phaeosphaeride A

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯啉
• 英文名称: phaeosphaeride A
• 英文别名: Phaeosphaeride A；(2S,3R,4S)-3,4-dihydroxy-6-methoxy-3-methyl-7-methylidene-2-pentyl-2,4-dihydropyrano[2,3-c]pyrrol-5-one
• 化学式: C₁₅H₂₃NO₅
• 分子量: 297.351
• InChiKey: PQXBZFLVJGBOAD-XEGUGMAKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  79.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  phaeosphaeride A 在 三氟乙酸 、 碳酸氢钠 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 1.5h， 以75%的产率得到phaeosphaeride B
  参考文献：
  名称：

  通过（-）-phaeosphaeride A的仿生转化全合成（-）-phaseosphaeride B

  摘要：

  我们已经完成了STAT3抑制（-）-phasophereride A和其立体异构体（-）-phasopheride B的首次合成。这项工作证实了这些天然产物的构型分配。值得注意的是，TFA介导的Phossphaeride A的脱水立体倒置提供了Pheosphaeride B，这是基于我们对Phphasphaeride A的Phossphaeride B生物合成机理的假设。

  DOI：

  10.1016/j.tet.2017.03.020
• 作为产物：
  描述：

  methyl (2S,3R,4S)-4-hydroxy-6-(methoxycarbamoyl)-3-(methoxymethoxy)-3-methyl-2-pentyl-3,4-dihydro-2H-pyran-5-carboxylate 在 三乙胺 作用下， 以 乙醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.0h， 生成 phaeosphaeride A
  参考文献：
  名称：

  通过（-）-phaeosphaeride A的仿生转化全合成（-）-phaseosphaeride B

  摘要：

  我们已经完成了STAT3抑制（-）-phasophereride A和其立体异构体（-）-phasopheride B的首次合成。这项工作证实了这些天然产物的构型分配。值得注意的是，TFA介导的Phossphaeride A的脱水立体倒置提供了Pheosphaeride B，这是基于我们对Phphasphaeride A的Phossphaeride B生物合成机理的假设。

  DOI：

  10.1016/j.tet.2017.03.020

文献信息

• Towards lead compounds as anti-cancer agents via new phaeosphaeride A derivatives
  作者：Victoria V. Abzianidze、Sofya A. Zakharenkova、Natalia I. Moiseeva、Petr P. Beltyukov、Valeriy A. Polukeev、Yaroslav A. Dubrovskii、Victor A. Kuznetsov、Yuri G. Trishin、Jennifer E. Mejia、Alvin A. Holder

  DOI：10.1016/j.bmcl.2018.11.003

  日期：2019.1

  New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor studies were carried out on the U937, HCT-116, PC3, MCF-7, A549, К562, NCI-H929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 (IC50 = 0.59 ± 0.27 µM) was observed to

  合成并表征了新的邻苯二酚A衍生物（PPA）。在U937，HCT-116，PC3，MCF-7，A549，К562，NCI-H929，Jurkat，THP-1，RPMI8228肿瘤细胞系和HEF细胞系上进行了抗肿瘤研究。发现所有合成的化合物对所述肿瘤细胞系具有比PPA更好的功效。化合物6（IC 50  = 0.59±0.27μM）被观察到11倍的活性比PPA（IC 50  = 6.5±0.30μM）朝向所述NCI-H929细胞系，与18的化合物的治疗指数6被确定为对NCI-H929（IC 50  = 0.9±0.05 µM）和A549（IC 50）的活性比依托泊苷高出一半以上，是其的16倍 = 100±7.0 µM）细胞系。
• Synthesis of natural phaeosphaeride A derivatives and an in vitro evaluation of their anti-cancer potential
  作者：Victoria V. Abzianidze、Daria S. Prokofieva、Leonid A. Chisty、Ksenia P. Bolshakova、Alexander O. Berestetskiy、Taras L. Panikorovskii、Alexander S. Bogachenkov、Alvin A. Holder

  DOI：10.1016/j.bmcl.2015.10.048

  日期：2015.12

  Derivatives of phaeosphaeride A (PPA) were synthesised and characterised; then anti-cancer studies were carried out on the A549 cancer cell line. It was found that the acetyl derivative (compound 3) displayed comparable in vitro cytotoxicity to that of PPA (EC50 = 49 ± 7 μM and EC50 = 46 ± 5 μM, respectively), while chloroacetyl derivative 6 (EC50 = 33 ± 7 μM) was found to have better efficacy towards

  合成了Phphasphaeride A（PPA）的衍生物并进行了表征；然后在A549癌细胞系上进行了抗癌研究。发现乙酰基衍生物（化合物3）具有与PPA相当的体外细胞毒性（分别为EC 50  = 49±7μM和EC 50  = 46±5μM），而氯乙酰基衍生物6（EC 50  = 33±发现7μM）对A549癌细胞系具有更好的功效。
• Synthesis and Biological Evaluation of Phaeosphaeride A Derivatives as Antitumor Agents
  作者：Victoria Abzianidze、Petr Beltyukov、Sofya Zakharenkova、Natalia Moiseeva、Jennifer Mejia、Alvin Holder、Yuri Trishin、Alexander Berestetskiy、Victor Kuznetsov

  DOI：10.3390/molecules23113043

  日期：——

  New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, К562, NCI-Н929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 was potent against six cancer cell

