5'-羟基-2',5',7'-三甲基螺[环丙烷-1,6'-茚]-4'-酮 | 125392-76-9

• 物质功能分类: 有机原料 - 酮类化合物
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 5'-羟基-2',5',7'-三甲基螺[环丙烷-1,6'-茚]-4'-酮
• 英文名称: (-)-acylfulvene
• 英文别名: Acylfulvene；(5'R)-5'-hydroxy-2',5',7'-trimethylspiro[cyclopropane-1,6'-indene]-4'-one
• CAS: 125392-76-9
• 化学式: C₁₄H₁₆O₂
• 分子量: 216.28
• InChiKey: HLAKJNQXUARACO-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5'-羟基-2',5',7'-三甲基螺[环丙烷-1,6'-茚]-4'-酮 在 吡啶 、 硼氘化钠 作用下， 以23%的产率得到(4'S,6'R)-4'-deutero-6'-hydroxy-2',4',6'-trimethyl-4',6'-dihydrospiro[cyclopropane-1,5'-inden]-7'(1'H)-one
  参考文献：
  名称：

  Chemical and Enzymatic Reductive Activation of Acylfulvene to Isomeric Cytotoxic Reactive Intermediates

  摘要：

  Acylfulvenes (AFs), a class of semisynthetic analogues of the sesquiterpene natural product illudin S, are cytotoxic toward cancer cells. The minor structural changes between illudin S and AFs translate to an improved therapeutic window in preclinical cell-based assays and xenograft models. AFs are, therefore, unique tools for addressing the chemical and biochemical basis of cytotoxic selectivity. AFs elicit cytotoxic responses by alkylation of biological targets, including DNA. While AFs are capable of direct alkylation, cytosolic reductive bioactivation to an electrophilic intermediate is correlated with enhanced cytotoxicity. Data obtained in this study illustrate chemical aspects of the process of AF activation. By tracking reaction mechanisms with stable isotope-labeled reagents, enzymatic versus chemical activation pathways for AF were compared for reactions involving the NADPH-dependent enzyme prostaglandin reductase 1 (PTGR1) or sodium borohydride, respectively. These two processes resulted in isomeric products that appear to give rise to similar patterns of DNA modification. The chemically activated isomer has been newly isolated and chemically characterized in this study, including an assessment of its relative stereochemistry and stability at varying pH and under bioassay conditions. In mammalian cancer cells, this chemically activated analogue was shown to not rely on further cellular activation to significantly enhance cytotoxic potency, in contrast to the requirements of AF. On the basis of this study, we anticipate that the chemically activated form of AF will serve as a useful chemical probe for evaluating biomolecular interactions independent of enzyme-mediated activation.

  DOI：

  10.1021/tx200401u
• 作为产物：
  描述：

  (4R,5R)-2,5,7-trimethylspiro[4H-indene-6,1'-cyclopropane]-4,5-diol 在 2-碘酰基苯甲酸 作用下， 以 二甲基亚砜 为溶剂， 反应 2.0h， 以98%的产率得到5'-羟基-2',5',7'-三甲基螺[环丙烷-1,6'-茚]-4'-酮
  参考文献：
  名称：

  [EN] ILLUDIN ANALOGS, USES THEREOF, AND METHODS FOR SYNTHESIZING THE SAME
  [FR] ANALOGUES D'ILLUDINE, UTILISATIONS ASSOCIÉES ET LEURS PROCÉDÉS DE SYNTHÈSE

  摘要：

  本发明提供了伊卢丁衍生物、中间体、制备方法、药物组合物及其用途。具体例子包括制备伊卢丁衍生物的新型合成途径和具有治疗价值的正旋光伊卢丁衍生物。

  公开号：

  WO2020051222A1

文献信息

• Enantioselective Total Synthesis of (−)-Acylfulvene and (−)-Irofulven
  作者：Dustin S. Siegel、Grazia Piizzi、Giovanni Piersanti、Mohammad Movassaghi

  DOI：10.1021/jo901926z

  日期：2009.12.18

  We report our full account of the enantioselective total synthesis of (−)-acylfulvene (1) and (−)-irofulven (2), which features metathesis reactions for the rapid assembly of the molecular framework of these antitumor agents. We discuss (1) the application of an Evans Cu-catalyzed aldol addition reaction using a strained cyclopropyl ketenethioacetal, (2) an efficient enyne ring-closing metathesis cascade

