(2S,5'R)-7-chloro-3'-hydroxy-4,6-dimethoxy-5'-methylspiro[1-benzofuran-2,4'-cyclohex-2-ene]-1',3-dione | 1158186-19-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: (2S,5'R)-7-chloro-3'-hydroxy-4,6-dimethoxy-5'-methylspiro[1-benzofuran-2,4'-cyclohex-2-ene]-1',3-dione
• 英文别名: griseofulvic acid
• CAS: 1158186-19-6
• 化学式: C₁₆H₁₅ClO₆
• 分子量: 338.745
• InChiKey: LCZOWFAREAROGH-QZTNRIJFSA-N

物化性质

• 熔点：
  177-181°C
• 沸点：
  581.6±50.0 °C(Predicted)
• 密度：
  1.47±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于二甲基亚砜，水

计算性质

• 辛醇/水分配系数(LogP)：
  2.72
• 重原子数：
  23.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  82.06
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (2S,5'R)-7-chloro-3'-hydroxy-4,6-dimethoxy-5'-methylspiro[1-benzofuran-2,4'-cyclohex-2-ene]-1',3-dione 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 lithium chloride 、 三氯氧磷 作用下， 以 1,4-二氧六环 为溶剂， 反应 0.5h， 生成 (2S,6'R)-(7-chloro-4,6-dimethoxy-benzofuran-3-on)-2-spiro-1'-(4'-methoxy-6'-methylcyclohex-3'-ene-2'-one)
  参考文献：
  名称：

  Disparate SAR Data of Griseofulvin Analogues for the Dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 Cancer Cells

  摘要：

  Griseofulvin and 53 analogues of this compound have been tested against the pathogenic dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes as well as against the breast cancer cell line MDA-MB-231. The modifications to griseofulvin include the 4, 5, 6, 2', 3', and 4' positions. The SAR of the griseofulvin analogues toward the two fungi followed the same trend with the majority being less active than griseofulvin and none had more than twice the potency of the parent compound. A comparison of the antifungal the anticancer SAR revealed distinct differences, as the majority of analogues showed increased activity against the cancer cell line MDA-MB-231, highlighted by 2'-benzyloxy-2'-demethoxy-griseofulvin, which showed low activity against both fungi but was among the most potent compounds against MDA-MB-231 cancer cells. Tubulin has been proposed as the target of griseofulvin in both fungal and mammalian cells, but the differences revealed by this SAR study strongly suggest that the mode-of-action of the compound class toward fungi and mammalian cancer cells is different.

  DOI：

  10.1021/jm200835c
• 作为产物：
  描述：

  灰黄霉素 在 硫酸 作用下， 以 溶剂黄146 为溶剂， 反应 0.75h， 以93%的产率得到(2S,5'R)-7-chloro-3'-hydroxy-4,6-dimethoxy-5'-methylspiro[1-benzofuran-2,4'-cyclohex-2-ene]-1',3-dione
  参考文献：
  名称：

  灰黄霉素类似物的合成和结构活性关系作为癌细胞中中心体簇的抑制剂

  摘要：

  在最近开发的测定中，灰黄霉素被鉴定为中心体簇的抑制剂。中心体簇是重要的细胞事件，其使具有过多数量中心体的癌细胞系实现双极有丝分裂。我们在此报道了34个灰黄霉素的类似物的合成和SAR，其为中心体簇的抑制剂。灰黄霉素结构的变化覆盖五个位置，即4、5、2'，3'和4'位置。4和5位的修饰提供了非活性分子。烯醇醚必须位于2'位置，并且4'位置必须为sp 2杂交的。与灰黄霉素相比，活性最高的类似物是2'-苄氧基和2'-（4-甲基苄氧基）类似物，以及前者的肟，其活性增加了25倍。在这项工作中获得的结果与先前报道的皮肤真菌的生长抑制数据的比较显示了相同点和不同点。

  DOI：

  10.1021/jm801517j

文献信息

• Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability
  作者：Asger B. Petersen、Nikolaj S. Andersen、Gleb Konotop、Nur Hafzan Md Hanafiah、Marc S. Raab、Alwin Krämer、Mads H. Clausen

