3-(8-hydroxy-3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)propanoic acid | 330451-55-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 3-(8-hydroxy-3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)propanoic acid
• 英文别名: 3-(8-Hydroxy-3-methyl-1,4-dioxo-2-naphthyl)propanoic acid；3-(8-hydroxy-3-methyl-1,4-dioxonaphthalen-2-yl)propanoic acid
• CAS: 330451-55-3
• 化学式: C₁₄H₁₂O₅
• 分子量: 260.246
• InChiKey: NXZAUINGPRFZPU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  91.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  亚精胺 、 3-(8-hydroxy-3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)propanoic acid 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 吡啶 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.17h， 以37%的产率得到3-(8-hydroxy-3-methyl-1,4-dioxonaphthalen-2-yl)-N-[4-[3-[3-(8-hydroxy-3-methyl-1,4-dioxonaphthalen-2-yl)propanoylamino]propylamino]butyl]propanamide
  参考文献：
  名称：

  2-和3-取代的1,4-萘醌衍生物作为锥虫锥虫还原酶和脂酰胺脱氢酶的颠覆性底物：氧化还原循环活性与体外细胞毒性之间的合成和相关性。

  摘要：

  Trypanothione还原酶（TR）是设计新的锥虫病药物的既有效又有吸引力的靶标。从甲萘醌，羽扇豆蛋白和胡桃木酮开始，合成了三个不同系列的1,4-萘醌（NQ）作为克氏锥虫（TcTR）潜在的TR抑制剂。三个母体分子通过各种多胺链在碳2和/或3上官能化。利用3,3'-[聚氨基双（羰基烷基）]双（1,4-NQ）系列19-20实现了相对于人类二硫键还原酶的TcTR抑制和TcTR特异性的优化，其中确定了抑制TcTR的最佳链长。锥虫二硫化物还原。还研究了在培养物中针对锥虫的活性最高的衍生物作为TcTR和脂酰胺脱氢酶（TcLipDH）的颠覆性底物。通过随后的NAD（P）H氧化以及将反应与细胞色素c的还原反应耦合来测量活性，从而可以检测单电子转移。对于TcTR，20（4-c）被证明是有效的颠覆性底物，并且是与锥硫磷二硫化物和NADPH相比有效的非竞争性抑制剂。进行了基于TcTR和hGR的已知X射线结构

  DOI：

  10.1021/jm001079l
• 作为产物：
  描述：

  丁二酸 、 兰雪醌 在 ammonium persulfate 、 silver nitrate 作用下， 以 水 、 乙腈 为溶剂， 反应 3.0h， 以61%的产率得到3-(8-hydroxy-3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)propanoic acid
  参考文献：
  名称：

  来自diazen-1-ium-1,2-glycate一氧化氮供体和ROS诱导剂plumbagin的新型抗癌杂种：设计，合成和生物学评估。

  摘要：

  高水平的一氧化氮（NO）和活性氧（ROS）可能在癌细胞中充当促凋亡信号。在这项研究中，我们将一类重要的NO供体diazeniumdiolates（NONOates）与天然的铅蛋白（PL）结合在一起，而后者主要是出色的ROS诱导剂。本文中，总共合成了12种新颖的lumbagin / NONOate杂种，并评估了它们对一组人类癌细胞系（MDA-MB-231，A549，HepG2和HCT-116细胞）和两个正常人类细胞（ HK-2和WRL-68电池）。其中，与上述母体化合物相比，化合物10a和10b显示出比其母体化合物优越的效力（IC 50值为3.48-6.68μM），但是对正常细胞的抑制作用较弱。根据其选择性的细胞毒性，10a和10b在癌细胞中释放的NO水平高于正常细胞。此外，与母体化合物plumbagin相比，有效的化合物10a以浓度依赖的方式诱导A549细胞凋亡，并导致更多的ROS产生。

  DOI：

  10.1016/j.ejmech.2018.04.047

文献信息

• Novel NO-releasing plumbagin derivatives: Design, synthesis and evaluation of antiproliferative activity
  作者：Na Bao、Jinfeng Ou、Manyi Xu、Fuqin Guan、Wei Shi、Jianbo Sun、Li Chen

  DOI：10.1016/j.ejmech.2017.05.046

  日期：2017.9

  donor hybrids were designed, synthesized and evaluated in vitro against triple negative breast cancer (MDA-MB-231), hepatocellular (HepG2) and lung (A549) carcinoma cells. Most furoxan-based plumbagin derivatives exhibited significantly superior potency compared to their parent compound. Noticeably, MDA-MB-231 cells are the most sensitive to these furoxan-based plumbagin derivatives as evidenced by IC50

  设计，合成和评估了一系列的plumbagin / NO供体杂种，以对抗三阴性乳腺癌（MDA-MB-231），肝细胞癌（HepG2）和肺癌细胞（A549）。与它们的母体化合物相比，大多数基于呋喃喃的lumbagin衍生物表现出显着优越的效力。值得注意的是，MDA-MB-231细胞对这些基于呋喃喃类的羽囊肽衍生物最敏感，IC 50值范围为1.24至5.20μM，这证明了这一点。此外，对所有杂种的NO释放量的检测表明，在大多数情况下，抗增殖活性与MDA-MB-231细胞中细胞内NO的释放水平呈正相关。活性最高的化合物（11a）在不同的pH值（6.0、7.4和8.0）下也比lumbagin具有更高的化学稳定性。综上所述，上述有希望的结果保证了lumbagin / NO杂化物作为抗三阴性乳腺癌的先导化合物的未来潜力，值得进一步研究。
• Design, synthesis and biological evaluation of novel plumbagin derivatives as potent antitumor agents with STAT3 inhibition
  作者：Na Li、Jinfeng Ou、Na Bao、Cheng Chen、Zhixian Shi、Li Chen、Jianbo Sun

