(7-methoxy-1-phenylsulfonyl-1H-2-indolyl)(1-phenylsulfonyl-1H-2-indolyl)methanone | 249762-48-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (7-methoxy-1-phenylsulfonyl-1H-2-indolyl)(1-phenylsulfonyl-1H-2-indolyl)methanone
• 英文别名: 7-Methoxy-1-phenylsulphonyl-1H-2-indolyl(1-phenylsulphonyl-1H-2-indolyl)methanone；[1-(Benzenesulfonyl)indol-2-yl]-[1-(benzenesulfonyl)-7-methoxyindol-2-yl]methanone
• CAS: 249762-48-9
• 化学式: C₃₀H₂₂N₂O₆S₂
• 分子量: 570.646
• InChiKey: WJMRAOOEWCYNPT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  40
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.03
• 拓扑面积：
  121
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (7-methoxy-1-phenylsulfonyl-1H-2-indolyl)(1-phenylsulfonyl-1H-2-indolyl)methanone 在 四丁基氟化铵 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 以91%的产率得到7-Methoxy-1H-2-indolyl(1H-2-indolyl)methanone
  参考文献：
  名称：

  Bis(1H-2-indolyl)methanones as a Novel Class of Inhibitors of the Platelet-Derived Growth Factor Receptor Kinase

  摘要：

  The novel lead bis(1H-2-indolyl)methanone inhibits autophosphorylation of platelet-derived growth factor (PDGF) receptor tyrosine kinase in intact cells. Various substituents in the 5- or 6-position of one indole ring increase or preserve potency, whereas most modifications of the ring structures and of the methanone group as well as substitution at both indoles result in weak or no activity. An ATP binding site model, derived by homology from the FGFR-1 tyrosine kinase crystal structure suggesting hydrogen bonds of one indole NH and the methanone oxygen with the backbone carbonyl and amide, respectively, of Cys684, explains why only one indole moiety is open for substitution and locates groups in the 5- or 6-position outside the pocket. The hitherto most active derivatives, 39, 53 and 67, inhibit both isoforms of the PDGF receptor kinase in intact cells, with IC50 of 0.1-0.3 muM, and purified PDGFbeta-receptor in vitro, with IC50 of 0.09, 0.1, or 0.02 muM, respectively. PDGF-stimulated DNA synthesis is inhibited by these derivatives with IC50 values of 1-3 muM. Kinetic analysis of 53 showed an ATP-competitive mode of inhibition. The compounds are inactive or weakly active toward a number of other tyrosine kinases, including the FGF receptor 1, EGF receptor, and c-Src kinase, as well as toward serine-threonine kinases, including different PKC isoforms and GRK2, and appear therefore selective for PDGF receptor inhibition.

  DOI：

  10.1021/jm010988n
• 作为产物：
  描述：

  1-(苯磺酰)-1H-吲哚-2-甲醛 在 重铬酸吡啶 、 正丁基锂 、 三氟乙酸吡啶 、 二异丙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 0.5h， 生成 (7-methoxy-1-phenylsulfonyl-1H-2-indolyl)(1-phenylsulfonyl-1H-2-indolyl)methanone
  参考文献：
  名称：

  Bis(1H-2-indolyl)methanones as a Novel Class of Inhibitors of the Platelet-Derived Growth Factor Receptor Kinase

  摘要：

  The novel lead bis(1H-2-indolyl)methanone inhibits autophosphorylation of platelet-derived growth factor (PDGF) receptor tyrosine kinase in intact cells. Various substituents in the 5- or 6-position of one indole ring increase or preserve potency, whereas most modifications of the ring structures and of the methanone group as well as substitution at both indoles result in weak or no activity. An ATP binding site model, derived by homology from the FGFR-1 tyrosine kinase crystal structure suggesting hydrogen bonds of one indole NH and the methanone oxygen with the backbone carbonyl and amide, respectively, of Cys684, explains why only one indole moiety is open for substitution and locates groups in the 5- or 6-position outside the pocket. The hitherto most active derivatives, 39, 53 and 67, inhibit both isoforms of the PDGF receptor kinase in intact cells, with IC50 of 0.1-0.3 muM, and purified PDGFbeta-receptor in vitro, with IC50 of 0.09, 0.1, or 0.02 muM, respectively. PDGF-stimulated DNA synthesis is inhibited by these derivatives with IC50 values of 1-3 muM. Kinetic analysis of 53 showed an ATP-competitive mode of inhibition. The compounds are inactive or weakly active toward a number of other tyrosine kinases, including the FGF receptor 1, EGF receptor, and c-Src kinase, as well as toward serine-threonine kinases, including different PKC isoforms and GRK2, and appear therefore selective for PDGF receptor inhibition.

  DOI：

  10.1021/jm010988n

文献信息

• Indole derivatives and their use for the treatment of malignant and other diseases based on pathological proliferation
  申请人：——

  公开号：US20030008898A1

  公开（公告）日：2003-01-09

  The invention relates to tyrosine kinase inhibitors of the bis-indolyl compound type of the general formula I: 1 pharmaceuticals containing them and their use for the treatment of malignant and other diseases based on pathological cell proliferation.

  本发明涉及一种通式I的双吲哚基酪氨酸激酶抑制剂，以及含有它们的药物，以及它们用于治疗基于病理细胞增殖的恶性和其他疾病的用途。
• INDOLDERIVATE UND DEREN VERWENDUNG ZUR BEHANDLUNG VON MALIGNEN UND ANDEREN, AUF PATHOLOGISCHEN ZELLPROLIFERATIONEN BERUHENDEN ERKRANKUNGEN
  申请人：Zentaris AG

  公开号：EP1109785B1

  公开（公告）日：2003-01-02
• US6407102B1
  申请人：——

  公开号：US6407102B1

  公开（公告）日：2002-06-18
• US6812243B2
  申请人：——

  公开号：US6812243B2

  公开（公告）日：2004-11-02
• [DE] INDOLDERIVATE UND DEREN VERWENDUNG ZUR BEHANDLUNG VON MALIGNEN UND ANDEREN, AUF PATHOLOGISCHEN ZELLPROLIFERATIONEN BERUHENDEN ERKRANKUNGEN<br/>[EN] INDOLE DERIVATIVES AND THEIR USE IN THE TREATMENT OF MALIGNANT AND OTHER DISEASES CAUSED BY PATHOLOGICAL CELL PROLIFERATION<br/>[FR] DERIVES INDOLIQUES ET LEUR UTILISATION POUR LE TRAITEMENT DE MALADIES MALIGNES ET AUTRES INDUITES PAR DES PROLIFERATIONS CELLULAIRES PATHOLOGIQUES
  申请人：——

  公开号：WO1999057117A2

  公开（公告）日：1999-11-11

  [EN] The invention relates to tyrosine kinase inhibitors of bis-indolyl compounds of formula (I), to the medicaments containing said inhibitors and to their use in treating malignant and other diseases caused by pathological cell proliferation.
  [FR] L'invention concerne des inhibiteurs de tyrosine kinase du type des composés bis-indolyle correspondant à la formule générale (I), des médicaments contenant ces inhibiteurs et leur utilisation pour le traitement de maladies malignes et autres induites par des proliférations cellulaires pathologiques.
  [DE] Die Erfindung betrifft Tyrosinkinase-Inhibitoren vom Typ der Bis-indolyl-Verbindungen der allgemeinen Formel (I), diese enthaltende Arzneimittel und deren Verwendung zur Behandlung von malignen und anderen, auf pathologischen Zellproliferationen beruhenden Erkrankungen.