6-(4-(2-(benzothiazol-2-yl)hydrazono)-2,3-dihydro-1,1-dioxide-4H-1-benzothiopyran-4-yl)picolinic acid | 1135871-05-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 硫铬烷
• 英文名称: 6-(4-(2-(benzothiazol-2-yl)hydrazono)-2,3-dihydro-1,1-dioxide-4H-1-benzothiopyran-4-yl)picolinic acid
• 英文别名: 6-[4-(benzothiazol-2-yl-hydrazono)-2,3-dihydro-1,1-dioxido-benzothiopyran-6-yl]-pyridine-2-carboxylic acid；6-[4-(1,3-Benzothiazol-2-ylhydrazinylidene)-1,1-dioxo-2,3-dihydrothiochromen-6-yl]pyridine-2-carboxylic acid；6-[4-(1,3-benzothiazol-2-ylhydrazinylidene)-1,1-dioxo-2,3-dihydrothiochromen-6-yl]pyridine-2-carboxylic acid
• CAS: 1135871-05-4
• 化学式: C₂₂H₁₆N₄O₄S₂
• 分子量: 464.525
• InChiKey: YPKPNUQEDMJIGX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  158
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  tert-butyl 6-(4-oxothiochroman-6-yl)picolinate 在 甲酸 、 间氯过氧苯甲酸 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 19.0h， 生成 6-(4-(2-(benzothiazol-2-yl)hydrazono)-2,3-dihydro-1,1-dioxide-4H-1-benzothiopyran-4-yl)picolinic acid
  参考文献：
  名称：

  Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl-X_L

  摘要：

  Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-X-L inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 < 20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (M-w < 450) and unprecedented selectivity for Bcl-X-L. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-X-L. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-X-L, for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-X-L and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.

  DOI：

  10.1021/jm400556w

文献信息

• [EN] BENZOTHIAZOLE COMPOUNDS<br/>[FR] COMPOSÉS DE BENZOTHIAZOLE
  申请人：INST MEDICAL W & E HALL

  公开号：WO2009039553A1

  公开（公告）日：2009-04-02

  The present invention relates to benzothiazole compounds that mimic the activity of BH3 only proteins and are capable of binding to and neutralizing pro survival Bcl 2 proteins. The invention also relates to the use of such compounds in the regulation of cell death or cell survival and the treatment and/or prophylaxis of diseases or conditions associated with the deregulation of cell death or cell survival.

  本发明涉及模拟BH3-only蛋白活性并能够结合和中和促生存Bcl-2蛋白的苯并噻唑化合物。该发明还涉及利用这类化合物调节细胞死亡或细胞存活，在治疗和/或预防与细胞死亡或细胞存活失调相关的疾病或病况。
• Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl-X_L
  作者：Brad E. Sleebs、Wilhemus J. A. Kersten、Sanji Kulasegaram、George Nikolakopoulos、Effie Hatzis、Rebecca M. Moss、John P. Parisot、Hong Yang、Peter E. Czabotar、W. Douglas Fairlie、Erinna F. Lee、Jerry M. Adams、Lin Chen、Mark F. van Delft、Kym N. Lowes、Andrew Wei、David C.S. Huang、Peter M. Colman、Ian P. Street、Jonathan B. Baell、Keith Watson、Guillaume Lessene

  DOI：10.1021/jm400556w

  日期：2013.7.11

  Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-X-L inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 < 20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (M-w < 450) and unprecedented selectivity for Bcl-X-L. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-X-L. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-X-L, for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-X-L and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.