13-hydroxyl-15-hydroxyl-ent-kaurene-19-oic acid | 1235561-65-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: 13-hydroxyl-15-hydroxyl-ent-kaurene-19-oic acid
• 英文别名: ent-13,15-dihydroxykaurene-19-acid；(1R,4S,5R,9S,10S,13S)-13,15-dihydroxy-5,9-dimethyl-14-methylidenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylic acid
• CAS: 1235561-65-5
• 化学式: C₂₀H₃₀O₄
• 分子量: 334.456
• InChiKey: MUUCXUURBKGVOZ-WIQRNHHTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  77.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  13-hydroxyl-15-hydroxyl-ent-kaurene-19-oic acid 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 生成 2-(4-methylpiperazin-1-yl)ethyl (1R,4S,5R,9S,10S,13S)-13,15-dihydroxy-5,9-dimethyl-14-methylidenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate
  参考文献：
  名称：

  ent-Kaurane Diterpenoids from Chinese Liverworts and Their Antitumor Activities through Michael Addition As Detected in Situ by a Fluorescence Probe

  摘要：

  It is generally accepted that the origin of the cytotoxicity of ent-kaurane diterpenoids is due to the formation of reactive oxygen species (ROS) and that the alpha,beta-unsaturated carbonyl is a pivotal moiety. Herein we demonstrate the isolation of 32 new and 12 known ent-kaurane diterpenoids from two Chinese liverworts. These compounds and three semisynthesized derivatives were screened against human cancer cell lines. The results revealed that their anticancer activities are caused by ROS formation through Michael modification of the protein thiols and depletion of glutathione unselectively. We also found that N-acetylcysteine reverses the cytotoxicity of these diterpenoids by forming Michael adducts, not through a well-recognized ROS scavenging pathway as previously reported. In situ intracellular thiol detection helped us visualize the intracellular distribution of the diterpenoids and determine the potency of their cytotoxicity. An alkaline analogue was found to be more selective because of the altered subcellular distribution.

  DOI：

  10.1021/acs.jmedchem.5b00208
• 作为产物：
  描述：

  甜叶菊甙元 在 叔丁基过氧化氢 、 selenium(IV) oxide 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 以52%的产率得到13-hydroxyl-15-hydroxyl-ent-kaurene-19-oic acid
  参考文献：
  名称：

  通过抑制铁死亡预防心肌病的新型甜菊醇衍生物的合成及体内评价

  摘要：

  心血管疾病 (CVD) 仍然是全球死亡的主要原因。抑制铁死亡从而预防心肌细胞死亡是预防和治疗心肌病的一种有前途且有效的策略。甜菊醇是一种对-贝壳杉烯二萜类化合物，具有广谱生物活性。在本研究中，为了发现治疗心血管疾病的新药物，合成了 30 种甜菊醇衍生物，包括 22 种新衍生物，并使用多柔比星 (DOX) 诱导的斑马鱼心肌病模型评估了它们的体内保护活性。我们的结果首先表明甜菊醇具有良好的心脏保护活性，进一步修饰甜菊醇可以大大提高活性。在新的衍生品中，16d和16e显示最有效的活动。16d (1 μM) 和16e (0.1 μM)均可有效维持斑马鱼的正常心脏形状并防止 DOX 损害的心脏功能障碍。其疗效远优于母体天然产物甜菊醇和阳性药物左西孟旦。进一步的研究表明，16d和16e通过抑制谷胱甘肽消耗、铁积累和脂质过氧化，减少活性氧过度积累，恢复线粒体膜电位，从而抑制 DOX 诱导的铁死亡，从而保

  DOI：

  10.1016/j.bioorg.2022.106142

文献信息

• Synthesis and Biological Evaluation of Steviol Derivatives with Improved Cytotoxic Activity and Selectivity
  作者：Jian-Song Liu、Li-Ping Luo、Geng Xu、Xiao-Jia Xu、Chao Xu、E Ou、Han-Yuan Zhang、Zheng-Qiang Yuan、Yu Zhao

