(+/-)-trans-ethyl 1-benzyl-4-hydroxy-5-oxopyrrolidine-3-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (+/-)-trans-ethyl 1-benzyl-4-hydroxy-5-oxopyrrolidine-3-carboxylate
• 英文别名: (+/-)-1-Benzyl-4β-ethoxycarbonyl-3α-hydroxy-2-oxopyrolidin；(+/-)-trans-1-N-benzyl-3-hydroxy-2-pyrrolidinone-4-carboxylic acid ethyl ester；3-Pyrrolidinecarboxylic acid, 4-hydroxy-5-oxo-1-(phenylmethyl)-, ethyl ester, (3R,4S)-rel-；ethyl (3R,4S)-1-benzyl-4-hydroxy-5-oxopyrrolidine-3-carboxylate
• 化学式: C₁₄H₁₇NO₄
• 分子量: 263.293
• InChiKey: YKDLEHPCPKSCPK-NEPJUHHUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (+/-)-trans-ethyl 1-benzyl-4-hydroxy-5-oxopyrrolidine-3-carboxylate 在 ammonium hydroxide 、 10 wt% Pd(OH)2 on carbon 、 三氟化硼乙醚 、 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 86.0h， 生成 (3S,4S)-4-(羟甲基)吡咯烷-3-醇
  参考文献：
  名称：

  Tight binding enantiomers of pre-clinical drug candidates

  摘要：

  MTDIA is a picomolar transition state analogue inhibitor of human methylthioadenosine phosphorylase and a femtomolar inhibitor of Escherichia coli methylthioadenosine nucleosidase. MTDIA has proven to be a non-toxic, orally available pre-clinical drug candidate with remarkable anti-tumour activity against a variety of human cancers in mouse xenografts. The structurally similar compound MTDIH is a potent inhibitor of human and malarial purine nucleoside phosphorylase (PNP) as well as the newly discovered enzyme, methylthioinosine phosphorylase, isolated from Pseudomonas aeruginosa. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the enantiomers of MTDIH and MTDIA, compounds 1 and 2, respectively, were prepared and their enzyme binding properties studied. Despite binding less tightly to their target enzymes than their enantiomers compounds 1 and 2 are nanomolar inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.07.059
• 作为产物：
  描述：

  N-Benzylidenebenzylamine N-oxide 在 盐酸 、 sodium acetate 、 溶剂黄146 、 锌 作用下， 以 乙醇 、 水 为溶剂， 反应 4.5h， 生成 (+/-)-trans-ethyl 1-benzyl-4-hydroxy-5-oxopyrrolidine-3-carboxylate
  参考文献：
  名称：

  Profiling base excision repair glycosylases with synthesized transition state analogs

  摘要：

  Two base excision repair glycosylase (BER) transition state (TS) mimics, (3R,4R)-1-benzyl (hydroxymethyl) pyrrolidin-3-ol (1NBn) and (3R,4R)-(hydroxymethyl) pyrrolidin-3-ol (1N), were synthesized using an improved method. Several BER glycosylases that repair oxidized DNA bases, bacterial formamidopyrimdine glycosylase (Fpg), human OG glycosylase (hOGG1) and human Nei-like glycosylase 1 (hNEIL1) exhibit exceptionally high affinity (K-d similar to pM) with DNA duplexes containing the 1NBn and 1N nucleotide. Notably, comparison of the K-d values of both TS mimics relative to an abasic analog (THF) in duplex contexts paired opposite C or A suggest that these DNA repair enzymes use distinctly different mechanisms for damaged base recognition and catalysis despite having overlapping substrate specificities. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.05.085

文献信息

• [EN] COMPOSITIONS AND METHODS FOR THERAPY OF PROSTATE CANCER USING DRUG COMBINATIONS TO TARGET POLYAMINE BIOSYNTHESIS AND RELATED PATHWAYS<br/>[FR] COMPOSITIONS ET MÉTHODES DE TRAITEMENT DU CANCER DE LA PROSTATE UTILISANT DES COMBINAISONS DE MÉDICAMENTS POUR CIBLER LA BIOSYNTHÈSE DES POLYAMINES ET LES VOIES ASSOCIÉES
  申请人：HEALTH RESEARCH INC

