(E)-N-hydroxy-3-(4-((methyl(2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide

• 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: (E)-N-hydroxy-3-(4-((methyl(2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide
• 英文别名: (E)-N-hydroxy-3-[4-[[methyl-[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2-enamide
• 化学式: C₂₂H₂₅N₃O₂
• 分子量: 363.459
• InChiKey: QLNNWCZDRFRKLS-VAWYXSNFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  68.4
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (E)-N-hydroxy-3-(4-((methyl(2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide 在 盐酸 、 potassium hydrogen bifluoride 、 N,N-二异丙基乙胺 、 氢氟酸 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成
  参考文献：
  名称：

  ¹⁸F-Radiolabeled Panobinostat Allows for Positron Emission Tomography Guided Delivery of a Histone Deacetylase Inhibitor

  摘要：

  Histone deacetylase (HDAC) inhibition is becoming an increasingly popular approach to treat cancer, as HDAC overexpression is common in many malignancies. The blood-brain barrier (BBB) prevents systemically delivered drugs from reaching brain at effective concentration, making small-molecule-HDAC inhibition in brain tumors particularly challenging. To circumvent the BBB, novel routes for administering therapeutics are being considered in the clinic, and a need exists for drugs whose deliveries can be directly imaged, so that effective delivery across the BBB can be monitored. We report chemistry for radiolabeling the HDAC inhibitor, panobinostat, with fluoride-18 (compound-1). Like panobinostat, compound 1 retains nanomolar efficacy in diffuse intrinsic pontine glioma (DIPG IV and XIII) cells (IC50 = 122 and 108 nM, respectively), with lesser activity against U87 glioma. With a favorable therapeutic ratio, 1 is highly selective to glioma and demonstrates considerably less toxicity toward healthy astrocyte controls (IC50 = 5265 nM). Compound 1 is stable in aqueous solution at physiological pH (>7 days, fetal bovine serum), and its delivery can be imaged by positron emission tomography (PET). Compound 1 is synthesized in two steps, and employs rapid, late-stage aqueous isotopic exchange F-18-radiochemistry. PET is used to image the in vivo delivery of [F-18]-1 to the murine central nervous system via convection enhanced delivery.

  DOI：

  10.1021/acsmedchemlett.7b00471
• 作为产物：
  描述：

  聚合甲醛 、 帕比司他 在 三乙酰氧基硼氢化钠 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 3.0h， 以45%的产率得到(E)-N-hydroxy-3-(4-((methyl(2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide
  参考文献：
  名称：

  ¹⁸F-Radiolabeled Panobinostat Allows for Positron Emission Tomography Guided Delivery of a Histone Deacetylase Inhibitor

  摘要：

  Histone deacetylase (HDAC) inhibition is becoming an increasingly popular approach to treat cancer, as HDAC overexpression is common in many malignancies. The blood-brain barrier (BBB) prevents systemically delivered drugs from reaching brain at effective concentration, making small-molecule-HDAC inhibition in brain tumors particularly challenging. To circumvent the BBB, novel routes for administering therapeutics are being considered in the clinic, and a need exists for drugs whose deliveries can be directly imaged, so that effective delivery across the BBB can be monitored. We report chemistry for radiolabeling the HDAC inhibitor, panobinostat, with fluoride-18 (compound-1). Like panobinostat, compound 1 retains nanomolar efficacy in diffuse intrinsic pontine glioma (DIPG IV and XIII) cells (IC50 = 122 and 108 nM, respectively), with lesser activity against U87 glioma. With a favorable therapeutic ratio, 1 is highly selective to glioma and demonstrates considerably less toxicity toward healthy astrocyte controls (IC50 = 5265 nM). Compound 1 is stable in aqueous solution at physiological pH (>7 days, fetal bovine serum), and its delivery can be imaged by positron emission tomography (PET). Compound 1 is synthesized in two steps, and employs rapid, late-stage aqueous isotopic exchange F-18-radiochemistry. PET is used to image the in vivo delivery of [F-18]-1 to the murine central nervous system via convection enhanced delivery.

  DOI：

  10.1021/acsmedchemlett.7b00471

文献信息

• [EN] MULTIFUNCTIONAL COMPOUND, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF IN PHARMACEUTICALS<br/>[FR] COMPOSÉ MULTIFONCTIONNEL, SON PROCÉDÉ DE PRÉPARATION ET SON APPLICATION DANS DES PRODUITS PHARMACEUTIQUES<br/>[ZH] 一种多功能化合物、其制备方法及其在医药上的应用
  申请人：SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD

  公开号：WO2019201123A1

  公开（公告）日：2019-10-24

  一类新的安全有效的通式为I或II的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药： (D) nL-G(L-D) m 式I 或(G) nL-D(L-G) m 式II 。
• [EN] MUTATIONS AND POLYMORPHISMS OF HDAC6<br/>[FR] MUTATIONS ET POLYMORPHISMES DE HDAC6
  申请人：NOVARTIS AG

