8-(4-二苯并噻吩基)-2-(4-吗啉基)-4H-1-苯并吡喃-4-酮 | 503468-95-9

• 物质功能分类: 生物化工 - 抑制剂 - DNA损伤(DNA Damage)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻吩类
• 中文名称: 8-(4-二苯并噻吩基)-2-(4-吗啉基)-4H-1-苯并吡喃-4-酮
• 英文名称: 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one
• 英文别名: NU 7441；8-(dibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-chromen-4-one；8-(4-dibenzothienyl)-2-(4-morpholinyl)-4H-1-benzopyran-4-one；8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one；8-dibenzothiophen-4-yl-2-morpholin-4-ylchromen-4-one；NU7441
• CAS: 503468-95-9
• 化学式: C₂₅H₁₉NO₃S
• 分子量: 413.497
• InChiKey: JAMULYFATHSZJM-UHFFFAOYSA-N

物化性质

• 熔点：
  220-221 °C
• 沸点：
  646.9±55.0 °C(Predicted)
• 密度：
  1.376±0.06 g/cm3(Predicted)
• 溶解度：
  溶于DMSO（升温时溶解度高达10mg/ml）。

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  30
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  67
• 氢给体数：
  0
• 氢受体数：
  5

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

**NU7441 (KU-57788)**是一种高度有效的选择性DNA-PK抑制剂，在无细胞试验中IC50为14 nM，也抑制mTOR和PI3K，对应的IC50值分别为1.7 μM和5 μM。它可降低NHEJ的频率，而增强Cas9介导DNA剪接后发生的同源重组修复率。

体外研究

NU7441抑制DNA依赖性蛋白激酶 (DNA-PK) 比其他PI3K相关激酶 (PIKK)家族成员选择性高，IC50为14 nM。在电离辐射或Etoposide诱导的DNA损伤后，1 μM浓度的NU7441能够提高γH2AX病灶的持久性。

当作用于SW620和LoVo细胞时，0.5 μM至1 μM浓度的NU7441显著提高了电离辐射、Etoposide和Doxorubicin诱导的G2-M期细胞累积。此外，在DNA-PK充足的M059-Fus-1和DNA-PK缺陷的M059 J人类肿瘤细胞中，1 μM浓度的NU7441引起了Doxorubicin和电离辐射诱导的DNA双链断裂的持久性，并稍微降低了同源重组活性。

在缺乏或表达polη的细胞中，10 μM浓度的NU7441能够抑制UV诱导RPA p34过度磷酸化。在慢性淋巴细胞性白血病细胞中，1 μM浓度的NU7441提高了Fludarabine诱导的γH2AX病灶水平，并相应地降低了Fludarabine诱导的细胞死亡。

此外，该药物还能够抑制Mitoxantrone诱导的DNA-PKcs自磷酸化和修复。它可降低NHEJ的频率，而增强Cas9介导DNA剪接后发生的同源重组修复率。

体内研究

以10 mg/kg剂量腹腔注射处理携带SW620移植瘤的小鼠，并按无毒剂量处理至少4小时后，NU7441能够提高Etoposide诱导的肿瘤生长延迟2倍。

靶点

Target	Value
DNA-PK (Cell-free assay)	14 nM
mTOR (cell-free assay)	1.7 μM
PI3K (cell-free assay)	5 μM

反应信息

• 作为产物：
  描述：

  4-乙酰基吗啉 在 四(三苯基膦)钯 、 三氟甲磺酸酐 、 potassium carbonate 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 正己烷 、 二氯甲烷 为溶剂， 反应 94.0h， 生成 8-(4-二苯并噻吩基)-2-(4-吗啉基)-4H-1-苯并吡喃-4-酮
  参考文献：
  名称：

  Discovery of Potent Chromen-4-one Inhibitors of the DNA-Dependent Protein Kinase (DNA-PK) Using a Small-Molecule Library Approach

  摘要：

  Structure-activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxysubstituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNAPK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6',7',8',9'-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32{38} sensitized HeLa cells to ionizing radiation in vitro, with dose modification factors of 2.5 at 10% survival being observed at 0.5 mu M. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.