  DOI：10.1021/acs.jnatprod.2c00161

  日期：2022.8.26

  with interesting pharmacological activity. Several steviol derivatives with an exo-methylene cyclopentanone unit were discovered as potent antitumor agents. However, their poor selectivity for tumor cells relative to normal cells reduces their prospects as potential anticancer drugs. In this study, based on previous work, 32 steviol derivatives, including 28 new analogues, were synthesized. Their cytotoxicity

  甜菊醇是一种具有有趣药理活性的ent -kaurene 二萜类化合物。发现了几种具有外-亚甲基环戊酮单元的甜菊醇衍生物作为有效的抗肿瘤剂。然而，相对于正常细胞，它们对肿瘤细胞的低选择性降低了它们作为潜在抗癌药物的前景。在本研究中，在前人工作的基础上，合成了 32 种甜菊醇衍生物，包括 28 种新的类似物。评估了它们对肿瘤细胞和正常细胞的细胞毒性。几个新的衍生物，例如7a、7h和8f，获得了改善的细胞毒选择性和抗增殖活性，并研究了构效关系的相关性。新化合物8f对 Huh7 细胞具有有效的抗增殖活性（IC 50 = 2.6 μM），对相应的正常细胞 HHL5 具有非常弱的细胞毒性（IC 50 = 97.0 μM）。进一步研究表明，8f通过抑制 PI3K/Akt/mTOR 和 NF-κB 通路以及抑制 PI3K/Akt/mTOR 和 NF-κB 通路，使细胞周期停滞在 G0/G1 期并导致活性氧过度产生，降低线粒体膜电位，并诱导
• Benzamidine Conjugation Converts Expelled Potential Active Agents into Antifungals against Drug-Resistant Fungi
  作者：Xue Wang、Xueyang Jin、Zhiyu Xie、Hongyang Zhang、Tiantian Liu、Hongbo Zheng、Xiaoyi Luan、Yan Sun、Wenjie Fang、Wenqiang Chang、Hongxiang Lou

  DOI：10.1021/acs.jmedchem.3c01068

  日期：2023.10.12

  Herein, we identified 68 EPAAs out of 2322 candidates with activity against a Candida albicans efflux pump-deficient strain and no inhibitory activity against the wild-type strain. Using a novel conjugation strategy involving benzamidine (BM) as a mitochondrion-targeting warhead, we successfully converted EPAAs into potent antifungals against various urgent-threat azole-resistantCandida strains. Among the

  真菌感染日益成为全球公共卫生问题，因此需要开发新型抗真菌药物。然而，许多潜在的抗真菌药物，特别是排出的潜在活性剂（EPAAs），由于其在细胞进入或外排泵排出方面的限制，常常被低估。在此，我们从 2322 个候选者中鉴定出 68 个 EPAAs 对白色念珠菌外排泵缺陷菌株具有活性，但对野生型菌株没有抑制活性。使用苯甲脒（BM）作为线粒体靶向弹头的新型结合策略，我们成功地将 EPAA 转化为有效的抗真菌剂，对抗各种紧急威胁的唑类抗性念珠菌菌株。在获得的EPAA-BM缀合物中，IS-2-BM (11)表现出优异的抗真菌活性，并且诱导的耐药性可以忽略不计。此外，IS-2-BM可防止生物膜形成，根除成熟生物膜，并在全身性念珠菌病小鼠模型中表现出优异的治疗效果。这些发现为增加发现更多抗真菌药物的可能性提供了一种有前景的策略。
• Synthesis and biological evaluation of novel exo-methylene cyclopentanone tetracyclic diterpenoids as antitumor agents
  作者：Jing Li、Dayong Zhang、Xiaoming Wu

