ilicicolin H | 12689-26-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: ilicicolin H
• 英文别名: 3-[(1R,2S,4aS,7S,8aR)-4,7-dimethyl-1-[(E)-prop-1-enyl]-1,2,4a,5,6,7,8,8a-octahydronaphthalene-2-carbonyl]-4-hydroxy-5-(4-hydroxyphenyl)-1H-pyridin-2-one
• CAS: 12689-26-8
• 化学式: C₂₇H₃₁NO₄
• 分子量: 433.547
• InChiKey: BYVVOONSAAQMKI-RFKCMYLBSA-N

物化性质

• 沸点：
  630.1±55.0 °C(Predicted)
• 密度：
  1.231±0.06 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  86.6
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ilicicolin H 在 肼 作用下， 以 甲醇 为溶剂， 以80%的产率得到3-{[(1R,2S,4aS,7S,8aR)-4,7-Dimethyl-1-((E)-propenyl)-1,2,4a,5,6,7,8,8a-octahydro-naphthalen-2-yl]-hydrazono-methyl}-4-hydroxy-5-(4-hydroxy-phenyl)-1H-pyridin-2-one
  参考文献：
  名称：

  A new method for the synthesis of 1,4,5-oxadiazocines and its application in the structure modification of natural products

  摘要：

  A new method for the synthesis of eight-membered heterocyclic 1,4,5-oxadiazocines has been described from beta-diketone and beta,beta,beta-triketone with an acidic alpha-hydrogen. The method entails the reaction of a di- or triketone with 2-hydroxyethylhydrazine and an aldehyde in the presence of acetic acid providing respectable yield. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2005.09.069
• 作为产物：
  描述：

  在 recombinant epimerase IccE from Escherichiacoli BL₂₁ 、 recombinant pericyclase IccD from Escherichiacoli BL₂₁ 作用下， 以 aq. buffer 为溶剂， 反应 4.0h， 生成 ilicicolin H
  参考文献：
  名称：

  酶催化逆电子需求 Diels-Alder 反应在抗真菌 Ilicicolin H 的生物合成中

  摘要：

  周环素酶是一个不断增长的酶超家族，可催化​​周环反应。我们报告了在真菌天然产物 ilicicolin H 的生物合成中催化逆电子需求 Diels-Alder (IEDDA) 反应的 pericyclase IccD 反应，速率加速 3 × 105 倍。我们证明 IccD 对 IEDDA 环加成具有高度选择性来自双峰过渡态的竞争性正常电子需求 Diels-Alder (NEDDA) 反应。预测的黄素酶 IccE 被鉴定为将 IEDDA 产物 8-epi-ilicicolin H 差向异构化为 ilicicolin H，这一步骤对于观察到 ilicicolin H 的抗真菌活性至关重要。我们的结果揭示了 ilicicolin H 生物合成途径并添加到周环素的集合中由环环素酶催化的反应。

  DOI：

  10.1021/jacs.9b02204

文献信息

• Antifungal Spectrum, In Vivo Efficacy, and Structure–Activity Relationship of Ilicicolin H
  作者：Sheo B. Singh、Weiguo Liu、Xiaohua Li、Tom Chen、Ali Shafiee、Deborah Card、George Abruzzo、Amy Flattery、Charles Gill、John R. Thompson、Mark Rosenbach、Sarah Dreikorn、Viktor Hornak、Maria Meinz、Myra Kurtz、Rosemarie Kelly、Janet C. Onishi

  DOI：10.1021/ml300173e

  日期：2012.10.11

  exhibits potent and broad spectrum antifungal activity, with sub-mug/mL MICs against Candida spp., Aspergillus fumigatus, and Cryptococcus spp. It showed a novel mode of action, potent inhibition (IC50 = 2-3 ng/mL) of the mitochondrial cytochrome bc1 reductase, and over 1000-fold selectivity relative to rat liver cytochrome bc1 reductase. Ilicicolin H exhibited in vivo efficacy in murine models of Candida

  Ilicicolin H是一种从玫瑰胶质胶中分离得到的聚酮化合物-非核糖体肽合酶（NRPS）天然产物，具有有效的广谱抗真菌活性，对亚念珠菌，烟曲霉和隐球菌具有亚杯/ mL MICs。它显示了一种新颖的作用方式，即线粒体细胞色素bc1还原酶的有效抑制（IC50 = 2-3 ng / mL），相对于大鼠肝脏细胞色素bc1还原酶的选择性超过1000倍。Ilicicolin H在白色念珠菌和新型隐球菌感染的鼠模型中表现出体内功效，但功效可能受到血浆蛋白高度结合的限制。为了了解抗真菌活性的结构要求，对系统进行了ilicicolin H的结构修饰。讨论了伊利卡林H的生物活性和分子的一些关键部分的结构修饰以及衍生物的最终活性的细节。这些数据表明，β-酮基对于抗真菌活性至关重要。
• Heterologous Expression of Ilicicolin H Biosynthetic Gene Cluster and Production of a New Potent Antifungal Reagent, Ilicicolin J
  作者：Xiaojing Lin、Siwen Yuan、Senhua Chen、Bin Chen、Hui Xu、Lan Liu、Huixian Li、Zhizeng Gao

