8-hydroxy-2,2-dimethyl-3a-(3-methylbut-2-en-1-yl)-1,2-dihydro-1,5-methanofuro[2,3-d]xanthene-4,7(3aH,5H)-dione | 1301159-99-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 8-hydroxy-2,2-dimethyl-3a-(3-methylbut-2-en-1-yl)-1,2-dihydro-1,5-methanofuro[2,3-d]xanthene-4,7(3aH,5H)-dione
• 英文别名: 8-hydroxy-1-(3-methylbut-2-en-yl)-3,3-dimethyl-3,3a,4,5-tetrahydro-1,5-methano-1H,7H-furo[3,4-d]xanthene-7,13-dione；MAD28；(±)-MAD28；8-Hydroxy-17,17-dimethyl-15-(3-methylbut-2-enyl)-3,16-dioxapentacyclo[11.4.1.02,11.02,15.04,9]octadeca-4,6,8,11-tetraene-10,14-dione
• CAS: 1301159-99-8
• 化学式: C₂₃H₂₄O₅
• 分子量: 380.441
• InChiKey: XZPYBDPGHSLINX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-hydroxy-2,2-dimethyl-3a-(3-methylbut-2-en-1-yl)-1,2-dihydro-1,5-methanofuro[2,3-d]xanthene-4,7(3aH,5H)-dione 在 叔丁基过氧化氢 、 selenium(IV) oxide 、 水杨酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 36.0h， 以64%的产率得到(E)-8-hydroxy-1-(4-hydroxy-3-methylbut-2-en-1-yl)-3,3-dimethyl-3,3a,4,5-tetrahydro-1,5-methano-1H,7H-furo[3,4-d]xanthene-7,13-dione
  参考文献：
  名称：

  组合的组学方法将藤黄酸和相关的氧杂蒽酮确定为丝氨酸棕榈酰转移酶复合物的共价抑制剂。

  摘要：

  在这项研究中，我们将天然产物藤黄酸以及与结构相关的合成氧杂蒽酮确定为从头鞘脂生物合成的同类共价抑制剂。我们应用化学蛋白质组学来确定藤黄酸与丝氨酸棕榈酰转移酶复合物（SPTSSB）的调节小亚基B结合。然后，我们测试与结构相关的合成氧杂蒽酮，以鉴定18个与SPTSSB具有同等效力但更具选择性的结合剂，并显示18降低了原位和体内鞘脂的水平。最后，使用各种生物学方法，我们证明18诱导特征性鞘氨醇-1-磷酸（S1P）信号转导减少的细胞反应。这项研究表明，SPTSSB可能成为具有病理性S1P信号传导的各种疾病的可行治疗靶标。此外，

  DOI：

  10.1016/j.chembiol.2020.03.008
• 作为产物：
  描述：

  2,6-二甲氧基苯甲酸 在 aluminum (III) chloride 、 copper(l) iodide 、 氯化亚砜 、 palladium 10% on activated carbon 、 10 percent palladium on barium sulphate 、 氢溴酸 、 氢气 、 sodium hydride 、 potassium carbonate 、 溶剂黄146 、 potassium iodide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 49.08h， 生成 8-hydroxy-2,2-dimethyl-3a-(3-methylbut-2-en-1-yl)-1,2-dihydro-1,5-methanofuro[2,3-d]xanthene-4,7(3aH,5H)-dione
  参考文献：
  名称：

  组合的组学方法将藤黄酸和相关的氧杂蒽酮确定为丝氨酸棕榈酰转移酶复合物的共价抑制剂。

  摘要：

  在这项研究中，我们将天然产物藤黄酸以及与结构相关的合成氧杂蒽酮确定为从头鞘脂生物合成的同类共价抑制剂。我们应用化学蛋白质组学来确定藤黄酸与丝氨酸棕榈酰转移酶复合物（SPTSSB）的调节小亚基B结合。然后，我们测试与结构相关的合成氧杂蒽酮，以鉴定18个与SPTSSB具有同等效力但更具选择性的结合剂，并显示18降低了原位和体内鞘脂的水平。最后，使用各种生物学方法，我们证明18诱导特征性鞘氨醇-1-磷酸（S1P）信号转导减少的细胞反应。这项研究表明，SPTSSB可能成为具有病理性S1P信号传导的各种疾病的可行治疗靶标。此外，

  DOI：

  10.1016/j.chembiol.2020.03.008

文献信息

• A-ring oxygenation modulates the chemistry and bioactivity of caged Garcinia xanthones
  作者：Kristyna M. Elbel、Gianni Guizzunti、Maria A. Theodoraki、Jing Xu、Ayse Batova、Marianna Dakanali、Emmanuel A. Theodorakis

  DOI：10.1039/c3ob40395e

  日期：——

  Natural products of the caged Garcinia xanthones (CGX) family are characterized by a unique chemical structure, potent bioactivities and promising pharmacological profiles. We have developed a Claisen/Diels–Alder reaction cascade that, in combination with a Pd(0)-catalyzed reverse prenylation, provides rapid and efficient access to the CGX pharmacophore, represented by the structure of cluvenone. To further explore this pharmacophore, we have synthesized various A-ring oxygenated analogues of cluvenone and have evaluated their bioactivities in terms of growth inhibition, mitochondrial fragmentation, induction of mitochondrial-dependent cell death and Hsp90 client inhibition. We found that installation of an oxygen functionality at various positions of the A-ring influences significantly both the site-selectivity of the Claisen/Diels–Alder reaction and the bioactivity of these compounds, due to remote electronic effects.

