2,6-bis((3-hydroxybenzene)carbamoyl)pyridine

• 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: 2,6-bis((3-hydroxybenzene)carbamoyl)pyridine
• 英文别名: N²,N⁶-bis(3-hydroxyphenyl)pyridine-2,6-dicarboxamide；2-N,6-N-bis(3-hydroxyphenyl)pyridine-2,6-dicarboxamide
• 化学式: C₁₉H₁₅N₃O₄
• 分子量: 349.346
• InChiKey: KLIHBKHJJDDJJO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  112
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,6-bis((3-methoxybenzene)carbamoyl)pyridine 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 8.0h， 以55%的产率得到2,6-bis((3-hydroxybenzene)carbamoyl)pyridine
  参考文献：
  名称：

  Syntheses, characterization, and anti-cancer activities of pyridine-amide based compounds containing appended phenol or catechol groups

  摘要：

  合成了几种带有酚/儿茶酚基团的吡啶酰胺化合物。这些化合物包括已保护或未保护的酚/儿茶酚基团，并提供了吡啶、酰胺和酚/儿茶酚官能团。所有化合物均已通过多种光谱方法、元素分析、热学研究和结晶学进行了充分的表征。所有化合物的生物活性均已得到研究，其中少数化合物在剂量依赖性方式下显著降低了T98G细胞的代谢活力、生长和克隆能力。在T98G细胞中观察到了ROS的积累，这些细胞显示出了受损的氧化还原状态，这一点从增加的细胞Caspase 3/7活性和微核的形成中可以明显看出。计算机模型药代动力学研究显示，所有化合物均具有良好的生物利用度、水溶性和其他类药物参数。由于以下原因，少数化合物被确定为未来研究的潜在先导分子：（a）对T98G脑、H-460肺和SNU-80甲状腺癌细胞具有高活性；（b）对非恶性HEK和MRC-5细胞具有低细胞毒性；（c）基于计算机模型的评估显示低毒性风险；（d）根据Lipinski的“五规则”药代动力学参数显示良好的理论口服生物利用度；以及（e）更好的药物相似性和药物评分值。

  DOI：

  10.1007/s12039-014-0671-3

文献信息

• [EN] 2,6-BIS(((1H-BENZO[D]IMIDAZOL-2-YL)THIO)METHYL)PYRIDINE AND N2,N6-DIBENZYLPYRIDINE-2,6-DICARBOXAMIDE DERIVATIVES AND RELATED COMPOUNDS AS PHOSPHOINOSITIDE 3-KINASE (PI3K) INHIBITORS FOR TREATING CANCER<br/>[FR] DÉRIVÉS DE 2,6-BIS(((1H-BENZO[D]IMIDAZOL-2-YL)THIO)MÉTHYL)PYRIDINE ET DE N2,N6-DIBENZYLPYRIDINE-2,6-DICARBOXAMIDE ET COMPOSÉS ASSOCIÉS EN TANT QU'INHIBITEURS DE PHOSPHOINOSITIDE 3-KINASE (PI3K) DANS LE TRAITEMENT DU CANCER
  申请人：BIOMEDICAL RES FOUNDATION OF THE ACADEMY OF ATHENS BRFAA

  公开号：WO2020039097A1

  公开（公告）日：2020-02-27

  2,6-bis(((lH-benzo[d]imidazol-2-yl)thio)methyl)pyridine and N2, N6-dibenzylpyridine-2, 6-dicarboxamide derivatives and related compounds as phosphoinositide 3-kinase (PI3K) inhibitors for treating cancer. The present invention relates to pharmaceutically active 2,6- bis(((lH-benzo[d]imidazol-2-yl)thio)methyl)pyridine, N2,N6- dibenzylpyridine-2, 6-dicarboxamide and N2,N6-bis(3-hydroxyphenyl) pyridine-2, 6-dicarboxamide, as well as to derivatives thereof, and to structurally related compounds. These compounds are phosphoinositide 3-kinase inhibitors (PI3K) and useful in treating or preventing cancerous diseases. The invention further relates methods of manufacturing such compounds as well as to pharmaceutical compositions and formulations comprising such compounds, optionally together with other pharmaceutically active compounds. The invention further relates to a method for determining the activity of PI3Kalpha or PI3Kalpha mutants, which method includes: a) providing a solid phase which is functionalized by immobilization of GST-GRPl-molecules onto the solid phase, b) performing a PI3Kalpha or PI3Kalpha mutant catalyzed enzyme reaction to convert PIP2 to PIP3, c) adding competitor PIP3 carrying a detectable label or reporter molecule, and d) determining enzyme activity based on the amount of PIP3 obtained in step b) which competes with competitor PIP3 for binding to the functionalized solid phase.

