1,5-二羟基-2,2,5,7-四甲基螺[1H-茚-6,1'-环丙烷]-4-酮 | 1146-04-9

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 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
• 中文名称: 1,5-二羟基-2,2,5,7-四甲基螺[1H-茚-6,1'-环丙烷]-4-酮
• 中文别名: 隐陡头菌素M
• 英文名称: illudin M
• 英文别名: (1S,5R)-1,5-dihydroxy-2,2,5,7-tetramethylspiro[1H-indene-6,1'-cyclopropane]-4-one
• CAS: 1146-04-9
• 化学式: C₁₅H₂₀O₃
• 分子量: 248.322
• InChiKey: QVMDIQLUNODCTG-OCCSQVGLSA-N

物化性质

• 熔点：
  120-122.5° (Matsumoto); mp 128-130° (McMorris)
• 沸点：
  452.4±45.0 °C(Predicted)
• 密度：
  1.24±0.1 g/cm3(Predicted)
• 溶解度：
  DMF：可溶； DMSO：可溶；乙醇：可溶；甲醇：可溶

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  18
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  57.5
• 氢给体数：
  2
• 氢受体数：
  3

制备方法与用途

生物活性

Illudin M 是一种细胞毒性真菌倍半萜，可以从 O. olearius 蘑菇培养基中分离得到。它能够使 DNA 烷基化，并具有抗肿瘤活性。

体外研究

在体外实验中，Illudin M 在浓度为 0.01-10 μM 的范围内（24-120 小时）表现出细胞毒性并诱导凋亡。具体结果显示如下：

细胞系	浓度	培养时间	结果
胰腺癌 PANC-1	0.01 μM, 1 μM, 10 μM	24 小时、48 小时、72 小时、96 小时、120 小时	在肿瘤细胞中诱导凋亡（PANC-1 中为 86%；HT-29 中为 48%），但在正常人类皮肤成纤维细胞 (HFs) 中诱导的凋亡更为显著（89%）

这些结果表明 Illudin M 对多种癌细胞表现出较高的选择性和有效性。

反应信息

• 作为反应物：
  描述：

  1,5-二羟基-2,2,5,7-四甲基螺[1H-茚-6,1'-环丙烷]-4-酮 在 重铬酸吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 20.0h， 以140 mg的产率得到(6R)-6'-羟基-2',2',4',6'-四甲基-螺[环丙烷-1,5'-[5H]茚]-3',7'(2'H,6'H)-二酮
  参考文献：
  名称：

  Structure-activity relationships of illudins: analogs with improved therapeutic index.

  摘要：

  Illudin S and M are extremely toxic sesquiterpenes produced by Omphalotus illudens. At low pH they behave as bifunctional alkylating agents, but at physiological pH they do not react with oxygen or nitrogen nucleophiles. Illudins react spontaneously with sulfur nucleophiles, glutathione or cysteine, at or slightly below pH 7, and toxicity to HL 60 cells can be modulated by altering glutathione levels in cells. Analogs of illudin M, e.g. the deoxy and, particularly, the dehydro derivatives, are less reactive to thiols and correspondingly less toxic to HL 60 cells than the parent compound. Dehydroilludin M has been found to be quite effective at inhibiting tumor growth in vivo at doses well tolerated by athymic nude mice.

  DOI：

  10.1021/jo00051a037
• 作为产物：
  描述：

  sodium acetate 、 alkaline earth salt of/the/ methylsulfuric acid 在 Omphalotus illudens strain 4435 作用下， 以 乙醇 、 水 为溶剂， 反应 504.0h， 以30 mg的产率得到隐陡头菌素; 隐杯伞素; 月亮霉素
  参考文献：
  名称：

  Synthesis of [3H]-illudin S, [3H]-acylfulvene, [3H] & [14C]-hydroxymethylacylfulvene (MGI 114)

  摘要：

  Tritiated derivatives of the toxic sesquiterpene illudin S (1) have been prepared by fermentation of Omphalotus illudens in the presence of [H-3]-sodium acetate. [H-3]-illudin S was converted to antitumor [H-3]-acylfulvene (4) by treatment with dilute sulfuric acid. Antitumor [C-14]-hydroxymethylacylfulvene (5) was best prepared by reacting acylfulvene with [C-14]-paraformaldehyde in dilute sulfuric acid.

  DOI：

  10.1002/(sici)1099-1344(199804)41:4<279::aid-jlcr86>3.0.co;2-j

文献信息

• AFFINITY ILLUDOFULVENE CONJUGATES
  申请人：AF Chemicals, LLC,

  公开号：US20210155583A1

  公开（公告）日：2021-05-27

  In an embodiment of the invention, a composition for treating a cell population comprises a medicant. The medicant moiety can be an illudofulvene analog. In an embodiment of the invention, a composition for treating a cell population comprises an Affinity Medicant Conjugate (AMC). The affinity moiety can be an antibody, an antibody fragment, a receptor protein, a peptidic growth factor, an anti-angiogenic protein, a specific binding peptide, protease cleavable peptide, a glycopeptide, a peptide, a peptidic toxin, a protein toxin and an oligonucleotide. The affinity moiety can be covalently bound to the medicant via a linker.

