4β-O-propargylpodophyllotoxin | 1310349-59-7

• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物 - 木脂素内酯
• 英文名称: 4β-O-propargylpodophyllotoxin
• 英文别名: 4β-(prop-2-ynyloxy)epipodophyllotoxin；4-(prop-2-ynyloxy) podophyllotosxin；(5S,5aR,8aR,9R)-5-prop-2-ynoxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
• CAS: 1310349-59-7
• 化学式: C₂₅H₂₄O₈
• 分子量: 452.461
• InChiKey: RPQQUCTXYJRJKL-AZIXLERZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.07
• 重原子数：
  33.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  81.68
• 氢给体数：
  0.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  2-azido-2-deoxy-β-D-glucose 、 4β-O-propargylpodophyllotoxin 在 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene silver chloride 作用下， 以 乙醇 为溶剂， 反应 1.33h， 生成 4β-(1-D-C2-glucosyl-4-methyl-1,2,3-triazolyl)epipodophyllotoxin
  参考文献：
  名称：

  Synthesis of podophyllotoxin-glycosyl triazoles via click protocol mediated by silver (I)-N-heterocyclic carbenes and their anticancer evaluation as topoisomerase-II inhibitors

  摘要：

  Herein we report the regioselective synthesis of podophyllotoxin-Glycosyl triazole hybrids catalysed by Ag(I)-N-heterocyclic carbene (Ag(I)-NHC) in a short reaction time (similar to 30 min) at ambient conditions. In principle, it is the first report of Click alkyne-azide cycloaddition catalysed by Ag(I)-NHC catalyst and moreover, this new methodology yielded good results when compared with traditional CuAAC in terms of reaction time and selectivity. The synthesised compounds were further explored for in vitro anticancer activity against four human cancer cell lines Du145, HeLa, A-549, and MCF-7 and found that these synthesised compounds possess significant anticancer activity. Further, the compounds 5a and 5e were identified as promising leads due to their better activity across all cell lines than that of the standard drug etoposide. Molecular docking studies of 5a & 5e with DNA Topoisomerase-II were revealed that the free energy calculations of active compounds were in good agreement with observed IC50 values.[GRAPHICS].

  DOI：

  10.1080/14786419.2019.1610958
• 作为产物：
  描述：

  2-丙炔-1-醇 、 鬼臼毒素 在 甲烷磺酸 、 sodium iodide 、 barium carbonate 作用下， 以 乙腈 、 四氢呋喃 为溶剂， 反应 0.75h， 以62%的产率得到4β-O-propargylpodophyllotoxin
  参考文献：
  名称：

  Differential Targeting of Human Topoisomerase II Isoforms with Small Molecules

  摘要：

  The TOP2 poison etoposide has been implicated in the generation of secondary malignancies during cancer treatment. Structural similarities between TOP2 isoforms challenge the rational design of isoform-specific poisons to further delineate these processes. Herein, we describe the synthesis and biological evaluation of a focused library of etoposide analogues, with the identification of two novel small molecules exhibiting TOP2B-dependent toxicity. Our findings pave the way toward studying isoform-specific cellular processes by means of small molecule intervention.

  DOI：

  10.1021/acs.jmedchem.5b00473

文献信息

• Organo NHC catalyzed aqueous synthesis of 4β-isoxazole-podophyllotoxins: in vitro anticancer, caspase activation, tubulin polymerization inhibition and molecular docking studies
  作者：Rajkumar Nagavath、Murali Krishna Thupurani、Vinitha Badithapuram、Ravinder Manchal、Chandra Sekhar Vasam、Narasimha Swamy Thirukovela

  DOI：10.1039/d4ra04297b

  日期：——

  afford regioselective 4β-isoxazolepodophyllotoxin hybrids (6a–n) in benign aqueous-organic media. Preliminary anticancer activity results showed that compound 6e displayed superior activity against MCF-7, HeLa and MIA PaCa2 human cell lines compared with podophyllotoxin. Compounds 6j and 6n showed greater activity against the MCF-7 cell line than the positive control. Caspase activation studies revealed

