(S)-ispinesib | 336113-54-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (S)-ispinesib
• 英文别名: SB-715992 (Ispinesib)；N-(3-aminopropyl)-N-[(1S)-1-(3-benzyl-7-chloro-4-oxoquinazolin-2-yl)-2-methylpropyl]-4-methylbenzamide
• CAS: 336113-54-3
• 化学式: C₃₀H₃₃ClN₄O₂
• 分子量: 517.071
• InChiKey: QJZRFPJCWMNVAV-MHZLTWQESA-N

物化性质

• 沸点：
  708.0±70.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  37
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  79
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-ispinesib 、 苯甲醛 在 三乙酰氧基硼氢化钠 作用下， 以 1,2-二氯乙烷 为溶剂， 以59%的产率得到(S)-N-(1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl)-N-(3-(benzylamino)propyl)-4-methylbenzamide
  参考文献：
  名称：

  二茂铁-Ispinesib 杂化物的设计、合成和生物活性评估：二茂铁基团对抗增殖和驱动蛋白纺锤体蛋白抑制活性的影响

  摘要：

  设计的二茂铁基-和金刚烷基-ispinesib 杂合体显示出比 ispinesib 显着更高的抗癌活性。ispinesb 核心的存在负责 KSP 抑制活性，而庞大的二茂铁基和金刚烷基取代基负责增加 ROS 生成的能力，并显着增加新化合物的G 2 /M 期细胞停滞。

  DOI：

  10.1002/chem.202300813
• 作为产物：
  描述：

  3-苄基-2-(1-溴-2-甲基丙基)-7-氯喹唑啉-4-酮 在 sodium azide 、 三乙酰氧基硼氢化钠 、 氯化铵 、 N,N-二异丙基乙胺 、 O,O'-dibenzoyl-L-tartaric acid 、 三氟乙酸 、 锌 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 55.5h， 生成 (S)-ispinesib
  参考文献：
  名称：

  Fluorinated quinazolinones as potential radiotracers for imaging kinesin spindle protein expression

  摘要：

  Anti-mitotic anti-cancer drugs offer a potential platform for developing new radiotracers for imaging proliferation markers associated with the mitosis-phase of the cell-cycle. One interesting target is kinesin spindle protein (KSP)-an ATP-dependent motor protein that plays a vital role in bipolar spindle formation. In this work we synthesised a range of new fluorinated-quinazolinone compounds based on the structure of the clinical candidate KSP inhibitor, ispinesib, and investigated their properties in vitro as potential anti-mitotic agents targeting KSP expression. Anti-proliferation (MTT and BrdU) assays combined with additional studies including fluorescence-assisted cell sorting (FACS) analysis of cell-cycle arrest confirmed the mechanism and potency of these biphenyl compounds in a range of human cancer cell lines. Additional studies using confocal fluorescence microscopy showed that these compounds induce M-phase arrest via monoaster spindle formation. Structural studies revealed that compound 20-(R) is the most potent fluorinated-quinazolinone inhibitor of KSP and represents a suitable lead candidate for further studies on designing F-18-radiolabelled agents for positron-emission tomography (PET). (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.013

文献信息

• Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib – impact of the organometallic group on the antimitotic activity
  作者：Michał Łomzik、Andrzej Błauż、Marta Głodek、Anna Makal、Daniel Tchoń、Daniel Moscoh Ayine-Tora、Christian Hartinger、Błażej Rychlik、Damian Plażuk

  DOI：10.1039/d3dt01217d

  日期：——

  proposed as a promising target for new antimitotic drugs. Herein, we report the synthesis of Ru, Os, Rh, and Ir half-sandwich complexes with the KSP inhibitor ispinesib and its (S)-enantiomer. Conjugation of the organometallic moiety with ispinesib and its (S)-enantiomer resulted in a significantly increased cytotoxicity of up to 5.6-fold compared to the parent compounds, with IC50 values in the nanomolar

  抗有丝分裂剂是抗癌治疗中使用的最重要的药物之一。驱动蛋白纺锤体蛋白（KSP）被提议作为新型抗有丝分裂药物的有希望的靶标。在此，我们报道了与 KSP 抑制剂 ispinesib 及其 ( S ) -对映体合成 Ru、Os、Rh 和 Ir 半夹心配合物。有机金属部分与 ispinesib 及其 ( S )-对映体的缀合导致细胞毒性显着增加，与母体化合物相比高达 5.6 倍，IC 50值在纳摩尔范围内。最活跃的衍生物是 ispinesib Ru 和 Rh 缀合物，它们能够产生活性氧 (ROS)，这至少可以部分解释它们的高细胞毒性。同时，Os 和 Ir 衍生物充当 KSP 抑制剂，对 ROS 的生成没有影响。
• [EN] HYDROXY-POLMER-DRUG-PROTEIN CONJUGATES<br/>[FR] CONJUGUÉS HYDROXY-POLYMÈRE-MÉDICAMENT-PROTÉINE
  申请人：MERSANA THERAPEUTICS INC

