

  通过临床认可的5-氨基乙酰丙酸己酯（ALA-Hex）治疗癌细胞可诱导荧光卟啉在肿瘤中蓄积。这允许通过蓝光照明对膀胱癌进行荧光光诊断（PD）。然而，该化合物的急性毒性阻碍了其他癌症的PD，从而限制了其在局部应用中的应用。我们设计并合成了一种新的ALA-Hex前药，该药可解决氨基修饰的5-ALA前药的稳定性-活性悖论。葡糖醛酸前药Glu-ALA-Hex在生理条件下表现出出色的稳定性，并在目标酶存在下被激活。β-葡萄糖醛酸苷酶触发的5-ALA释放被编程为在肿瘤环境中产生荧光，β-葡萄糖醛酸苷酶活性升高，这是许多实体瘤的特征。体外，但非特异性细胞毒性低得多。

  DOI：

  10.1016/j.bioorg.2018.03.020