Nα-fluorenylmethoxycarbonyl-trans-4-hydroxy-L-proline allyl ester | 468096-64-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: Nα-fluorenylmethoxycarbonyl-trans-4-hydroxy-L-proline allyl ester
• 英文别名: (2S,4R)-1-((9H-fluoren-9-yl)methyl) 2-allyl 4-hydroxypyrrolidine-1,2-dicarboxylate；4-hydroxypyrrolidine-1,2-dicarboxylic acid 2-allyl ester 1-(9H-fluoren-9-ylmethyl) ester；Fmoc-Hyp(OH)-OAllyl；1-((9H-fluoren-9-yl)methyl) 2-allyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate；1-O-(9H-fluoren-9-ylmethyl) 2-O-prop-2-enyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate
• CAS: 468096-64-2
• 化学式: C₂₃H₂₃NO₅
• 分子量: 393.439
• InChiKey: YOPSSWWHIZQZBA-VFNWGFHPSA-N

物化性质

• 沸点：
  568.0±50.0 °C(Predicted)
• 密度：
  1.292±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Nα-fluorenylmethoxycarbonyl-trans-4-hydroxy-L-proline allyl ester 在 吡啶 、 sodium azide 、 dimethyl azodicarboxylate 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 31.0h， 生成 (2S,4S)-4-Trifluoromethanesulfonyloxy-pyrrolidine-1,2-dicarboxylic acid 2-allyl ester 1-(9H-fluoren-9-ylmethyl) ester
  参考文献：
  名称：

  β-Glycosides of Hydroxyproline via an Umpolung Approach

  摘要：

  Reaction of 1,2-O-dibutylstannylene-3,4-6-tri-O-benzyl-beta-D-mannopyranose with N alpha-fluorenylmethoxycarbonyl-cis-4-trifluoromethanesulfonyloxyproline allyl ester led to formation of beta-mannoside of trans-4-hydroxyproline. Subsequent manipulation of the C2 hydroxy group gave rise to beta-D-Glc and beta-D-GlcNAc derivatives.

  DOI：

  10.1021/ol061424m
• 作为产物：
  描述：

  (2S,4R)-1-((9H-fluoren-9-yl)methyl) 2-allyl 4-(tert-butoxy)pyrrolidine-1,2-dicarboxylate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 13.0h， 以81%的产率得到Nα-fluorenylmethoxycarbonyl-trans-4-hydroxy-L-proline allyl ester
  参考文献：
  名称：

  使用小分子靶向 von Hippel-Lindau E3 泛素连接酶以破坏 VHL/HIF-1α 相互作用

  摘要：

  E3 泛素连接酶结合蛋白质靶标，导致其泛素化和随后的降解，由于其出色的底物特异性，是有吸引力的药物靶标。然而，小分子抑制剂的开发已证明极具挑战性，因为调节 E3 连接酶活性需要靶向蛋白质-蛋白质相互作用。通过合理的设计，我们生成了第一个靶向 von Hippel-Lindau 蛋白 (VHL) 的小分子，VHL 是 E3 连接酶的底物识别亚基，也是癌症、慢性贫血和缺血的重要靶点。我们还获得了与我们最有效的抑制剂结合的 VHL 的晶体结构，证实该化合物模拟了转录因子 HIF-1α（VHL 的底物）的结合模式。

  DOI：

  10.1021/ja209924v

文献信息

• [EN] NOVEL METHOD FOR SYNTHESIZING AMANITINS<br/>[FR] NOUVEAU PROCÉDÉ DE SYNTHÈSE D'AMANITINES
  申请人：HEIDELBERG PHARMA GMBH

  公开号：WO2019030171A1

  公开（公告）日：2019-02-14

  The invention relates to novel methods for synthesizing amanitin derivatives having an amino group attached to position 6' of the central tryptophan moiety. The invention furthermore relates to a novel amanitin derivative having an amino group attached to position 6' of the central tryptophan moiety, novel conjugates of such amanitin derivative, and pharmaceutical compositions comprising such conjugates.

  该发明涉及新的方法，用于合成在中心色氨酸部分6'位置带有氨基的鹅膏蕈碱衍生物。此外，该发明还涉及一种新的鹅膏蕈碱衍生物，其中心色氨酸部分6'位置带有氨基，以及这种鹅膏蕈碱衍生物的新结合物，以及包含这种结合物的药物组合物。
• [EN] AMANITIN CONJUGATES<br/>[FR] CONJUGUÉS D'AMANITINE
  申请人：HEIDELBERG PHARMA GMBH

  公开号：WO2017149077A1

  公开（公告）日：2017-09-08

  The invention relates to a conjugate comprising (a) an amatoxin comprising (i) an amino acid 4 with a 6'-deoxy position; and (ii) an amino acid 8 with an S-deoxy position; (b) a target-binding moiety; and (c) optionally a linker linking said amatoxin and said target-binding moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate.