  DOI：10.3390/molecules24122267

  日期：——

  Ilicicolin H is a broad-spectrum antifungal agent targeting mitochondrial cytochrome bc1 reductase. Unfortunately, ilicicolin H shows reduced activities in vivo. Here, we report our effort on the identification of ilicicolin H biosynthetic gene cluster (BGC) by genomic sequencing a producing strain, Neonectria sp. DH2, and its heterologous production in Aspergillus nidulans. In addition, a shunt product with similar antifungal activities, ilicicolin J, was uncovered. This effort would provide a base for future combinatorial biosynthesis of ilicicolin H analogues. Bioinformatics analysis suggests that the backbone of ilicicolin H is assembled by a polyketide-nonribosomal peptide synthethase (IliA), and then offloaded with a tetramic acid moiety. Similar to tenellin biosynthesis, the tetramic acid is then converted to pyridone by a putative P450, IliC. The decalin portion is most possibly constructed by a S-adenosyl-l-methionine (SAM)-dependent Diels-Alderase (IliD).

  Ilicicolin H是一种广谱抗真菌药物，针对线粒体细胞色素bc1还原酶。不幸的是，Ilicicolin H在体内显示出降低的活性。在这里，我们通过对生产菌株Neonectria sp. DH2进行基因组测序和其在曲霉中的异源生产，报告了我们对Ilicicolin H生物合成基因簇（BGC）的鉴定。此外，发现了一种具有类似抗真菌活性的旁路产物Ilicicolin J。这一努力将为未来Ilicicolin H类似物的组合生物合成提供基础。生物信息学分析表明，Ilicicolin H的骨架是由聚酮-非核糖肽合成酶（IliA）组装而成，然后卸载四元酸基团。与tenellin生物合成类似，四元酸然后由一种假定的P450（IliC）转化为吡啶酮。蒎烯部分最可能由S-腺苷甲硫氨酸（SAM）依赖性Diels-Alderase（IliD）构建。
• 10.1016/j.tetlet.2024.155095
  作者：Li, Jilong、Mo, Zhen、Liu, Longchun、Tian, Shuai、Tang, Yu、Li, Dehai

  DOI：10.1016/j.tetlet.2024.155095

  日期：——

  A concise total synthesis of (-)-ilicicolin H was efficiently achieved in 9 steps from commercially available ()-(-)-citronellol. Key steps include a strategic convergent method to synthesize the densely substituted pyridone key intermediate by Suzuki-Miyaura cross-coupling reaction, a facile construction of polyene fragment through a regioselective Wittig olefination and construction of the decalin

  以市售 ()-(-)-香茅醇为原料，通过 9 个步骤高效地实现了 (-)-ilicicolin H 的简明全合成。关键步骤包括通过 Suzuki-Miyaura 交叉偶联反应合成密集取代的吡啶酮关键中间体的策略收敛方法、通过区域选择性 Wittig 烯化轻松构建多烯片段以及通过 IMDA 构建十氢萘部分。在此，我们描述了我们在合成 (-)-ililicicolin H 方面所做的努力。
• Structure–activity relationship of cytochrome bc1 reductase inhibitor broad spectrum antifungal ilicicolin H
  作者：Sheo B. Singh、Weiguo Liu、Xiaohua Li、Tom Chen、Ali Shafiee、Sarah Dreikorn、Viktor Hornak、Maria Meinz、Janet C. Onishi

  DOI：10.1016/j.bmcl.2013.03.023

  日期：2013.5

  Ilicicolin H is a broad spectrum antifungal agent showing sub micro g/mL MICs against Candida spp., Aspergillus fumigatus and Cryptococcus spp. It is a potent inhibitor (C-50 2-3 ng/mL) of the mitochondrial cytochrome bc1 reductase with over 1000-fold selectivity against rat liver cytochrome bc1 reductase. Structure-activity relationship of semisynthetic derivatives by chemical modification of ilicicolin H and its 19-hydroxy derivative produced by biotransformation have been described. Basic 4'-esters and moderately polar N- and O-alkyl derivatives retained antifungal and the cytochrome bc1 reductase activities. 4',19-Diacetate and 19-cyclopropyl acetate retained antifungal and enzyme activity and selectivity with over 20-fold improvement of plasma protein binding. (C) 2013 Elsevier Ltd. All rights reserved.
• A new method for the synthesis of 1,4,5-oxadiazocines and its application in the structure modification of natural products
  作者：Weiguo Liu、Ziqiang Guan、Sheo B. Singh

  DOI：10.1016/j.tetlet.2005.09.069

  日期：2005.11

  A new method for the synthesis of eight-membered heterocyclic 1,4,5-oxadiazocines has been described from beta-diketone and beta,beta,beta-triketone with an acidic alpha-hydrogen. The method entails the reaction of a di- or triketone with 2-hydroxyethylhydrazine and an aldehyde in the presence of acetic acid providing respectable yield. (c) 2005 Elsevier Ltd. All rights reserved.