  在该发明实施例中，用于治疗细胞群的组合物包括一种药物。该药物部分可以是伊卢多富烯类似物。在该发明实施例中，用于治疗细胞群的组合物包括亲和药物结合物（AMC）。亲和部分可以是抗体、抗体片段、受体蛋白、肽生长因子、抗血管生成蛋白、特异结合肽、蛋白酶可切割肽、糖肽、肽、肽毒素、蛋白毒素和寡核苷酸。亲和部分可以通过连接剂与药物共价结合。
• [EN] SELECTIVE PHOSPHATASE INHIBITORS BASED ON ILLUDALIC ACID<br/>[FR] INHIBITEURS SÉLECTIFS DE PHOSPHATASE À BASE DE L'ACIDE ILLUDALIQUE
  申请人：WEST VIRGINIA UNIV BOARD OF GOVERNORS ON BEHALF OF WEST VIRGINIA UNIV

  公开号：WO2022026717A1

  公开（公告）日：2022-02-03

  The present disclosure provides novel selective phosphatase inhibitor compounds based on illudalic acid. The present disclosure provides a streamlined method of synthesizing illudalic acid and a method for synthesizing phosphatase inhibitor compounds. The method of this invention provides convergent benzannulation of β-keto amides and esters, followed by a one-pot reduction / hydrolysis sequence. The concise synthetic approach provided by this invention enables rapid assembly of illudalog compounds of this invention that are potent protein tyrosine phosphatase receptor-type D (PTPRD) inhibitors.

  本公开提供基于伊卢达酸的新型选择性磷酸酶抑制剂化合物。本公开提供了一种简化的合成伊卢达酸的方法和一种合成磷酸酶抑制剂化合物的方法。本发明的方法提供了β-酮酰胺和酯的汇合苯环化，随后进行一锅法还原/水解序列。本发明提供的简洁合成方法使得能够快速组装本发明的伊卢达酸化合物，这些化合物是有效的蛋白酪氨酸磷酸酶受体D型（PTPRD）抑制剂。
• Conjugates of the fungal cytotoxin illudin M with improved tumour specificity
  作者：Rainer Schobert、Bernhard Biersack、Sebastian Knauer、Matthias Ocker

  DOI：10.1016/j.bmc.2008.08.015

  日期：2008.9

  A simplified procedure for the isolation of gram quantities of illudin M from culture broths of basidiomycete Omphalotus olearius is described. Esters of illudin M with docosahexaenoic acid, chlorambucil, demethylcantharidinic acid (endothall) and 2,2'-bipyridyl-5,5'-dicarboxylic acid were synthesised and tested for cytotoxicity and induction of apoptosis in two clinically relevant tumour cell lines

  描述了一种从巴斯德油菌Omphalotus olearius的培养液中分离出克量的illudin M的简化程序。合成了含有二十二碳六烯酸，苯丁酸氮芥，去甲基邻苯二甲din啶酸（endothall）和2,2'-联吡啶基-5,5'-二羧酸的illudin M酯，并测试了两种临床相关肿瘤细胞系（Panc- 1胰腺癌和HT-29结肠癌）和非恶性人包皮成纤维细胞。脱甲基cantharidin和联吡啶共轭物保留了母体illudin M的细胞毒性，同时对成纤维细胞的肿瘤细胞显示出更高的特异性。
• A Chemical Proteomic Analysis of Illudin‐Interacting Proteins
  作者：Philipp Le、Matthew B. Nodwell、Jürgen Eirich、Stephan A. Sieber

  DOI：10.1002/chem.201902919

  日期：2019.9.25

  binding to protein sites in a cellular context. To reveal putative protein targets of the illudin family in live cancer cells, we employed a semisynthetic strategy to access a series of illudin-based probes for activity-based protein profiling (ABPP). While the probes largely retained potent cytotoxicity, proteomic profiling studies unraveled multiple protein hits, suggesting that illudins exert their

  illudin天然产物家族是具有特征性螺环丙基取代的稠合6,5-双环系统的真菌次级代谢产物。已经对其在各种肿瘤细胞类型中的细胞毒性进行了广泛的研究，具有改善的治疗特性的半合成衍生物已进入临床试验。尽管人们认为这种有效的烷基化化合物主要通过DNA修饰起作用，但在细胞中与蛋白质位点的结合却知之甚少。为了揭示活癌细胞中illudin家族的推定蛋白质靶标，我们采用半合成策略来访问一系列基于illudin的探针，用于基于活性的蛋白质谱分析（ABPP）。尽管这些探针在很大程度上保留了强力的细胞毒性作用，但蛋白质组学分析研究揭示了多种蛋白质命中情况，
• Secondary mould metabolites. Part 59. Sesquiterpene illudanes: semi-synthesis of new illudins, structures and biological activity
  作者：Alberto Arnone、Lucio Merlini、Gianluca Nasini、Orso Vajna de Pava、Franco Zunino

  DOI：10.1039/b007633n

  日期：——

  their unacceptable toxicity natural illudins are of limited interest as antitumor agents. In an attempt to exploit their cytotoxic potential several derivatives have been synthesized to obtain compounds with an improved therapeutic index. In this paper we describe some alkylation and oxidation reactions giving rise in some cases to less cytotoxic derivatives. Structures and relative stereochemistries have

  由于其天然毒性，天然伊兰度作为其抗肿瘤剂的兴趣有限。为了开发其细胞毒性潜力，已经合成了几种衍生物以获得具有改善的治疗指数的化合物。在本文中，我们描述了一些烷基化和氧化反应在某些情况下会产生较少的细胞毒性衍生物。结构和相对立体化学是根据1 H和13 C NMR证据。所有化合物的细胞毒性均不如illudin M和S，但仍具有很高的活性。