  公开号：WO2007058992A2

  公开（公告）日：2007-05-24

  [EN] This invention relates generally to the analytical testing of tissue samples in vitro, and more particularly to aspects of genetic polymorphisms and mutations of the HDAC6 gene. The invention provides new HDAC6 mutations and SNPs5 useful in the diagnosis and treatment of subjects in need thereof. Accordingly, the various aspects of the present invention relate to polynucleotides encoding the HDAC6 mutations of the invention, expression vectors encoding the HDAC6 mutant polypeptides of the invention and organisms that express the HDAC6 mutant and polymorphic ' polynucleotides and/or HDAC6 mutant/polymorphic polypeptides of the invention. The various aspects of the present invention further relate to diagnostic/theranostic methods and kits that use the HDAC6 mutations and polymorphisms of the invention to identify individuals predisposed to disease or to classify individuals with regard to drug responsiveness, side effects, or optimal drug dose.
  [FR] L'invention concerne en général l'analyse d'échantillons tissulaires in vitro et, en particulier, des aspects de polymorphismes et de mutations génétiques du gène HDAC6. L'invention concerne également de nouvelles mutations de HDAC6 et des polymorphismes nucléotidiques simples (SNP) utilisés pour effectuer un diagnostic ou traiter des sujets qui en ont besoin. En conséquence, les différents aspects de l'invention concernent des polynucléotides codant pour les mutations de HDAC6, des vecteurs d'expression codant pour les polypeptides mutants de HDAC6, des organismes qui expriment le mutant de HDAC6, des polynucléotides polymorphiques et/ou des polypeptides mutants/polymorphiques de HDAC6. Les différents aspects de l'invention concernent également des méthodes diagnostiques/théranostiques et des trousses qui utilisent les mutations et les polymorphismes de HDAC6 pour identifier les individus prédisposés à une maladie ou pour classer des individus en fonction de leur sensibilité à un médicament, d'effets secondaires ou d'une dose de médicament optimale.
• [EN] COMBINATIONS INCLUDING A CPG-C TYPE OLIGONUCLEOTIDE AND A HISTONE DEACETYLASE INHIBITOR FOR TREATING CANCER<br/>[FR] COMBINAISONS COMPRENANT UN OLIGONUCLÉOTIDE DE TYPE CPG-C ET UN INHIBITEUR D'HISTONE DÉSACÉTYLASE POUR LE TRAITEMENT DU CANCER
  申请人：DYNAVAX TECH CORP

  公开号：WO2019200238A1

  公开（公告）日：2019-10-17

  The present disclosure describes combination therapies comprising a histone deacetylase inhibitor and a toll-like receptor 9 agonist. In particular, the present disclosure describes combinations of an inhibitor of a zinc-dependent histone deacetylase and a CpG-C type oligonucleotide for the treatment of cancer.
• ¹⁸F-Radiolabeled Panobinostat Allows for Positron Emission Tomography Guided Delivery of a Histone Deacetylase Inhibitor
  作者：Harikrishna Kommidi、Umberto Tosi、Uday B. Maachani、Hua Guo、Christopher S. Marnell、Benedict Law、Mark M. Souweidane、Richard Ting

  DOI：10.1021/acsmedchemlett.7b00471

  日期：2018.2.8

  Histone deacetylase (HDAC) inhibition is becoming an increasingly popular approach to treat cancer, as HDAC overexpression is common in many malignancies. The blood-brain barrier (BBB) prevents systemically delivered drugs from reaching brain at effective concentration, making small-molecule-HDAC inhibition in brain tumors particularly challenging. To circumvent the BBB, novel routes for administering therapeutics are being considered in the clinic, and a need exists for drugs whose deliveries can be directly imaged, so that effective delivery across the BBB can be monitored. We report chemistry for radiolabeling the HDAC inhibitor, panobinostat, with fluoride-18 (compound-1). Like panobinostat, compound 1 retains nanomolar efficacy in diffuse intrinsic pontine glioma (DIPG IV and XIII) cells (IC50 = 122 and 108 nM, respectively), with lesser activity against U87 glioma. With a favorable therapeutic ratio, 1 is highly selective to glioma and demonstrates considerably less toxicity toward healthy astrocyte controls (IC50 = 5265 nM). Compound 1 is stable in aqueous solution at physiological pH (>7 days, fetal bovine serum), and its delivery can be imaged by positron emission tomography (PET). Compound 1 is synthesized in two steps, and employs rapid, late-stage aqueous isotopic exchange F-18-radiochemistry. PET is used to image the in vivo delivery of [F-18]-1 to the murine central nervous system via convection enhanced delivery.