  我们首次提出，有机-N-杂环卡宾（NHC）催化4β- O-炔丙基鬼臼毒素（ 1 ）与原位芳香族腈氧化物的1,3-偶极环加成反应，得到区域选择性4β-异恶唑鬼臼毒素杂化物（ 6a） –n ) 在良性水-有机介质中。初步抗癌活性结果表明，与鬼臼毒素相比，化合物6e对MCF-7、HeLa和MIA PaCa2人类细胞系表现出更优异的活性。化合物6j和6n对 MCF-7 细胞系表现出比阳性对照更高的活性。 Caspase 激活研究表明，20 μg ml -1浓度的化合物6e在 MCF-7 和 MIAPaCa2 细胞中比鬼臼毒素具有更强的 caspase 3/7 激活作用。此外，体外微管蛋白聚合抑制研究表明，化合物6e显示出与鬼臼毒素相当的活性。最后，化合物6e 、 6j 、 6n和鬼臼毒素在α,β-微管蛋白(pdb id 1SA0)上的计算机分子对接研究表明，与鬼臼毒素相比，化合物6n表现出优异的结合能和抑制常数。
• A convergent synthesis of alkyne–azide cycloaddition derivatives of 4-α,β-2-propyne podophyllotoxin depicting potent cytotoxic activity
  作者：Mahesh K. Zilla、Debasis Nayak、Ram A. Vishwakarma、Parduman Raj Sharma、Anindya Goswami、Asif Ali

  DOI：10.1016/j.ejmech.2014.02.030

  日期：2014.4

  A facile synthetic approach to construct the O-propargyl derivatives of 4 alpha and 4 beta-(1,2,3-triazol-4-yl)-podophyllotoxin (9a-k & 10a-k) and 4 '-Demethy1-4 '-4 beta-(1,2,3-triazol-4-yl)-epipodophyllotoxin (12a-d) were synthesized by means of click chemistry. The chemical structures were confirmed by H-1, C-13, 2D NMR and HRMS spectral analysis and their cytotoxicities were measured against diverse human cancer cell lines viz. PC-3, PANC-1, COLO-205 and A-549 by MU assay. Some of the compounds were found more potent than the parent molecule Podophyllotoxin, like; 9a & 10a, 9h & 10h, 9k & 10k, 10d, 8 and 12a. The most potent molecule discovered was compound 9k that exhibited the highest cytotoxicity on all the four cancer cell lines with IC50 values of 3.8-22 nM. The compound further found to induce apoptosis and strongly hindered the motility of aggressive prostate cancer PC-3 cells. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Synthesis and biological evaluation of a series of podophyllotoxins derivatives as a class of potent antitubulin agents
  作者：Yingqian Liu、Dongfeng Wei、Yonglong Zhao、Weidong Cheng、Yan Lu、Yaqiong Ma、Xin Li、Chao Han、Yanxia Wei、Huiming Cao、Chunyan Zhao

  DOI：10.1016/j.bmc.2012.09.009

  日期：2012.11

  A series of eight novel podophyllotoxin derivatives were designed, synthesized and evaluated for biological activities. The antiproliferative activities were tested against a panel of human cancer cell lines (1(562, SGC, Hela and HepG) and the inhibition of tubulin polymerization was also evaluated. Compound 8e displayed significant antiproliferative activities for all four cell lines and strong levels of tubulin polymerization inhibition effect. Combined with cell apoptosis and cell cycle analysis, it demonstrated that compound 3e that effectively interfere with tubulin dynamics prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually dose dependent apoptosis. All experimental measurements were also supported by molecular docking simulations of colchicine binding site, which revealed the governing forces for the binding behavior and a good relationship with anti-tubulin activity and antiproliferative activities. The synthesis and biological studies provided an interesting new class of antitubulin agents for development of lead compounds and also a direction for further structure modification to obtain more potent anti-cancer drugs. (C) 2012 Elsevier Ltd. All rights reserved.