  我们报告了对 (-)-acylfulvene ( 1 ) 和 (-)-irofulven ( 2 )的对映选择性全合成的完整描述，其特征是复分解反应，用于快速组装这些抗肿瘤药物的分子框架。我们讨论了 (1) 使用应变环丙基烯酮硫缩醛的 Evans Cu 催化羟醛加成反应的应用，(2) 在具有挑战性的环境中有效的烯炔闭环复分解级联反应，(3) 用于后期阶段的试剂 IPNBSH还原烯丙基转座反应，和（4）的形成最终RCM /脱氢序列（ - ） - acylfulvene（1）和（ - ） - irofulven（2）。
• 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。
• Metabolism of antitumor acylfulvene by rat liver cytosol
  作者：Trevor C. McMorris、Anissa N. Elayadi、Jian Yu、Michael J. Kelner

  DOI：10.1016/s0006-2952(98)00273-1

  日期：1999.1

  NADPH and rat liver cytosol yielded two metabolites. One metabolite, the aromatic product, is similar to that obtained with illudin S in this in vitro system and was anticipated. The other metabolite, the hydroxylated product, was not expected and no corresponding metabolite for illudin S could be detected. The production of this hydroxylated metabolite from acylfulvene may explain, in part, the increased

  伊路菌素是新颖的化合物，从中合成了有效的一类抗肿瘤药，称为酰基富烯。illudin模型illudin S具有明显的体外和体内毒性，但治疗指数较差。人们认为，illudin S的毒性涉及酶促还原和化学反应的结合。胞质NADPH依赖性酶的酶促还原产生芳族代谢产物，与硫醇的反应也是如此。酰基富勒烯是由illudin S通过反向Prins反应形成的。酰基富烯在体外和体内的毒性比illudin S低100倍，但在体内具有明显的抗肿瘤功效，因此与illudin S表现出相反的性质。因此，我们研究了酰基富烯的体外代谢。用NADPH和大鼠肝细胞液孵育酰基富烯产生两种代谢物。一种代谢产物，即芳香族产物，与在体外系统中用illudin S所获得的类似。预计不会出现另一种代谢产物，即羟基化产物，并且无法检测到与伊洛定S相应的代谢产物。由酰基富烯产生的这种羟基化代谢产物可能部分解释了与illudins相比，新型酰基富烯具有更高的抗肿瘤活性。
• Synthesis and Biological Activity of Enantiomers of Antitumor Irofulven
  作者：Trevor C. McMorris、Michael D. Staake、Michael J. Kelner

  DOI：10.1021/jo035084j

  日期：2004.2.1

  Stereoselective synthesis of (−)-irofulven has been achieved by cycloaddition of (R)-5-chloro-5-methyl-2-cyclopentenone to the 1,3-dipolar intermediate from 1-acetyl-1-(diazoacetyl)cyclopropane. The enantiomer, (+)-irofulven, was prepared in a similar way starting with (S)-5-chloro-5-methyl-2-cyclopentenone. (+)-Irofulven was 5 to 6 times less toxic than (−)-irofulven to adenocarcinoma (MV 522) cells

  通过将（R）-5-氯-5-甲基-2-环戊烯酮环加成到1-乙酰基-1-（重氮乙酰基）环丙烷的1,3-偶极中间体中，已经实现了（-）-碘富勒烯的立体选择性合成。以（S）-5-氯-5-甲基-2-环戊烯酮为起始原料，以类似的方式制备对映体（+）-碘伏富烯。（+）-艾洛富尔文对腺癌（MV 522）细胞的毒性比（-）-艾洛富尔文低5至6倍。
• Acylfulvenes, a new class of potent antitumor agents
  作者：T. C. McMorris、M. J. Kelner、W. Wang、M. A. Diaz、L. A. Estes、R. Taetle

  DOI：10.1007/bf01922420

  日期：1996.1

  Acylfulvene, derived from the sesquiterpene illudin S by treatment with acid (reverse Prins reaction), is far less reactive to thiols than illudin S. However, it is reduced readily to an aromatic product, in the same way as illudin S. This may explain its greatly improved therapeutic index compared to that of the parent compound.

  酰基富烯通过倍半萜烯伊洛丁S酸经酸处理（反向Prins反应）得到，其对硫醇的反应性远低于伊洛丁S。但是，与伊洛丁S相同，它容易还原为芳香族产品。这可能解释了与母体化合物相比，其治疗指数大大提高。