  这项发明涉及一种共轭物，包括(a) 包括(i) 具有6'-去氧位的氨基酸4；和(ii) 具有S-去氧位的氨基酸8 的阿马毒素；(b) 一个靶向结合基团；以及(c) 可选地连接所述阿马毒素和所述靶向结合基团的连接剂。此外，该发明还涉及包含这种共轭物的药物组合物。
• [EN] AMANITIN ANTIBODY CONJUGATES<br/>[FR] CONJUGUÉS D'ANTICORPS À BASE D'AMANITINE
  申请人：HEIDELBERG PHARMA RES GMBH

  公开号：WO2018115466A1

  公开（公告）日：2018-06-28

  The invention relates to a conjugate comprising (a) an amatoxin comprising (i) an amino acid 4 with a 6'-deoxy position; and (ii) an amino acid 8 with an S-deoxy position; (b) a BCMA-binding moiety comprising (i) the variable domains of humanized antibody J22.9-ISY, and (ii) a heavy chain constant region comprising a D265C mutation; and (c) a protease-cleavable linker linking said amatoxin and said target-binding moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate, particularly for use in the treatment of multiple myeloma.

  该发明涉及一种共轭物，包括(a) 包含(i) 具有6'-去氧位的氨基酸4；和(ii) 具有S-去氧位的氨基酸8 的毒蕈碱；(b) 包括(i) 人源化抗体J22.9-ISY的可变区域；和(ii) 包括D265C突变的重链常数区域的BCMA结合基团；以及(c) 连接所述毒蕈碱和目标结合基团的蛋白酶可切割连接物。该发明还涉及包括这种共轭物的药物组合物，特别用于治疗多发性骨髓瘤。
• Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase
  申请人：YALE UNIVERSITY

  公开号：US20140356322A1

  公开（公告）日：2014-12-04

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins that are degraded and/or otherwise inhibited by bifunctional compounds of the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand that binds to the ubiquitin ligase and on the other end a moiety that binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds of the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，其作为靶向泛素化的调节剂具有实用性，特别是作为本发明的双功能化合物对各种被降解和/或受到抑制的多肽和其他蛋白质的抑制剂。具体而言，本发明涉及含有一端结合泛素连接酶的VHL配体，另一端结合靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。本发明展示了与本发明化合物相关的广泛的药理活性范围，与靶向多肽的降解/抑制一致。
• Synthesis of D-Galactopyranosides of trans-4-Hydroxy-L-proline Utilizing the Sulfoxide Glycosylation Method
  作者：C. M. Taylor、C. A. Weir、C. G. Jørgensen

  DOI：10.1071/ch01156

  日期：——

  Phenyl 1-thio-β-D-galactopyranoside (1) was converted into two sulfoxide glycosyl donors: phenyl (2,3,4,6-tetra-O-benzyl)-1-thio-β-D-galactopyranoside S-oxide (3) and phenyl (2,3,4,6-tetra-O-pivaloyl)- 1-thio-β-D-galactopyranoside S-oxide (5). These glycosyl donors were then each reacted with Na- fluorenylmethoxycarbonyl-trans-4-hydroxy-L-proline allyl ester (7). The glycosylation reactions were conducted at -70°C with triflic anhydride as promotor, in the presence of 2,6-di-tert-butyl-4-methylpyridine. In the case of the perbenzylated sulfoxide donor (3), the major product was Na-fluorenylmethoxycarbonyl-trans-4-hydroxy- 4-O-[(2,3,4,6-tetra-O-benzyl)-a-D-galactopyranosyl]-L-proline allyl ester (8a). In dichloromethane, the a-to-β ratio was 3 : 1 and in toluene this improved to 5 : 1, with a combined yield of 41%. In the case of the perpivaloylated sulfoxide donor (5), Na-fluorenylmethoxycarbonyl-trans-4-hydroxy-4-O-[(2,3,4,6-tetra-O-pivaloyl)-β-D- galactopyranosyl]-L-proline allyl ester (9) was obtained as the sole glycoside product in 46% yield.

  将苯基 1-硫代-β-D-吡喃半乳糖苷（1）转化为两种亚砜糖基供体：苯基（2,3,4,6-四-O-苄基）-1-硫代-β-D-吡喃半乳糖苷 S-氧化物（3）和苯基（2,3,4,6-四-O-特戊酰基）-1-硫代-β-D-吡喃半乳糖苷 S-氧化物（5）。然后，这些糖基供体分别与芴甲氧羰基-反式-4-羟基-L-脯氨酸烯丙基酯（7）反应。糖基化反应是在 2,6-二叔丁基-4-甲基吡啶存在下，以三酸酐为促进剂，于 -70°C 温度下进行的。在过苄基亚砜供体（3）的情况下，主要产物为 Na-芴甲氧羰基-反式-4-羟基-4-O-[(2,3,4,6-四-O-苄基)-a-D-吡喃半乳糖基]-L-脯氨酸烯丙基酯（8a）。在二氯甲烷中，a-β 的比例为 3:1，在甲苯中提高到 5:1，总产率为 41%。在过新戊酰化亚砜供体（5）的情况下，Na-芴甲氧羰基-反式-4-羟基-4-O-[(2,3,4,6-四-O-新戊酰基)-β-D-吡喃半乳糖基]-L-脯氨酸烯丙基酯（9）作为唯一的糖苷产物被获得，收率为 46%。