19-O-tert-butyldimethylsilyl-3,14-di-O-acetyl-andrographolide | 1355018-52-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 19-O-tert-butyldimethylsilyl-3,14-di-O-acetyl-andrographolide
• 英文别名: 3,14-diacetyl-19-TBDMS-andrographolide；ethyl (3S,4E)-4-{2-[(1R,4aS,5R,6R,8aS)-6-(acetoxy)-5-{[(tert-butyldimethylchlorosilyl)methoxy]}-5,8a-dimethyl-2-ethylenedecalin-1-yl]ethylene}-5-oxooxolan-3-acetate；19-TBS-3,14-Ac-andrographolide；[(1R,2R,4aS,5R,8aS)-5-[(2E)-2-[(4S)-4-acetyloxy-2-oxooxolan-3-ylidene]ethyl]-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-1,4a-dimethyl-6-methylidene-3,4,5,7,8,8a-hexahydro-2H-naphthalen-2-yl] acetate
• CAS: 1355018-52-8
• 化学式: C₃₀H₄₈O₇Si
• 分子量: 548.792
• InChiKey: TYSIIYDVTAHYDU-HMPHPEQUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.13
• 重原子数：
  38
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  88.1
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  19-O-tert-butyldimethylsilyl-3,14-di-O-acetyl-andrographolide 在 水 、 叔丁基二甲基氯硅烷 、 2-碘酰基苯甲酸 作用下， 以 二甲基亚砜 、 乙腈 为溶剂， 反应 4.0h， 生成 3-acetyl-14-acetyl-19-dehydroandrographolide
  参考文献：
  名称：

  从头连续化学/区域选择性 IBX 介导穿心莲内酯及其衍生物的氧化

  摘要：

  摘要 开发了一种新的 IBX 介导的穿心莲内酯 (1) 区域/化学选择性氧化方案，穿心莲内酯是一种从穿心莲中分离出来的劳丹烷二萜。该协议与穿心莲内酯 (1) 初步成功以提供 19-脱氢穿心莲内酯 (5) 或 3,19-二脱氢穿心莲内酯 (6) 作为主要产品后，该程序进一步应用于穿心莲内酯衍生物中羟基官能团的氧化，即 2 、3、14 和 16。该过程同样适用于毫克到克的范围内。在乙腈-水 (8:2) 系统中使用 TBDMS-Cl 以良好的收率实现了化合物 15 和 18 中 C-19-OTBDMS 的脱保护。图形概要

  DOI：

  10.1080/00397911.2019.1587775
• 作为产物：
  描述：

  穿心莲内酯 在 吡啶 作用下， 反应 1.0h， 生成 19-O-tert-butyldimethylsilyl-3,14-di-O-acetyl-andrographolide
  参考文献：
  名称：

  新的7-乙酰氧基-12-氨基-14-脱氧穿心莲内酯类似物的合成和细胞毒活性

  摘要：

  从天然穿心莲内酯通过关键步骤反应，包括烯丙基羟基化，串联CAE反应和一锅甲酰化反应，设计并合成了两个新系列的19-甲硅烷基醚-和19-甲酰基-7-乙酰基-12-氨基-14-脱氧穿心莲内酯类似物。评估其对八种癌细胞系的细胞毒性后发现6e对MCF-7癌细胞表现出最高活性（IC 502.93），与药物eticticin相当。在C-19处用甲酰基取代甲硅烷基醚对P-388细胞系表现出选择性活性。计算研究表明，C-12处的氨基和C-7处的O-乙酰氧基在针对MCF-7癌细胞的细胞毒性中起重要作用。这两个系列的细胞毒性突出了12-取代的14-脱氧穿心莲内酯支架的重要性，并且这些类型的化合物可用于抗乳腺癌的未来发展中。

  DOI：

  10.1016/j.bmcl.2020.127741

文献信息

• 12-Amino-andrographolide analogues: synthesis and cytotoxic activity
  作者：Sakkasem Kasemsuk、Uthaiwan Sirion、Kanoknetr Suksen、Pawinee Piyachaturawat、Apichart Suksamrarn、Rungnapha Saeeng

  DOI：10.1007/s12272-013-0152-0

  日期：2013.12

  Andrographolide, a diterpenoid lactone of the plant Andrographis paniculata, has been shown to be cytotoxic against various cancer cells in vitro. In the present study, a series of β-amino-γ-butyrolactone analogues has been synthesized from naturally occurring andrographolide via one pot tandem aza-conjugate addition–elimination reaction. By using economic procedure without any base or catalyst at room temperature, the products obtained were in fair to excellent yields with high stereoselectivity. The cytotoxicity of all new amino analogues were evaluated against six cancer cell lines and revealed their potential for being developed as promising anti-cancer agents.

