methyl 5-fluoro-2-(methylamino)benzoate

• 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: methyl 5-fluoro-2-(methylamino)benzoate
• 化学式: C₉H₁₀FNO₂
• 分子量: 183.182
• InChiKey: ACDZIHOCIOJCLI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 5-fluoro-2-(methylamino)benzoate 在 [N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2, 3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium 、 10% Pd/C 、 氢气 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲酸 、 乙酸乙酯 、 三乙胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 92.67h， 生成 3-fluoro-10-hydroxy evodiamine
  参考文献：
  名称：

  New Tricks for an Old Natural Product: Discovery of Highly Potent Evodiamine Derivatives as Novel Antitumor Agents by Systemic Structure–Activity Relationship Analysis and Biological Evaluations

  摘要：

  Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.

  DOI：

  10.1021/jm300605m
• 作为产物：
  描述：

  2-氨基-5-氟苯甲酸 在 4-二甲氨基吡啶 、 氯化亚砜 、 sodium hydride 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 26.5h， 生成 methyl 5-fluoro-2-(methylamino)benzoate
  参考文献：
  名称：

  Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer

  摘要：

  Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.

  DOI：

  10.1021/acs.jmedchem.9b01626

文献信息

• Synthesis of Xanthones, Thioxanthones, and Acridones by the Coupling of Arynes and Substituted Benzoates
  作者：Jian Zhao、Richard C. Larock

  DOI：10.1021/jo0620718

  日期：2007.1.1

  The reaction of silylaryl triflates, CsF, and ortho-heteroatom-substituted benzoates affords a general and efficient way to prepare biologically interesting xanthones, thioxanthones, and acridones. This chemistry presumably proceeds by a tandem intermolecular nucleophilic coupling of the benzoate with an aryne and a subsequent intramolecular electrophilic cyclization.

  甲硅烷基芳基三氟甲磺酸酯，CsF和邻杂原子取代的苯甲酸酯的反应提供了制备生物学上有趣的氧杂蒽酮，噻吨杂蒽和a啶酮的通用且有效的方法。据推测，该化学反应是通过苯甲酸酯与芳烃的串联分子间亲核偶联和随后的分子内亲电环化而进行的。
• Optical evodiamine derivatives: Asymmetric synthesis and antitumor activity
  作者：Zhen-Gang Li、Guo-Qiang Dong、Sheng-Zheng Wang、Zhen-Yuan Miao、Jian-Zhong Yao、Wan-Nian Zhang、Chun-Quan Sheng

  DOI：10.1016/j.cclet.2014.11.011

  日期：2015.3

  of evodiamine derivatives 2 and 3 were obtained by straightforward asymmetric total synthesis. Their inhibitory activities toward topoisomerases I and II and their cytotoxicities in cancer cell lines were evaluated. All the four isomers exhibited good to excellent antitumor potency and the (S)-isomers were generally more active than the (R)-isomers. The binding modes of (S)-2 with topoisomerases I and

  Evodiamine及其衍生物在C13b位置具有不对称中心。在此，通过简单的不对称全合成获得了evodiamine衍生物2和3的异构体。评估了它们对拓扑异构酶I和II的抑制活性以及它们在癌细胞系中的细胞毒性。所有四种异构体均表现出良好至优异的抗肿瘤效力，并且（S）-异构体通常比（R）-异构体更具活性。（S）-2与拓扑异构酶I和II的结合模式也通过分子对接得以阐明。
• Design and synthesis of doublecortin-like kinase 1 inhibitors and their bioactivity evaluation
  作者：Pengming Pan、Dengbo Ji、Zhongjun Li、Xiangbao Meng

  DOI：10.1080/14756366.2023.2287990

  日期：2024.12.31

  Doublecortin-like kinase 1 (DCLK) is a microtubule-associated serine/threonine kinase that is upregulated in a wide range of cancers and is believed to be related to tumour growth and development. ...

  双皮质素样激酶 1 (DCLK) 是一种微管相关丝氨酸/苏氨酸激酶，在多种癌症中表达上调，并被认为与肿瘤生长和发展有关。 ...
• XAT‐Catalysis for Intramolecular Biaryl Synthesis
  作者：Thomas Sephton、Jonathan M. Large、Louise S. Natrajan、Sam Butterworth、Michael F. Greaney

  DOI：10.1002/anie.202407979

  日期：2024.8.26

  A photocatalytic, XAT mediated Smiles-Truce biaryl synthesis is described. The reaction uses mild methods to generate and chemoselectively harness capricious aryl radicals, efficiently furnishing valuable biaryl products. The reaction utilises a simple yet underexplored amide linker, which enables a challenging formal C−N arylation of anilines.

  描述了光催化、XAT 介导的 Smiles-Truce 联芳基合成。该反应采用温和的方法来生成和化学选择性地利用反复无常的芳基自由基，有效地提供有价值的联芳基产物。该反应利用了一个简单但尚未充分研究的酰胺连接体，可实现苯胺的具有挑战性的形式 C−N 芳基化。
• Benzopyrimidodiazepinone inhibitors of TNK2
  作者：Brian J. Groendyke、Chelsea E. Powell、Frederic Feru、Thomas W. Gero、Zhengnian Li、Hilary Szabo、Kevin Pang、John Feutrill、Bailing Chen、Bin Li、Nathanael S. Gray、David A. Scott

  DOI：10.1016/j.bmcl.2020.126948

  日期：2020.2

  The SAR of a series of benzopyrimidodiazepinone inhibitors of TNK2 was developed, starting from the potent and selective compound XMD8-87. A diverse set of anilines was introduced in an effort to improve the in vivo PK profile and minimize the risk of quinone diimine formation.