(R)-5-oxo-pyrrolidine-2-carboxylic acid ((S)-6-mercapto-1-phenylcarbamoyl-hexyl)-amide | 1428536-05-3

• 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: (R)-5-oxo-pyrrolidine-2-carboxylic acid ((S)-6-mercapto-1-phenylcarbamoyl-hexyl)-amide
• 英文别名: (2R)-N-[(2S)-1-anilino-1-oxo-7-sulfanylheptan-2-yl]-5-oxopyrrolidine-2-carboxamide
• CAS: 1428536-05-3
• 化学式: C₁₈H₂₅N₃O₃S
• 分子量: 363.481
• InChiKey: YYSCXBPFYMVUDP-LSDHHAIUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  88.3
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-5-oxo-pyrrolidine-2-carboxylic acid ((S)-6-mercapto-1-phenylcarbamoyl-hexyl)-amide 、 4-[[6-(2,5-Dioxopyrrol-1-yl)hexanoylamino]methyl]cyclohexane-1-carboxylic acid 以 甲醇 为溶剂， 以69%的产率得到4-[[6-[3-[(6S)-7-anilino-7-oxo-6-[[(2R)-5-oxopyrrolidine-2-carbonyl]amino]heptyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]hexanoylamino]methyl]cyclohexane-1-carboxylic acid
  参考文献：
  名称：

  Antibody drug conjugates (ADCs) charged with HDAC inhibitor for targeted epigenetic modulation

  摘要：

  ADC武器库中新增了一种硫醇基HDAC抑制剂。毒性低，能够命中目标并在许多小鼠模型中阻止肿瘤生长。

  DOI：

  10.1039/c7sc05266a
• 作为产物：
  描述：

  ((S)-1-phenylcarbamoyl-hex-5-enyl)-carbamic acid tert-butyl ester 在 偶氮二异丁腈 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 、 sodium thiomethoxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 (R)-5-oxo-pyrrolidine-2-carboxylic acid ((S)-6-mercapto-1-phenylcarbamoyl-hexyl)-amide
  参考文献：
  名称：

  ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors

  摘要：

  A systematic study of medicinal chemistry aimed at identifying a new generation of HDAC inhibitors, through the introduction of a thiol zinc-binding group (ZBG) and of an amide-lactam in the ?-position of the polyethylene chain of the vorinostat scaffold, allowed the selection of a new class of potent pan-HDAC inhibitors (pan-HDACis). Simple, highly versatile, and efficient synthetic approaches were used to synthesize a library of these new derivatives, which were then submitted to a screening for HDAC inhibition as well as to a preliminary in vitro assessment of their antiproliferative activity. Molecular docking into HDAC crystal structures suggested a binding mode for these thiol derivatives consistent with the stereoselectivity observed upon insertion of amide-lactam substituents in the ?-position. ST7612AA1 (117), selected as a drug candidate for further development, showed an in vitro activity in the nanomolar range associated with a remarkable in vivo antitumor activity, highly competitive with the most potent HDAC inhibitors, currently under clinical trials. A preliminary study of PK and metabolism is also illustrated.

  DOI：

  10.1021/jm5008209

文献信息

• A novel bioresponsive self-immolative spacer based on aza-quinone methide reactivity for the controlled release of thiols, phenols, amines, sulfonamides or amides
  作者：Elena Ermini、Annalaura Brai、Elena Cini、Federica Finetti、Giuseppe Giannini、Daniele Padula、Lucrezia Paradisi、Federica Poggialini、Lorenza Trabalzini、Paola Tolu、Maurizio Taddei

  DOI：10.1039/d4sc01576b

  日期：2024.4.24

  stimulus. The spacer is based on the structure of (5-nitro-2-pyrrolyl)methanol (NPYM-OH), which was used for the direct alkylation of the functional groups mentioned above. The spacer is metabolically stable and has three indispensable sites for bioconjugation: the bioresponsive trigger, the conjugated 1,6 self-immolative system and a third arm suitable for conjugation with a carrier or other modifiers. Release