  合成和表征了 phaeosphaeride A (PPA) 的新衍生物。对 HCT-116、PC3、MCF-7、A549、К562、NCI-Н929、Jurkat、THP-1、RPMI8228 肿瘤细胞系和 HEF 细胞系进行了抗肿瘤活性研究。发现所有合成的化合物对提到的肿瘤细胞系都具有比 PPA 更好的功效。化合物 6 对六种癌细胞系 HCT-116、PC-3、K562、NCI-H929、Jurkat 和 RPMI8226 有效，显示抗癌活性增加 47、13.5、16、4、1.5 和 7 倍分别为依托泊苷。化合物 1 对 NCI-H929 细胞系具有选择性 (IC50 = 1.35 ± 0.69 μM)，而产物 7 对三种癌细胞系 HCT-116、MCF-7 和 NCI-H929 具有选择性，IC50 值为 1.65分别为 μM、1.80 μM 和 2.00 μM。
• Natural Phaeosphaeride A Derivatives Overcome Drug Resistance of Tumor Cells and Modulate Signaling Pathways
  作者：Victoria Abzianidze、Natalia Moiseeva、Diana Suponina、Sofya Zakharenkova、Nadezhda Rogovskaya、Lidia Laletina、Alvin A. Holder、Denis Krivorotov、Alexander Bogachenkov、Alexander Garabadzhiu、Anton Ukolov、Vyacheslav Kosorukov

  DOI：10.3390/ph15040395

  日期：——

  In the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds synthesized turned out to have better efficacy than PPA towards the tumor cell lines listed. Among them, three compounds exhibited an ability to overcome the drug resistance of tumor cells associated with the overexpression of the P-glycoprotein by modulating the work of this transporter. Luminex xMAP technology was used to assess the effect of five synthesized compounds on the activation of intracellular kinase cascades in A431 cells. MILLIPLEX MAP Multi-Pathway Magnetic Bead 9-Plex was used, which allowed for the simultaneous detection of the following nine phosphorylated protein markers of the main intracellular signaling pathways: a universal transcription factor that controls the expression of immune-response genes, apoptosis and cell cycle NFκB (pS536); cAMP-dependent transcription factor (CREB (pS133); mitogen-activated kinase p38 (pT180/pY182); stress-activated protein kinase JNK (pT183/pY185); ribosomal SK; transcription factors STAT3 (pS727) and STAT5A/B (pY694/699); protein kinase B (Akt) (pS473); and kinase regulated by extracellular signals ERK1/2 (pT185/pY187). The effect of various concentrations of PPA derivatives on the cell culture was studied using xCelligence RTCA equipment. The compounds were found to modulate JNK, ERK1/2, and p38 signaling pathways. The set of activated kinase cascades suggests that oxidative stress is the main probable mechanism of the toxic action of PPA derivatives.

  在本研究中，合成了天然phaeosphaeride A (PPA)衍生物。对PC3、K562、HCT-116、THP-1、MCF-7、A549、NCI-H929、Jurkat和RPMI8226肿瘤细胞系以及人类胚胎肾(HEK293)细胞系进行了抗肿瘤研究。所有合成的化合物对列出的肿瘤细胞系的疗效均优于PPA。其中，三种化合物表现出克服与P-糖蛋白过表达相关的肿瘤细胞的耐药性的能力，通过调节这种转运蛋白的作用。使用Luminex xMAP技术评估了五种合成化合物对A431细胞内激酶级联激活的影响。使用了MILLIPLEX MAP Multi-Pathway Magnetic Bead 9-Plex，可以同时检测主要细胞内信号通路的以下九个磷酸化蛋白标记：控制免疫反应基因、凋亡和细胞周期的通用转录因子NFκB (pS536)；cAMP依赖的转录因子(CREB (pS133))；丝裂原激活激酶p38 (pT180/pY182)；应激蛋白激酶JNK (pT183/pY185)；核糖体SK；转录因子STAT3 (pS727)和STAT5A/B (pY694/699)；蛋白激酶B (Akt) (pS473)；以及受细胞外信号调节的激酶ERK1/2 (pT185/pY187)。使用xCelligence RTCA设备研究了不同浓度的PPA衍生物对细胞培养的影响。发现这些化合物调节了JNK、ERK1/2和p38信号通路。激活的激酶级联集合表明，氧化应激是PPA衍生物毒性作用的主要可能机制。
• Synthesis of 7-(4-methylphenyl)thiomethyl and 7-morpholylmethyl derivatives of natural phaeosphaeride A and their cytotoxic activity
  作者：Victoria V. Abzianidze、Ksenia P. Bolshakova、Daria S. Prokofieva、Alexander O. Berestetskiy、Victor A. Kuznetsov、Yuri G. Trishin

  DOI：10.1016/j.mencom.2017.01.026

  日期：2017.1

  The herein synthesized 7-(4-methylphenyl)thiomethyl and 7-morpholylmethyl derivatives of natural phaeosphaeride A have lower cytotoxic activity towards the human lung adenocarcinoma A549 cell line compared to phaeosphaeride A. The presence of exocyclic C=C bond and N–OMe group in such compounds is suggested to be a factor in their antitumor activity.

  与phasphaeride A相比，本文合成的天然phasphaeride A的7-（4-甲基苯基）硫甲基和7-吗啉基甲基衍生物对人肺腺癌A549细胞株的杀伤活性较低。存在环外C = C键和N–OMe基团提示此类化合物中的抗肿瘤活性是其抗肿瘤活性的一个因素。