  被笼罩的伽马林黄酮(CGX)家族的天然产物具有独特的化学结构、强大的生物活性和良好的药理特征。我们开发了一种Claisen/Diels–Alder反应级联反应，并结合Pd(0)催化的逆普瑞尼基反应，快速高效地获得了以cluvenone结构为代表的CGX药效基团。为进一步探索该药效基团，我们合成了多种cluvenone的A环氧化类衍生物，并评估了它们在生长抑制、线粒体碎片化、诱导线粒体依赖性细胞死亡和Hsp90底物抑制等方面的生物活性。我们发现，在A环不同位置引入氧功能团显著影响了Claisen/Diels–Alder反应的位点选择性以及这些化合物的生物活性，原因在于远程电子效应。
• GARCINIA DERIVATIVE, ITS PREPARING METHOD AND MEDICINAL USE
  申请人：You Qidong

  公开号：US20120059050A1

  公开（公告）日：2012-03-08

  The present invention relates to a field of pharmaceutical chemistry, more specifically, the present invention relates to a garcinia derivative Formula (I), its preparing method, and medicinal use. Wherein the definitions of R 1 and R 2 are disclosed in the specification of the present invention, and the derivative of the present invention is a structurally simplified analogue of the gambogic acid compound; wherein the gambogic acid compound possesses anti-cancer characteristics, and could be used for preparation of anti-tumor drugs.

  本发明涉及药物化学领域，更具体地说，本发明涉及一种藤黄衍生物配方（I），其制备方法和药用。其中，R1和R2的定义在本发明的说明书中披露，本发明的衍生物是甘黄酸化合物的结构简化类似物；甘黄酸化合物具有抗癌特性，可用于制备抗肿瘤药物。
• Structure–activity relationship of Garcinia xanthones analogues: Potent Hsp90 inhibitors with cytotoxicity and antiangiogenesis activity
  作者：Xiaoli Xu、Yue Wu、Mingyang Hu、Xiang Li、Congying Gu、Qidong You、Xiaojin Zhang

  DOI：10.1016/j.bmc.2016.07.067

  日期：2016.10

  present the structure-activity relationship of Garcinia xanthones analogues as Hsp90 inhibitors and identify that compound 25, with a simplified skeleton, had an improved inhibitory effect toward Hsp90. Compound 25 inhibited the ATPase activity of Hsp90 with an IC50 value of 3.68±0.18μM. It also exhibited potent antiproliferative activities in some solid tumor cells. In SK-BR-3 cells with high Hsp90 expression

  Hsp90长期以来一直被认为是用于癌症治疗的有吸引力且至关重要的分子靶标。甘布酸（Gambogic hanburyi）的主要活性化合物甘草酸（GA）已被报道为Hsp90的天然抑制剂。在这里，我们介绍了藤黄果黄酮类似物作为Hsp90抑制剂的构效关系，并确定了具有简化骨架的化合物25对Hsp90的抑制作用。化合物25抑制Hsp90的ATP酶活性，IC50值为3.68±0.18μM。它还在某些实体瘤细胞中表现出有效的抗增殖活性。在具有高Hsp90表达的SK-BR-3细胞中，化合物25诱导了Hsp90客户蛋白（包括Akt和Erk1 / 2）降解，而没有引起热激反应。此外，化合物25通过对HIF-1α途径的Hsp90调节来抑制HUVEC细胞中的血管生成。这些结果表明作为具有新结构的Hsp90抑制剂的化合物25可以进一步研究用于肿瘤治疗的发展。
• Novel natural-product-like caged xanthones with improved druglike properties and in vivo antitumor potency
  作者：Yue Wu、Mingyang Hu、Li Yang、Xiang Li、Jinlei Bian、Fen Jiang、Haopeng Sun、Qidong You、Xiaojin Zhang

  DOI：10.1016/j.bmcl.2015.04.031

  日期：2015.6

  DDO-6101, a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro but poor efficacy in vivo due to its poor druglike properties. In order to improve the druglike properties and in vivo cytotoxic potency, a novel series of 19 prenyl group- modified derivatives of DDO-6101 was synthesized and evaluated for their in vitro antitumor activity and druglike properties. The SAR and SPR information of these compounds was also obtained. In the light of the in vitro antitumor activity and druglike properties such as aqueous solubility and permeability, compound 6f (named as DDO-6306) was advanced into in vivo efficacy experiment. The results showed that DDO-6306 is more potent than DDO-6101 in vivo and is a promising antitumor candidate for further evaluation. (C) 2015 Elsevier Ltd. All rights reserved.
• Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer
  作者：Oraphin Chantarasriwong、Andrew T. Milcarek、Theodore Habarth Morales、Aspen L. Settle、Celso O. Rezende、Bashayer D. Althufairi、Maria A. Theodoraki、Mary L. Alpaugh、Emmanuel A. Theodorakis

  DOI：10.1016/j.ejmech.2019.02.047

  日期：2019.4

  Inflammatory breast cancer (IBC) is a highly metastatic, lethal form of breast cancer that lacks targeted therapeutic strategies. Inspired by the promising cytotoxicity of gambogic acid and related caged xanthones in spheroids(MARY-X), an in vitro preclinical IBC model, we constructed a library of synthetic analogs and performed structure-activity relationship studies. The studies revealed that functionalizing the A-ring of the caged xanthone framework can significantly affect potency. Specifically, introduction of hydroxyl or fluorine groups at discrete positions of the A-ring leads to enhanced cytotoxicity at sub-micromolar concentrations. These compounds induce complete dissolution of spheroids(MARY-X) with subsequent apoptosis of both the peripherally- and centrally-located cells, proliferative and quiescent-prone (e.g. hypoxic), respectively. These results highlight the structural flexibility and pharmacological potential of the caged xanthone motif for the design of IBC-targeting therapeutics. (C) 2019 Elsevier Masson SAS. All rights reserved.