  2,6-双(((1H-苯并[d]咪唑-2-基)硫)甲基)吡啶和N2，N6-二苄基吡啶-2,6-二甲酰胺衍生物及相关化合物作为治疗癌症的磷脂酰肌醇3-激酶（PI3K）抑制剂。本发明涉及具有药用活性的2,6-双(((1H-苯并[d]咪唑-2-基)硫)甲基)吡啶，N2，N6-二苄基吡啶-2,6-二甲酰胺和N2，N6-双(3-羟基苯基)吡啶-2,6-二甲酰胺，以及其衍生物和结构相关化合物。这些化合物是磷脂酰肌醇3-激酶抑制剂（PI3K），可用于治疗或预防癌症性疾病。本发明还涉及制造这类化合物的方法，以及包含这类化合物的药物组合物和配方，可选地与其他药用活性化合物一起使用。本发明还涉及一种确定PI3Kalpha或PI3Kalpha突变体活性的方法，该方法包括：a)提供通过将GST-GRPl分子固定在固相上而功能化的固相，b)执行PI3Kalpha或PI3Kalpha突变体催化的酶反应将PIP2转化为PIP3，c)添加携带可检测标签或报告分子的竞争物PIP3，d)根据步骤b)中获得的与竞争物PIP3竞争与功能化固相结合的PIP3的数量确定酶活性。
• METHOD OF PREPARATION AND USE OF PHOSPHOINOSITIDE 3-KINASE INHIBITORS IN TREATING CANCER
  申请人：COURNIA Zoe

  公开号：US20210246120A1

  公开（公告）日：2021-08-12

  2,6-bis(((1H-benzo[d]imidazol-2-yl)thio)methyl)pyridine and N2, N6-dibenzylpyridine-2, 6-dicarboxamide derivatives and related compounds as phosphoinositide 3-kinase (PI3K) inhibitors for treating cancer. The present invention relates to pharmaceutically active 2,6-bis((1H-benzo[d]imidazol-2-yl)thio)methyl)pyridine, N2,N6-dibenzylpyridine-2, 6-dicarboxamide and N2,N6-bis(3-hydroxyphenyl) pyridine-2, 6-dicarboxamide, as well as to derivatives thereof, and to structurally related compounds. These compounds are phosphoinositide 3-kinase inhibitors (PI3K) and useful in treating or preventing cancerous diseases. The invention further relates methods of manufacturing such compounds as well as to pharmaceutical compositions and formulations comprising such compounds, optionally together with other pharmaceutically active compounds. The invention further relates to a method for determining the activity of PI3Kalpha or PI3Kalpha mutants, which method includes: a) providing a solid phase which is functionalized by immobilization of GST-GRP1-molecules onto the solid phase, b) performing a PI3Kalpha or PI3Kalpha mutant catalyzed enzyme reaction to convert PIP2 to PIP3, c) adding competitor PIP3 carrying a detectable label or reporter molecule, and d) determining enzyme activity based on the amount of PIP3 obtained in step b) which competes with competitor PIP3 for binding to the functionalized solid phase.
• Syntheses, characterization, and anti-cancer activities of pyridine-amide based compounds containing appended phenol or catechol groups
  作者：AFSAR ALI、DEEPAK BANSAL、NAGENDRA K KAUSHIK、NEHA KAUSHIK、EUN HA CHOI、RAJEEV GUPTA

  DOI：10.1007/s12039-014-0671-3

  日期：2014.7

  Several pyridine-amide compounds appended with phenol/catechol groups are synthesized. These compounds consist of protected or deprotected phenol/catechol groups and offer pyridine, amide, and phenol/catechol functional groups. All compounds have been well-characterized by various spectroscopic methods, elemental analysis, thermal studies, and crystallography. The biological activities of all compounds were investigated while a few compounds significantly decreased the metabolic viability, growth and clonogenicity of T98G cells in dose dependent manner. Accumulation of ROS was observed in T98G cells, which displayed a compromised redox status as evident from increased cellular Caspase 3/7 activity and formation of micronuclei. The in silico pharmacokinetic studies suggest that all compounds have good bioavailability, water solubility and other drug-like parameters. A few compounds were identified as the lead molecules for future investigation due to their: (a) high activity against T98G brain, H-460 lung, and SNU-80 thyroid cancer cells; (b) low cytotoxicity in non-malignant HEK and MRC-5 cells; (c) low toxic risks based on in silico evaluation; (d) good theoretical oral bioavailability according to Lipinski ‘rule of five′ pharmacokinetic parameters; and (e) better drug-likeness and drug-score values.

  合成了几种带有酚/儿茶酚基团的吡啶酰胺化合物。这些化合物包括已保护或未保护的酚/儿茶酚基团，并提供了吡啶、酰胺和酚/儿茶酚官能团。所有化合物均已通过多种光谱方法、元素分析、热学研究和结晶学进行了充分的表征。所有化合物的生物活性均已得到研究，其中少数化合物在剂量依赖性方式下显著降低了T98G细胞的代谢活力、生长和克隆能力。在T98G细胞中观察到了ROS的积累，这些细胞显示出了受损的氧化还原状态，这一点从增加的细胞Caspase 3/7活性和微核的形成中可以明显看出。计算机模型药代动力学研究显示，所有化合物均具有良好的生物利用度、水溶性和其他类药物参数。由于以下原因，少数化合物被确定为未来研究的潜在先导分子：（a）对T98G脑、H-460肺和SNU-80甲状腺癌细胞具有高活性；（b）对非恶性HEK和MRC-5细胞具有低细胞毒性；（c）基于计算机模型的评估显示低毒性风险；（d）根据Lipinski的“五规则”药代动力学参数显示良好的理论口服生物利用度；以及（e）更好的药物相似性和药物评分值。