  公开号：WO2014093640A1

  公开（公告）日：2014-06-19

  A drug conjugate is provided herein. The conjugate comprises a protein based recognition-molecule (PBRM) and a polymeric scaffold having one or more -LD-D, the PBRM being connected to the polymeric scaffold by Lp, wherein the polymeric scaffold comprises a linear, branched or cyclic polymer having four or more -OH groups. Each occurrence of D is independently a therapeutic agent having a molecular weight < 5 kDa. LD and Lp are linkers connecting the therapeutic agent and PBRM to the polymeric scaffold respectively. Also disclosed are polymeric scaffolds useful for conjugating with a PBRM to form a polymer-drug-PBRM conjugate described herein, compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions.
• [EN] PROTEIN-POLYMER-DRUG CONJUGATES<br/>[FR] CONJUGUÉS PROTÉINE-POLYMÈRE-MÉDICAMENT
  申请人：MERSANA THERAPEUTICS INC

  公开号：WO2014093394A1

  公开（公告）日：2014-06-19

  A drug conjugate is provided herein. The conjugate comprises a protein based recognition-molecule (PBRM) and a polymeric carrier substituted with one or more -LD-D, the protein based recognition-molecule being connected to the polymeric carrier by Lp. Each occurrence of D is independently a therapeutic agent having a molecular weight < 5 kDa. LD and Lp are linkers connecting the therapeutic agent and PBRM to the polymeric carrier respectively. Also disclosed are polymeric scaffolds useful for conjugating with a PBRM to form a polymer- drug-PBRM conjugate described herein, compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions.
• Fluorinated quinazolinones as potential radiotracers for imaging kinesin spindle protein expression
  作者：Jason P. Holland、Michael W. Jones、Susan Cohrs、Roger Schibli、Eliane Fischer

  DOI：10.1016/j.bmc.2012.11.013

  日期：2013.1

  Anti-mitotic anti-cancer drugs offer a potential platform for developing new radiotracers for imaging proliferation markers associated with the mitosis-phase of the cell-cycle. One interesting target is kinesin spindle protein (KSP)-an ATP-dependent motor protein that plays a vital role in bipolar spindle formation. In this work we synthesised a range of new fluorinated-quinazolinone compounds based on the structure of the clinical candidate KSP inhibitor, ispinesib, and investigated their properties in vitro as potential anti-mitotic agents targeting KSP expression. Anti-proliferation (MTT and BrdU) assays combined with additional studies including fluorescence-assisted cell sorting (FACS) analysis of cell-cycle arrest confirmed the mechanism and potency of these biphenyl compounds in a range of human cancer cell lines. Additional studies using confocal fluorescence microscopy showed that these compounds induce M-phase arrest via monoaster spindle formation. Structural studies revealed that compound 20-(R) is the most potent fluorinated-quinazolinone inhibitor of KSP and represents a suitable lead candidate for further studies on designing F-18-radiolabelled agents for positron-emission tomography (PET). (C) 2012 Elsevier Ltd. All rights reserved.
• Design, Synthesis, and Evaluation of Biological Activity of Ferrocene‐Ispinesib Hybrids: Impact of a Ferrocenyl Group on the Antiproliferative and Kinesin Spindle Protein Inhibitory Activity
  作者：Karolina Kowalczyk、Andrzej Błauż、Daniel Moscoh Ayine‐Tora、Christian G. Hartinger、Błażej Rychlik、Damian Plażuk

  DOI：10.1002/chem.202300813

  日期：2023.9

  KSP inhibitory activity, whereas bulky ferrocenyl and adamantyl substituents are responsible for increased ability to ROS generation and significantly increased G2/M phase cell arrest of the new compounds.

  设计的二茂铁基-和金刚烷基-ispinesib 杂合体显示出比 ispinesib 显着更高的抗癌活性。ispinesb 核心的存在负责 KSP 抑制活性，而庞大的二茂铁基和金刚烷基取代基负责增加 ROS 生成的能力，并显着增加新化合物的G 2 /M 期细胞停滞。