  DOI：10.1016/j.bmcl.2010.11.055

  日期：2011.1

  The structure of exo-methylene cyclopentanone, which exists in nature tetracyclic diterpenoids products, has been proved to be an innate group for the treatment of cancer and inflammation. In this letter, four different scaffolds of tetracyclic diterpenoids including the structure exo-methylene cyclopentanone were synthesized from steviol and isosteviol and evaluated in vitro for their antitumor activity against three human cancer lines. Compounds 1a, 1b, 2b and 3b showed significant cytotoxicity, particularly, tetracyclic diterpenoids 2b, 3b were identified as the most potent and selective anticancer agents superior to adriamycin with IC50 values of 0.9 mu M and 1.5 mu M, against Hep-G2 and MDA-MB-231 cell lines, respectively. (C) 2010 Elsevier Ltd. All rights reserved.
• <i>ent</i>-Kaurane Diterpenoids from Chinese Liverworts and Their Antitumor Activities through Michael Addition As Detected in Situ by a Fluorescence Probe
  作者：Zhaomin Lin、Yanxia Guo、Yanhui Gao、Shuqi Wang、Xiaoning Wang、Zhiyu Xie、Huanmin Niu、Wenqiang Chang、Lei Liu、Huiqing Yuan、Hongxiang Lou

  DOI：10.1021/acs.jmedchem.5b00208

  日期：2015.5.14

  It is generally accepted that the origin of the cytotoxicity of ent-kaurane diterpenoids is due to the formation of reactive oxygen species (ROS) and that the alpha,beta-unsaturated carbonyl is a pivotal moiety. Herein we demonstrate the isolation of 32 new and 12 known ent-kaurane diterpenoids from two Chinese liverworts. These compounds and three semisynthesized derivatives were screened against human cancer cell lines. The results revealed that their anticancer activities are caused by ROS formation through Michael modification of the protein thiols and depletion of glutathione unselectively. We also found that N-acetylcysteine reverses the cytotoxicity of these diterpenoids by forming Michael adducts, not through a well-recognized ROS scavenging pathway as previously reported. In situ intracellular thiol detection helped us visualize the intracellular distribution of the diterpenoids and determine the potency of their cytotoxicity. An alkaline analogue was found to be more selective because of the altered subcellular distribution.
• Synthesis and in vivo evaluation of new steviol derivatives that protect against cardiomyopathy by inhibiting ferroptosis
  作者：Chao Xu、E Ou、Zhiyin Li、Zhenyu Chen、Qi Jia、Xiaojia Xu、Liping Luo、Geng Xu、Jiansong Liu、Zhengqiang Yuan、Yu Zhao

  DOI：10.1016/j.bioorg.2022.106142

  日期：2022.12

  discover new agents for CVDs treatment, 30 derivatives of steviol, including 22 new ones, were synthesized, and evaluated their protective activity in vivo using the doxorubicin (DOX) induced zebrafish cardiomyopathy model. Our results firstly demonstrated that steviol has promising cardioprotective activity and further modification of steviol can greatly improve the activity. Among the new derivatives

  心血管疾病 (CVD) 仍然是全球死亡的主要原因。抑制铁死亡从而预防心肌细胞死亡是预防和治疗心肌病的一种有前途且有效的策略。甜菊醇是一种对-贝壳杉烯二萜类化合物，具有广谱生物活性。在本研究中，为了发现治疗心血管疾病的新药物，合成了 30 种甜菊醇衍生物，包括 22 种新衍生物，并使用多柔比星 (DOX) 诱导的斑马鱼心肌病模型评估了它们的体内保护活性。我们的结果首先表明甜菊醇具有良好的心脏保护活性，进一步修饰甜菊醇可以大大提高活性。在新的衍生品中，16d和16e显示最有效的活动。16d (1 μM) 和16e (0.1 μM)均可有效维持斑马鱼的正常心脏形状并防止 DOX 损害的心脏功能障碍。其疗效远优于母体天然产物甜菊醇和阳性药物左西孟旦。进一步的研究表明，16d和16e通过抑制谷胱甘肽消耗、铁积累和脂质过氧化，减少活性氧过度积累，恢复线粒体膜电位，从而抑制 DOX 诱导的铁死亡，从而保