  穿心莲内酯是穿心莲属植物的一种二萜内酯，已被证明在体外对多种癌细胞具有细胞毒性。本研究以天然穿心莲内酯为原料，通过一锅串联杂环共轭加成-消除反应合成了一系列 β-氨基-γ-丁内酯类似物。在室温下使用经济的方法，不使用任何碱或催化剂，获得的产品具有很高的产率和立体选择性。对所有新氨基类似物针对六种癌细胞系的细胞毒性进行了评估，结果表明它们具有开发为有前途的抗癌药物的潜力。
• Inhibition of topoisomerase II α activity and induction of apoptosis in mammalian cells by semi-synthetic andrographolide analogues
  作者：Jintapat Nateewattana、Rungnapha Saeeng、Sakkasem Kasemsook、Kanoknetr Suksen、Suman Dutta、Surawat Jariyawat、Arthit Chairoungdua、Apichart Suksamrarn、Pawinee Piyachaturawat

  DOI：10.1007/s10637-012-9868-9

  日期：2013.4

  Topoisomerase II α enzyme plays a critical role in DNA replication process. It controls the topologic states of DNA during transcription and is essential for cell proliferation. Human DNA topoisomerase II α (hTopo II α) is a promising chemotherapeutic target for anticancer agents against a variety of cancer types. In the present study, andrographolide and its structurally modified analogues were investigated for their inhibitory activities on hTopo II α enzyme. Five out of nine andrographolide analogues potently reduced hTopo II α activity and inhibited cell proliferation in four mammalian cell lines (Hela, CHO, BCA-1 and HepG2 cells). IC50 values for cytotoxicity of analogues 3A.1, 3A.2, 3A.3, 1B and 2C were 4 to 7 μM. Structure-activity relationship studies revealed that both core structure of andrographolide and silicon based molecule of functional group were important for the inhibition of hTopo II α activity whereas position C-19 of analogues was required for anti-proliferation. In addition, the analogue 2C at 10 μM concentration inhibited hTopo II α, and induced apoptosis with nuclear fragmentation and formation of apoptotic bodies in HepG2 cells. The analogue 2C may, therefore, have a therapeutic potential as effective anticancer agent targeting the hTopo II α functions.

  拓扑异构酶 II α 在 DNA 复制过程中发挥着关键作用。它在转录过程中控制 DNA 的拓扑状态，对细胞增殖至关重要。人类DNA拓扑异构酶II α（hTopo II α）是一种很有前景的抗癌化疗靶点。本研究研究了穿心莲内酯及其结构修饰类似物对 hTopo II α 酶的抑制活性。九种穿心莲内酯类似物中有五种能有效降低 hTopo II α 的活性，并抑制四种哺乳动物细胞系（Hela、CHO、BCA-1 和 HepG2 细胞）的细胞增殖。类似物 3A.1、3A.2、3A.3、1B 和 2C 的细胞毒性 IC50 值为 4 至 7 μM。结构-活性关系研究表明，穿心莲内酯的核心结构和功能基团的硅基分子对抑制 hTopo II α 的活性非常重要，而类似物的 C-19 位则是抗增殖的必要条件。此外，类似物 2C 在 10 μM 浓度下可抑制 hTopo II α，并诱导 HepG2 细胞凋亡，使细胞核破碎并形成凋亡体。因此，类似物 2C 可能具有治疗潜力，可作为针对 hTopo II α 功能的有效抗癌剂。
• New substituted C-19-andrographolide analogues with potent cytotoxic activities
  作者：Uthaiwan Sirion、Sakkasem Kasemsook、Kanoknetr Suksen、Pawinee Piyachaturawat、Apichart Suksamrarn、Rungnapha Saeeng

