bortezomib | 179324-79-9

• 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: bortezomib
• 英文别名: ((R)-1-((S)-2-Benzamido-3-phenylpropanamido)-3-methylbutyl)boronic acid；[(1R)-1-[[(2S)-2-benzamido-3-phenylpropanoyl]amino]-3-methylbutyl]boronic acid
• CAS: 179324-79-9
• 化学式: C₂₁H₂₇BN₂O₄
• 分子量: 382.267
• InChiKey: VYJGIZAZFZWYOU-OALUTQOASA-N

物化性质

• 密度：
  1.158±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.57
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  98.7
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (1S,3R,5S)-pinanediol-N-(phenyl)carbonyl-β-(1-phenyl)-L-alanine-L-leucineboronate 在 盐酸 、 异丁基硼酸 、 水 作用下， 以 甲醇 、 正庚烷 为溶剂， 以40.5%的产率得到bortezomib
  参考文献：
  名称：

  [EN] NOVEL BORONIC ACID DERIVATIVES AS ANTI CANCER AGENTS
  [FR] NOUVEAUX DÉRIVÉS D'ACIDE BORONIQUE AN TANT QU'AGENTS ANTICANCÉREUX

  摘要：

  这项发明涉及公式5的新硼酸衍生物的合成和抗癌活性，或其药用可接受的盐和酯。化合物的抗癌活性通过体外研究评估，涉及前列腺癌、肺癌、头颈癌或乳腺癌等癌细胞系。

  公开号：

  WO2014072985A1
• 作为试剂：
  描述：

  4-methyl-3-[(1-oxohexadecyl)oxy]-2(3H)-thiazolethione 在 bortezomib 作用下， 以 甲苯 为溶剂， 反应 1.0h， 以30%的产率得到2-(5-methylthiazol-2-ylthio)-3-pentadecylcyclopentanone
  参考文献：
  名称：

  与衍生自硫代异羟肟酸酯的基团形成碳-碳键

  摘要：

  由硫代异羟肟酸的酯形成的自由基容易加到缺电子的烯烃上，以可变的产率得到具有潜在合成价值的加合物。在某些情况下，通过重整烯烃很容易消除添加的硫官能团。

  DOI：

  10.1016/s0040-4039(01)80099-x

文献信息

• Bortezomib Congeners Induce Apoptosis of Hepatocellular Carcinoma via CIP2A Inhibition
  作者：Duen-Ren Hou、Ann-Chi Huang、Chung-Wai Shiau、Chun-Yi Wang、Hui-Chuan Yu、Kuen-Feng Chen

  DOI：10.3390/molecules181215398

  日期：——

  CIP2A is an oncoprotein that upregulates p-Akt and promotes cancer cell proliferation and survival. The proteasome inhibitor bortezomib has been shown to reduce CIP2A and lead to cell apoptosis. Here; we modified the functional group of bortezomib to generate a series of novel compounds and conducted a structure–activity relationship (SAR) study. The results showed that compound 1 was able to repress CIP2A expression and cell apoptosis in the same manner as bortezomib, but with less potency in inhibition of proteasome activity. This finding provides a new direction for the design of CIP2A inhibitors.

  CIP2A 是一种上调 p-Akt 并促进癌细胞增殖和存活的肿瘤蛋白。蛋白酶体抑制剂硼替佐米已被证明能减少 CIP2A 并导致细胞凋亡。在此，我们对硼替佐米的官能团进行了修饰，生成了一系列新型化合物，并进行了结构-活性关系（SAR）研究。结果表明，化合物 1 能够以与硼替佐米相同的方式抑制 CIP2A 的表达和细胞凋亡，但对蛋白酶体活性的抑制作用较弱。这一发现为 CIP2A 抑制剂的设计提供了新的方向。
• Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein
  作者：Marine Peuchmaur、Marie-Agnès Lacour、Jean Sévalle、Vincent Lisowski、Youness Touati-Jallabe、Fabien Rodier、Jean Martinez、Frédéric Checler、Jean-François Hernandez

  DOI：10.1016/j.bmc.2012.11.045

  日期：2013.2

  The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid beta-peptide (A beta) by Amyloid-beta Precursor Protein (APP) expressing HEK293 cells by affecting the gamma-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent gamma-secretase complex but more likely interfere with an upstream target involved in gamma-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for A beta-lowering activity and supported the involvement of a seri ne protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC50 between 10 and 30 mu M. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular A beta production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives. (C) 2012 Elsevier Ltd. All rights reserved.
• [EN] NOVEL BORONIC ACID DERIVATIVES AS ANTI CANCER AGENTS<br/>[FR] NOUVEAUX DÉRIVÉS D'ACIDE BORONIQUE AN TANT QU'AGENTS ANTICANCÉREUX
  申请人：NATCO PHARMA LTD

  公开号：WO2014072985A1

  公开（公告）日：2014-05-15

  The invention relates to synthesis and anticancer activity of novel boronic acid derivatives of formula 5 or pharmaceutical acceptable salts and esters thereof. Anti cancer activity of the compounds is evaluated by in vitro study on cancer cell lines like prostate cancer, lung cancer, head and neck cancer or breast cancer.

  这项发明涉及公式5的新硼酸衍生物的合成和抗癌活性，或其药用可接受的盐和酯。化合物的抗癌活性通过体外研究评估，涉及前列腺癌、肺癌、头颈癌或乳腺癌等癌细胞系。