  DOI：

  10.1021/jm050444b

文献信息

• [EN] DIBENZOTHIOPHENE DERIVATIVES AS DNA- PK INHIBITORS<br/>[FR] DÉRIVÉS DE DIBENZOTHIOPHÈNE EN TANT QU'INHIBITEURS D'ADN-PK
  申请人：KUDOS PHARM LTD

  公开号：WO2010136778A1

  公开（公告）日：2010-12-02

  Compound formula I: wherein: X1 and X2 may be either (a) C and O, (b) N and N, or (c) C and NH, where the dotted bonds represents a double bond in the appropriate location; R1 and R2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, an optionally substituted C3-20 heterocyclyl group, or an optionally substituted C5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; RN1 is selected from hydrogen and an optionally substituted C1-4 alkyl group; RC1 is selected from an optionally substituted C1-7 alkyl group, an optionally substituted C3-20 heterocyclyl group, or an optionally substituted C5-20 aryl group; or RN1 and RC1 may together form an optionally substituted C2-4 alkylene group.

  化合物公式I：其中：X1和X2可以是（a）C和O，（b）N和N，或（c）C和NH，其中点线代表适当位置的双键；R1和R2分别从氢，可选择的取代的C1-7烷基基团，可选择的取代的C3-20杂环基团，或可选择的取代的C5-20芳基基团中独立选择，或者可以与它们附着的氮原子一起形成具有4至8个环原子的可选择取代的杂环环；RN1从氢和可选择的取代的C1-4烷基基团中选择；RC1从可选择的取代的C1-7烷基基团，可选择的取代的C3-20杂环基团，或可选择的取代的C5-20芳基基团中选择；或RN1和RC1可以一起形成一个可选择取代的C2-4烷基烃基团。
• [EN] DNA PK INHIBITORS<br/>[FR] INHIBITEURS DE L'ADN-PK
  申请人：KUDOS PHARM LTD

  公开号：WO2009010761A1

  公开（公告）日：2009-01-22

  A compound of formula (I): wherein: R1 and R2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, C3-20 heterocydyl group, or C5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; X is CH or N; n is 1 or 2; RC1 and RC2 are independently selected from H and methyl; when X is N, Rx is selected from the group consisting of H, and optionally substituted C1-7 alkyl, C3-20 heterocydyl, C5-20 aryl, acyl, ester, amido and sulfonyl; and when X is CH, Rx is selected from the group consisting of H, and optionally substituted C1-7 alkyl, C3-2O heterocyclyl, C5-20 aryl, acyl, ester, amido, sulfonyl, amino and ether. The compounds according to formula (I) are DNA-PK inhibitors, useful in the treatment of tumours and retroviral mediated diseases.

  公式(I)的化合物：其中：R1和R2独立地选自氢、一个可选地取代的C1-7烷基团、C3-20杂环烷基团或C5-20芳基团，或者可以共同形成，连同它们所连接的氮原子，一个从4到8个环原子组成的可选地取代的杂环；X是CH或N；n是1或2；RC1和RC2独立地选自H和甲基；当X是N时，Rx选自由H、和可选地取代的C1-7烷基、C3-20杂环烷基、C5-20芳基、酰基、酯、酰胺和磺酰基组成的组；当X是CH时，Rx选自由H、和可选地取代的C1-7烷基、C3-20杂环烷基、C5-20芳基、酰基、酯、酰胺、磺酰基、氨基和醚组成的组。根据公式(I)的化合物是DNA-PK抑制剂，在治疗肿瘤和逆转录病毒介导的疾病中有效。
• [EN] 1H-PYRAZOLO[3,4-D]PYRIMIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF PLATINUM-RESISTANT CANCER<br/>[FR] COMPOSÉS DE 1H-PYRAZOLO[3,4-D]PYRIMIDINE UTILES POUR LE TRAITEMENT DU CANCER RÉSISTANT AU PLATINE
  申请人：IMPERIAL COLLEGE INNOVATIONS LTD

  公开号：WO2021123798A1

  公开（公告）日：2021-06-24

  The invention relates to compounds of formula (I) and related compounds and their use in the treatment of cancer, especially platinum resistant cancer. The invention also provides a treatment comprising administration of a compound of formula (I) and a platinum containing drug.