  公开号：WO2016187183A1

  公开（公告）日：2016-11-24

  Provided are compositions and methods for treating prostate conditions. The methods involve administering to an individual in need thereof a composition that contains i) an inhibitor of methionine salvage pathway in prostate of the individual and ii) a polyamine analogue. The methods are for use in individuals who have been diagnosed with, or are suspected of having or at risk for developing androgen sensitive prostate cancer (AS-CaP), or Castration recurrent CaP (CR-CaP), or benign prostate hyperplasia (BPH). The disclosure includes use of inhibitors of methylthioadenosine phosphorylase (MTAP), and a polyamine analog that upregulates polyamine catabolism by increasing spermidine/spermine Nl -acetyl transferase (SAT1) activity, such as methylthio-DADMe-Immucillin (MTDIA), andl),N(11)-bisethylnorspermine (BENSpm), respectively. Pharmaceutical formulations that contain a combination of the inhibitor of the methionine salvage pathway and a polyamine analogue are included, as are kits that contain such agents.

  提供了用于治疗前列腺疾病的组合物和方法。这些方法涉及向需要的个体施用一种含有i) 抑制前列腺中蛋氨酸拯救途径的抑制剂和ii) 多胺类似物的组合物。这些方法适用于被诊断出患有、或被怀疑患有或有发展为雄激素敏感的前列腺癌（AS-CaP）、或去势复发型前列腺癌（CR-CaP）、或良性前列腺增生（BPH）的个体。该公开包括使用甲硫氨酸腺苷磷酸化酶（MTAP）的抑制剂，以及通过增加精胺/精氨酸Nl-乙酰转移酶（SAT1）活性来上调多胺代谢的多胺类似物，如甲硫-DADMe-Immucillin（MTDIA）和N(11)-双乙基诺精胺（BENSpm）。包含抑制蛋氨酸拯救途径的抑制剂和多胺类似物的药物配方被纳入，还包括包含这些药剂的试剂盒。
• C5‐Iminosugar modification of casein kinase 1δ lead 3‐(4‐fluorophenyl)‐5‐isopropyl‐4‐(pyridin‐4‐yl)isoxazole promotes enhanced inhibitor affinity and selectivity
  作者：Thorsten Drathen、Elizabeth M. Ure、Stefan Kirschner、Aileen Roth、Laura Meier、Anthony D. Woolhouse、Scott A. Cameron、Uwe Knippschild、Christian Peifer、Andreas Luxenburger

  DOI：10.1002/ardp.202100497

  日期：2022.5

  pocket/solvent-open area of the ATP binding pocket of CK1δ. Here, we describe the synthesis of analogs of 1 ((−)-/(+)-34, (−)-/(+)-48), which were prepared in 13 steps from enantiomerically pure ethyl (3R,4S)- and ethyl (3S,4R)-1-benzyl-4-[(tert-butyldimethylsilyl)oxy]-5-oxopyrrolidine-3-carboxylate ((–)-11 and (+)-11), respectively. The synthesis involved the coupling of Weinreb amide-activated chiral pyrrolidine

  对异构体选择性和特异性 ATP 竞争性蛋白激酶抑制剂的探索引起了极大的兴趣，因为具有这些特性的抑制剂会降低毒性并提高疗效。然而，由于激酶 ATP 活性位点的高分子相似性，创建此类抑制剂非常具有挑战性。为了实现对我们的酪蛋白激酶 (CK) 1 抑制剂系列的选择性，我们选择赋予我们之前的 CK1δ-hit, 3-(4-fluorophenyl)-5-isopropyl-4-(pyridin-4-yl)isoxazole ( 1 ),手性亚氨基糖支架。这些支架连接到异恶唑环的 C5 上，该位置被认为有利于促进与 CK1δ 的 ATP 结合袋的核糖袋/溶剂开放区域的结合相互作用。在这里，我们描述了1 ((-)-/(+)-的类似物的合成34 , (-)-/(+)- 48 )，由对映体纯的乙基 (3 R ,4 S )- 和乙基 (3 S ,4 R )-1-benzyl-4-[(叔丁基二甲基甲硅烷基）氧
• Development of a Practical Synthesis of a Purine Nucleoside Phosphorylase Inhibitor: BCX-4208
  作者：Vivekanand P. Kamath、Jesus J. Juarez-Brambila、Christopher B. Morris、Christopher D. Winslow、Philip E. Morris

