thioacetic acid S-{(S)-6-[((R)-5-oxo-pyrrolidine-2-carbonyl)-amino]-6-phenylcarbamoyl-hexyl} ester | 1428535-92-5

• 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: thioacetic acid S-{(S)-6-[((R)-5-oxo-pyrrolidine-2-carbonyl)-amino]-6-phenylcarbamoyl-hexyl} ester
• 英文别名: Thioacetic acid S-[(S)-6-[[(R)-5-oxopyrrolidine-2-ylcarbonyl]amino]-6-(phenylcarbamoyl)hexyl] ester；S-[(6S)-7-anilino-7-oxo-6-[[(2R)-5-oxopyrrolidine-2-carbonyl]amino]heptyl] ethanethioate
• CAS: 1428535-92-5
• 化学式: C₂₀H₂₇N₃O₄S
• 分子量: 405.518
• InChiKey: QGYPCQAYENIOOF-DLBZAZTESA-N

物化性质

• 沸点：
  748.4±60.0 °C(Predicted)
• 密度：
  1.244±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  28
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  thioacetic acid S-{(S)-6-[((R)-5-oxo-pyrrolidine-2-carbonyl)-amino]-6-phenylcarbamoyl-hexyl} ester 在 sodium thiomethoxide 作用下， 以 甲醇 为溶剂， 以90%的产率得到(R)-5-oxo-pyrrolidine-2-carboxylic acid ((S)-6-mercapto-1-phenylcarbamoyl-hexyl)-amide
  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)-2-((叔丁氧羰基)氨基)庚-6-烯酸 在 偶氮二异丁腈 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.33h， 生成 thioacetic acid S-{(S)-6-[((R)-5-oxo-pyrrolidine-2-carbonyl)-amino]-6-phenylcarbamoyl-hexyl} ester
  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

• [EN] HDAC INHIBITORS-BASED ANTIBODY DRUG CONJUGATES (ADCs) AND USE IN THERAPY<br/>[FR] CONJUGUÉS ANTICORPS-MÉDICAMENTS (CAM) À BASE D'INHIBITEURS D'HDAC ET LEUR UTILISATION DANS LA THÉRAPIE
  申请人：ALFASIGMA SPA

  公开号：WO2018178060A1

  公开（公告）日：2018-10-04

  The present invention relates to novel Histone Deacetylase Inhibitors (HDACi)- based antibody drug conjugates particularly with antibodies directed to ErbB1, 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.

  本发明涉及一种新型组蛋白去乙酰化酶抑制剂（HDACi）基于抗体药物偶联物，特别是与针对ErbB1、ErbB2和ErbB3受体的抗体结合的抗体药物偶联物，包括所述抗体的制药组合物，以及它们在癌症或肿瘤以及其他需要调节一个或多个组蛋白去乙酰化酶亚型以实现治疗干预的疾病的治疗中的用途。
• [EN] NEW THIO DERIVATIVES BEARING LACTAMS AS POTENT HDAC INHIBITORS AND THEIR USES AS MEDICAMENTS<br/>[FR] NOUVEAUX DÉRIVÉS THIO PORTANT DES LACTAMES EN TANT QU'INHIBITEURS PUISSANTS D'HDAC, ET LEURS UTILISATIONS EN TANT QUE MÉDICAMENTS
  申请人：SIGMA TAU IND FARMACEUTI

  公开号：WO2013041480A1

  公开（公告）日：2013-03-28

  The present invention relates to novel amide compounds of Formula (I), and their use as anti-tumoral and pro-apoptotic agents. The invention includes the use of such compounds in medicine, in relation to cancer disease as well as other diseases where an inhibition of HDAC is responsive, and the pharmaceutical composition containing such compounds.

  本发明涉及一种新型酰胺化合物（式I），以及其作为抗肿瘤和促凋亡剂的用途。该发明包括在医学上使用这些化合物，涉及癌症疾病以及其他需要抑制HDAC的疾病，以及含有这些化合物的药物组合物。
• NEW THIO DERIVATIVES BEARING LACTAMS AS POTENT HDAC INHIBITORS AND THEIR USES AS MEDICAMENTS
  申请人：SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A.

  公开号：EP2758371A1

  公开（公告）日：2014-07-30
• 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.
• METHODS AND COMPOUNDS FOR THE TREATMENT OF GENETIC DISEASE
  申请人：Design Therapeutics, Inc.

  公开号：US20210238226A1

  公开（公告）日：2021-08-05

  The present disclosure relates to compounds and methods for modulating the expression of dmpk, atxn1, atxn2, atxn3, cacna1a, atxn7, ppp2r2br tbp, htt, jph3r ar, or atn1 and treating diseases and conditions in which dmpk, atxn1, atxn2, atxn3, cacna1a, atxn1, ppp2r2b, tbp, htt, jph3, ar, or atn1 plays an active role. The compound can be a transcription modulator molecule having a first terminus, a second terminus, and oligomeric backbone, wherein: a) the first terminus comprises a DNA-binding moiety capable of noncovalently binding to a nucleotide repeat sequence CAG or CTG; b) the second terminus comprises a protein-binding moiety binding to a regulatory molecule that modulates an expression of a gene comprising the nucleotide repeat sequence CAG or CTG; and c) the oligomeric backbone comprising a linker between the first terminus and the second terminus.