  DOI：10.1016/j.bmcl.2011.11.085

  日期：2012.1

  structure–activity relationships (SARs) of 19 andrographolide analogues which were synthesized by modification at the three hydroxyl groups. A number of the andrographolide analogues showed much higher cytotoxic activities than that of the parent compound on cancer cells including P-388, KB, COL-2, MCF-7, LU-1 and ASK cells. SAR studies of the synthetic analogues indicated that the introduction of silyl ether or

  穿心莲内酯是穿心莲的主要二萜类内酯，对癌细胞有毒性。在本研究中，我们研究了19种穿心莲内酯类似物的结构-活性关系（SAR），它们通过在三个羟基上的修饰合成。许多穿心莲内酯类似物对癌细胞的细胞毒性活性比母体化合物高得多，包括P-388，KB，COL-2，MCF-7，LU-1和ASK细胞。合成类似物的SAR研究表明，将甲硅烷基醚或三苯基甲基醚基团引入母体化合物的C-19中会导致对癌细胞的毒性增加。19- O-三苯甲基醚类似物18 与有效的抗癌药玫瑰树碱相比，它显示出更高的细胞毒活性，该类似物可能是潜在的潜在结构导致开发新的抗癌药。
• Andrographolide derivative as STAT3 inhibitor that protects acute liver damage in mice
  作者：Shao-Ru Chen、Feng Li、Mo-Yu Ding、Decai Wang、Qi Zhao、Yitao Wang、Guo-Chun Zhou、Ying Wang

  DOI：10.1016/j.bmc.2018.09.002

  日期：2018.10

  Sustained activation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway contributed to the progression of cancer and liver diseases. STAT3 signaling inhibitor has been extensively investigated for pharmacological use. We synthesized a series of andrographolide derivatives, and characterized their activity against STAT3 signaling pathway both in vitro and in the CCl4-induced acute liver damage mice model. Among these derivatives, compound 24 effectively inhibited phosphorylation and dimerization of STAT3 but not its DNA binding activity. Compound 24 significantly ameliorated carbon tetrachloride-induced acute liver damage in vivo without changing mice body weight. Treatment with 24 attenuated hepatic pathologic damage and promoted hepatic proliferation and activation of STAT3. Compound 24 inhibited elevated expression of alpha-smooth muscle actin and serum pro-inflammatory cytokines downstream of STAT3 but not those factors that are regulated by NF-kappa B or SMADs. In summary, our results suggest that compound 24 may serve as a potential therapeutic agent for the treatment of hepatic damage or a liver protection agent via regulating STAT3 activation.
• Synthesis and cytotoxic activity of new 7-acetoxy-12-amino-14-deoxy andrographolide analogues
  作者：Rada Bunthawong、Uthaiwan Sirion、Arthit Chairoungdua、Kanoknetr Suksen、Pawinee Piyachaturawat、Apichart Suksamrarn、Rungnapha Saeeng

  DOI：10.1016/j.bmcl.2020.127741

  日期：2021.2

  19-silylether- and 19-formyl-7-acetyl-12-amino-14-deoxyandrographolide analogues were designed and synthesized from natural andrographolide via key step reactions including allylic hydroxylation, tandem CAE reaction and one pot formylation. Evaluation of their cytotoxicity against eight cancer cells line found 6e exhibited the highest activity on MCF-7 cancer cell (IC50 2.93) and comparable to the drug elipticin

  从天然穿心莲内酯通过关键步骤反应，包括烯丙基羟基化，串联CAE反应和一锅甲酰化反应，设计并合成了两个新系列的19-甲硅烷基醚-和19-甲酰基-7-乙酰基-12-氨基-14-脱氧穿心莲内酯类似物。评估其对八种癌细胞系的细胞毒性后发现6e对MCF-7癌细胞表现出最高活性（IC 502.93），与药物eticticin相当。在C-19处用甲酰基取代甲硅烷基醚对P-388细胞系表现出选择性活性。计算研究表明，C-12处的氨基和C-7处的O-乙酰氧基在针对MCF-7癌细胞的细胞毒性中起重要作用。这两个系列的细胞毒性突出了12-取代的14-脱氧穿心莲内酯支架的重要性，并且这些类型的化合物可用于抗乳腺癌的未来发展中。