  DOI：10.1021/op9001142

  日期：2009.9.18

  A practical synthesis of the purine nucleoside phosphorylase (PNP) inhibitor BCX-4208 (1) was accomplished in three telescoped steps. Mannich condensation of the 4-benzyloxy-9-deazahypoxanthine with (3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidine and formaldehyde followed by removal of the protecting group and crystallization furnished the desired product as a hydrochloride salt in 85% overall yield

  嘌呤核苷磷酸化酶（PNP）抑制剂BCX-4208（1）的实用合成可通过三个伸缩步骤完成。4-苄氧基-9-脱氮杂并黄嘌呤与（3 R，4 R）-3-羟基-4-（羟甲基）吡咯烷和甲醛的曼尼希缩合，然后除去保护基并结晶，得到所需产物，为盐酸盐。总产率为85％，纯度为99.8％。还报道了9-脱氮杂黄嘌呤的可扩展合成。
• [EN] IMPROVED METHOD FOR PREPARING 3-HYDROXY-4-HYDROXYMETHYL-PYRROLIDINE COMPOUNDS<br/>[FR] PROCEDE AMELIORE DE PREPARATION DE COMPOSES 3-HYDROXY-4-HYDROXYMETHYL-PYRROLIDINE
  申请人：IND RES LTD

  公开号：WO2005118532A1

  公开（公告）日：2005-12-15

  A process for preparing (3R,4R)-3-hydroxy-4-hydroxymethylpyrrolidine, the compound of formula (I), or (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidine, the compound of formula (Ia) involving, as a key step, the enzyme-catalysed enantioselective hydrolysis of a racemic 3,4-trans-disubstituted pyrrolidinone compound of formula (II).

  一种制备式（I）化合物（（3R,4R）-3-羟基-4-羟甲基吡咯烷）或式（Ia）化合物（（3S,4S）-3-羟基-4-羟甲基吡咯烷）的方法，其中关键步骤涉及以酶催化的对称选择性水解3,4-反式二取代吡咯烷酮化合物（II）。
• A practical synthesis of (3R,4R)-N-tert-butoxycarbonyl-4-hydroxymethylpyrrolidin-3-ol
  作者：Keith Clinch、Gary B. Evans、Richard H. Furneaux、Dirk H. Lenz、Jennifer M. Mason、Simon P. H. Mee、Peter C. Tyler、Sarah J. Wilcox

  DOI：10.1039/b708796a

  日期：——

  The title compound (+)-5, required for production of transition state analogue inhibitors of enzymes involved in T-cell-dependent disorders, was synthesized in five steps. A 1,3-dipolar cycloaddition of the nitrone formed from formaldehyde and N-benzylhydroxylamine to diethyl maleate gave the racemic cis-isoxazolidine (±)-7. Reduction of the N–O bond of this compound gave pyrrolidone (±)-8 in excellent yield. A very efficient enzymic resolution of this racemic product led to the title enantiomer (+)-5. This route employs only one chromatographic purification.

  标题化合物 (+)-5 是生产涉及 T 细胞依赖性疾病的酶的过渡态类似物抑制剂所需的，分五个步骤合成。由甲醛和N-苄基羟胺形成的硝酮与马来酸二乙酯进行1,3-偶极环加成得到外消旋顺式异恶唑烷(±)-7。该化合物的 N-O 键还原得到了吡咯烷酮 (±)-8，收率极佳。对该外消旋产物进行非常有效的酶解，得到标题对映体 (+)-5。该路线仅采用一种色谱纯化。