  DOI：10.1016/j.bioorg.2020.104208

  日期：2020.11

  hydroxyl group at C-5 of PL might interact with STAT3 in the form of hydrogen bonds, which is conducive to the binding of this kind structures with STAT3. Among the target compounds, 7a displayed the most potent inhibition against cancer cells and weaker cytotoxicity on normal cells than PL. The western bolting analysis showed that 7a could suppress the phosphorylation of STAT3 as well as the downstream genes

  基于信号转导和转录激活因子3（STAT3）的结构，设计，合成了一系列具有STAT3抑制潜能的plumbagin（PL）衍生的1,4-萘醌，并在体外对几种人类癌细胞系进行了生物学评估。（MDA-MB-231，HepG2和A549细胞）和三个正常细胞。结构-活性关系（SAR）和分子对接结果表明，PL C-5处的羟基可能以氢键形式与STAT3相互作用，这有利于这种结构与STAT3的结合。在目标化合物中，与PL相比，7a对癌细胞的抑制作用最强，对正常细胞的细胞毒性较弱。西方螺栓分析显示7a可以抑制STAT3及其下游基因的磷酸化，而不影响其上游酪氨酸激酶（Src和JAK2）水平和p-STAT1表达。此外，分子对接表明7a与STAT3的结合比PL更紧密，并且可以显着诱导体外癌细胞的凋亡。所有这些结果可为发现有效的STAT3抑制剂提供参考。
• Conjugates of plumbagin and phenyl-2-amino-1-thioglucoside inhibit MshB, a deacetylase involved in the biosynthesis of mycothiol
  作者：David W. Gammon、Daniel J. Steenkamp、Vuyo Mavumengwana、Mohlopheni J. Marakalala、Theophilus T. Mudzunga、Roger Hunter、Muganza Munyololo

  DOI：10.1016/j.bmc.2010.02.049

  日期：2010.4

  N-Acetylglucosaminylinositol (GlcNAc-Ins)-deacetylase (MshB) and mycothiol-S-conjugate amidase (Mca), structurally related amidases present in mycobacteria and other Actinomycetes, are involved in the biosynthesis of mycothiol and in the detoxification of xenobiotics as their mycothiol-S-conjugates, respectively. With substrate analogs of GlcNAc-Ins, MshB showed a marked preference for inositol as the aglycon present in GlcNAc-Ins. The inhibition of MshB and Mca by 10 thioglycosides, 7 cyclohexyl-2-deoxy-2-C-alkylglucosides, and 4 redox cyclers was evaluated. The latter contained plumbagin tethered via 2 to 5 methylene carbons and an amide linkage to phenyl-2-deoxy-2-amino-1-thio-alpha-D-glucopyranoside. These proved to be the most potent amongst the 21 compounds tested as inhibitors of MshB. Their inhibitory potency varied with the length of the spacer, with the compound with longest spacer being the most effective. (C) 2010 Elsevier Ltd. All rights reserved.
• Effects of highly active novel artemisinin–chloroquinoline hybrid compounds on β-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum
  作者：Tzu-Shean Feng、Eric M. Guantai、Margo Nell、Constance E.J. van Rensburg、Kanyile Ncokazi、Timothy J. Egan、Heinrich C. Hoppe、Kelly Chibale

  DOI：10.1016/j.bcp.2011.04.018

  日期：2011.8

  4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi-four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a-c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent beta-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials. (C) 2011 Elsevier Inc. All rights reserved.
• 2- and 3-Substituted 1,4-Naphthoquinone Derivatives as Subversive Substrates of Trypanothione Reductase and Lipoamide Dehydrogenase from <i>Trypanosoma</i> <i>c</i><i>ruzi</i>:  Synthesis and Correlation between Redox Cycling Activities and in Vitro Cytotoxicity
  作者：Laurence Salmon-Chemin、Eric Buisine、Vanessa Yardley、Sven Kohler、Marie-Ange Debreu、Valérie Landry、Christian Sergheraert、Simon L. Croft、R. Luise Krauth-Siegel、Elisabeth Davioud-Charvet

  DOI：10.1021/jm001079l

  日期：2001.2.1

  Trypanothione reductase (TR) is both a valid and an attractive target for the design of new trypanocidal drugs. Starting from menadione, plumbagin, and juglone, three distinct series of 1,4-naphthoquinones (NQ) were synthesized as potential inhibitors of TR from Trypanosoma cruzi (TcTR). The three parent molecules were functionalized at carbons 2 and/or 3 by various polyamine chains. Optimization of

  Trypanothione还原酶（TR）是设计新的锥虫病药物的既有效又有吸引力的靶标。从甲萘醌，羽扇豆蛋白和胡桃木酮开始，合成了三个不同系列的1,4-萘醌（NQ）作为克氏锥虫（TcTR）潜在的TR抑制剂。三个母体分子通过各种多胺链在碳2和/或3上官能化。利用3,3'-[聚氨基双（羰基烷基）]双（1,4-NQ）系列19-20实现了相对于人类二硫键还原酶的TcTR抑制和TcTR特异性的优化，其中确定了抑制TcTR的最佳链长。锥虫二硫化物还原。还研究了在培养物中针对锥虫的活性最高的衍生物作为TcTR和脂酰胺脱氢酶（TcLipDH）的颠覆性底物。通过随后的NAD（P）H氧化以及将反应与细胞色素c的还原反应耦合来测量活性，从而可以检测单电子转移。对于TcTR，20（4-c）被证明是有效的颠覆性底物，并且是与锥硫磷二硫化物和NADPH相比有效的非竞争性抑制剂。进行了基于TcTR和hGR的已知X射线结构