  该发明涉及式(I)的化合物及相关化合物，以及它们在治疗癌症，特别是铂类耐药性癌症中的应用。该发明还提供了一种治疗方法，包括给予式(I)的化合物和含铂药物的组合。
• SYNTHESIS OF 2-AMINO-SUBSTITUTED 4-OXO-4H-CHROMEN-8.YL-TRIFLUORO-METHANESULFONIC ACID ESTERS
  申请人：Griffin Roger John

  公开号：US20090326223A1

  公开（公告）日：2009-12-31

  A method of synthesising a compound of formula (I): wherein R N1 and R N2 are independently selected from hydrogen, an optionally substituted C 1-7 alkyl group, C 3-20 heterocyclyl group, or C 5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; from a compound of formula (III): comprising the steps of: (a) removing the allyl group from the compound of formula (III) with appropriate reaction conditions to yield a compound of formula (II): and (b) reacting the compound of formula (II) with a triflating agent to yield a compound of formula (I).

  一种合成公式(I)化合物的方法：其中RN1和RN2分别选自氢、可选择取代的C1-7烷基、C3-20杂环基或C5-20芳基，或者与它们所连接的氮原子一起形成一个具有4到8个环原子的可选择取代的杂环环；从公式(III)化合物开始，包括以下步骤：(a)使用适当的反应条件去除公式(III)化合物的烯丙基，得到公式(II)化合物；(b)将公式(II)化合物与三氟甲烷磺酰化试剂反应，得到公式(I)化合物。
• Dna-Pk Inhibitors
  申请人：Smith Cameron Murray Graeme

  公开号：US20070238731A1

  公开（公告）日：2007-10-11

  A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: R 1 and R 2 are independently selected from hydrogen, an optionally substituted C 1-7 alkyl group, C 3-20 heterocyclyl group, or C 5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; Q is —NH—C(═O)— or —O—; Y is an optionally substituted C 1-5 alkylene group; X is selected from SR 3 or NR 4 R 5 , wherein, R 3 or R 4 and R 5 are independently selected from hydrogen, optionally substituted C 1-7 alkyl, C 5-20 aryl, or C 3-20 heterocyclyl groups, or R 4 and R 5 may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; if Q is —O—, X is additionally selected from —C(═O)—NR 6 R 7 , wherein R 6 and R 7 are independently selected from hydrogen, optionally substituted C 1-7 alkyl, C 5-20 aryl, or C 3-20 heterocyclyl groups, or R 6 and R 7 may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; and if Q is —NH—C(═O)—, —Y—X may additionally be selected from C 1-7 alkyl.

  化合物I的化学式为：以及其异构体、盐、溶剂合物、化学保护形式和前药，其中：R1和R2独立地选自氢、可选择性地取代的C1-7烷基、C3-20杂环基或C5-20芳基，或者与它们连接的氮原子一起形成具有4至8个环原子的可选择性地取代的杂环环；Q为—NH—C(═O)—或—O—；Y为可选择性地取代的C1-5烷基；X选自SR3或NR4R5，其中，R3或R4和R5独立地选自氢、可选择性地取代的C1-7烷基、C5-20芳基或C3-20杂环基，或者R4和R5可以与它们连接的氮原子一起形成具有4至8个环原子的可选择性地取代的杂环环；如果Q为—O—，则X还可以从—C(═O)—NR6R7中选取，其中R6和R7独立地选自氢、可选择性地取代的C1-7烷基、C5-20芳基或C3-20杂环基，或者R6和R7可以与它们连接的氮原子一起形成具有4至8个环原子的可选择性地取代的杂环环；如果Q为—NH—C(═O)—，则—Y—X还可以从C1-7烷基中选取。