  DOI：10.1016/j.ejmech.2017.02.055

  日期：2017.4

  metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue

  灰黄霉素（1）是一种重要的抗真菌剂，由于其在哺乳动物癌细胞中的抗增殖活性，最近受到关注。全面的SAR研究已导致鉴定2'-苄氧基灰黄霉素2，这是一种更有效的类似物，在体外具有较低的微摩尔抗癌效力。在结肠癌和多发性骨髓瘤的小鼠异种移植模型中，类似物2还显示出通过抑制中心体簇而延迟了肿瘤的生长。然而，类似于灰黄霉素，化合物2表现出较差的代谢稳定性和水溶性。为了改善不良的药代动力学特性，合成了11种灰黄霉素的类似物，并对其生物学活性和生理稳定性进行了评估，包括SGF，血浆和代谢稳定性。最后，在热力学溶解度和配方研究方面对最有前途的化合物进行了研究。2'-苄胺类似物10被证明是最有前途的化合物，其体外抗癌潜能低，PBS溶解度比化合物2高200倍，并且代谢稳定性更高。此外，已证明该类似物与适用于口服和静脉内给药的制剂相容。最后，证实了2'-苄胺类似物10在体外诱导G2 / M细胞周期停滞。该类似物被证
• GRISEOFULVIN DERIVATIVES
  申请人：PIERRE FABRE MEDICAMENT

  公开号：US20150210713A1

  公开（公告）日：2015-07-30

  The present invention relates to compounds of the following general formula (I), or to a pharmaceutically acceptable salt thereof, as well as to the uses thereof as a drug, in particular in the treatment of cancerous or precancerous hyperproliferative conditions, and to the pharmaceutical compositions containing same.

  本发明涉及以下一般式(I)的化合物，或其药学上可接受的盐，以及它们作为药物的用途，特别是在治疗癌症或癌前期增生病症方面的用途，以及含有它们的制药组合物。
• US9416143B2
  申请人：——

  公开号：US9416143B2

  公开（公告）日：2016-08-16
• Disparate SAR Data of Griseofulvin Analogues for the Dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 Cancer Cells
  作者：Mads H. Rønnest、Marc S. Raab、Simon Anderhub、Sven Boesen、Alwin Krämer、Thomas O. Larsen、Mads H. Clausen

  DOI：10.1021/jm200835c

  日期：2012.1.26

  Griseofulvin and 53 analogues of this compound have been tested against the pathogenic dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes as well as against the breast cancer cell line MDA-MB-231. The modifications to griseofulvin include the 4, 5, 6, 2', 3', and 4' positions. The SAR of the griseofulvin analogues toward the two fungi followed the same trend with the majority being less active than griseofulvin and none had more than twice the potency of the parent compound. A comparison of the antifungal the anticancer SAR revealed distinct differences, as the majority of analogues showed increased activity against the cancer cell line MDA-MB-231, highlighted by 2'-benzyloxy-2'-demethoxy-griseofulvin, which showed low activity against both fungi but was among the most potent compounds against MDA-MB-231 cancer cells. Tubulin has been proposed as the target of griseofulvin in both fungal and mammalian cells, but the differences revealed by this SAR study strongly suggest that the mode-of-action of the compound class toward fungi and mammalian cancer cells is different.
• Synthesis and Structure−Activity Relationship of Griseofulvin Analogues as Inhibitors of Centrosomal Clustering in Cancer Cells
  作者：Mads H. Rønnest、Blanka Rebacz、Lene Markworth、Anette H. Terp、Thomas O. Larsen、Alwin Krämer、Mads H. Clausen

  DOI：10.1021/jm801517j

  日期：2009.5.28

  Griseofulvin was identified as an inhibitor of centrosomal clustering in a recently developed assay. Centrosomal clustering is an important cellular event that enables bipolar mitosis for cancer cell lines harboring supernumerary centrosomes. We report herein the synthesis and SAR of 34 griseofulvin analogues as inhibitors of centrosomal clustering. The variations in the griseofulvin structure cover

  在最近开发的测定中，灰黄霉素被鉴定为中心体簇的抑制剂。中心体簇是重要的细胞事件，其使具有过多数量中心体的癌细胞系实现双极有丝分裂。我们在此报道了34个灰黄霉素的类似物的合成和SAR，其为中心体簇的抑制剂。灰黄霉素结构的变化覆盖五个位置，即4、5、2'，3'和4'位置。4和5位的修饰提供了非活性分子。烯醇醚必须位于2'位置，并且4'位置必须为sp 2杂交的。与灰黄霉素相比，活性最高的类似物是2'-苄氧基和2'-（4-甲基苄氧基）类似物，以及前者的肟，其活性增加了25倍。在这项工作中获得的结果与先前报道的皮肤真菌的生长抑制数据的比较显示了相同点和不同点。