  刺激敏感连接体是癌症治疗前药不可或缺的成分之一，因为它与药物共价结合，并在肿瘤部位受到外部刺激时将其释放。醌甲基化物消除已被广泛用作基于离核性释放药物的关键转化。通常的方法是将药物以氨基甲酸酯的形式与接头结合，并在自毁 1,6-消除后以游离胺的形式释放。尽管这种方法非常有效，但它仅限于胺（作为氨基甲酸酯）、醇或酚（作为碳酸酯）或其他酸性官能团。我们在这里报告了一种自焚间隔基，能够在还原刺激后直接连接和释放胺、酚、硫醇、磺酰胺和羧酰胺。该间隔基基于(5-硝基-2-吡咯基)甲醇(NPYM-OH)的结构，其用于上述官能团的直接烷基化。间隔物是代谢稳定的，并且具有三个不可或缺的生物缀合位点：生物响应触发器、缀合的1,6自焚系统和适合与载体或其他修饰物缀合的第三臂。通过在胶束水环境 (H 2 O/TPGS-750-M) 中选择性还原 Fe/Pd 纳米颗粒 (NP) 上的硝基，或通过 NADH 介导的硝基还原酶激活来实现释放。
• HDAC INHIBITORS-BASED ANTIBODY DRUG CONJUGATES (ADCs) AND USE IN THERAPY
  申请人：ALFASIGMA S.P.A.

  公开号：US20210128740A1

  公开（公告）日：2021-05-06

  The present invention relates to novel Histone Deacetylase Inhibitors (HDACi)-based antibody drug conjugates particularly with antibodies directed to ErbB, ErbB2 and ErbB3 receptors, pharmaceutical compositions comprising said antibodies as well as to their use in the treatment of cancer or tumor and other diseases where a modulation of one or more histone deacetylase isoforms can be effective for therapeutic interventions.
• ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors
  作者：Giuseppe Giannini、Loredana Vesci、Gianfranco Battistuzzi、Davide Vignola、Ferdinando M. Milazzo、Mario Berardino Guglielmi、Marcella Barbarino、Mosè Santaniello、Nicola Fantò、Marco Mor、Silvia Rivara、Daniele Pala、Maurizio Taddei、Claudio Pisano、Walter Cabri

  DOI：10.1021/jm5008209

  日期：2014.10.23

  A systematic study of medicinal chemistry aimed at identifying a new generation of HDAC inhibitors, through the introduction of a thiol zinc-binding group (ZBG) and of an amide-lactam in the ?-position of the polyethylene chain of the vorinostat scaffold, allowed the selection of a new class of potent pan-HDAC inhibitors (pan-HDACis). Simple, highly versatile, and efficient synthetic approaches were used to synthesize a library of these new derivatives, which were then submitted to a screening for HDAC inhibition as well as to a preliminary in vitro assessment of their antiproliferative activity. Molecular docking into HDAC crystal structures suggested a binding mode for these thiol derivatives consistent with the stereoselectivity observed upon insertion of amide-lactam substituents in the ?-position. ST7612AA1 (117), selected as a drug candidate for further development, showed an in vitro activity in the nanomolar range associated with a remarkable in vivo antitumor activity, highly competitive with the most potent HDAC inhibitors, currently under clinical trials. A preliminary study of PK and metabolism is also illustrated.
• Antibody drug conjugates (ADCs) charged with HDAC inhibitor for targeted epigenetic modulation
  作者：Elena Cini、Valentina Faltoni、Elena Petricci、Maurizio Taddei、Laura Salvini、Giuseppe Giannini、Loredana Vesci、Ferdinando Maria Milazzo、Anna Maria Anastasi、Gianfranco Battistuzzi、Rita De Santis

  DOI：10.1039/c7sc05266a

  日期：——

  A new weapon is added to the ADC arsenal, a thiol based HDAC inhibitor. Low toxic, hits the target and stops tumor growth in many mouse models.

  ADC武器库中新增了一种硫醇基HDAC抑制剂。毒性低，能够命中目标并在许多小鼠模型中阻止肿瘤生长。