(R)-2-acetyl-3,7,9-trihydroxy-8,9b-dimethyl-6-(2-methylthiazol-4-yl)dibenzo[b,d]furan-1(9bH)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 香豆素
• 英文名称: (R)-2-acetyl-3,7,9-trihydroxy-8,9b-dimethyl-6-(2-methylthiazol-4-yl)dibenzo[b,d]furan-1(9bH)-one
• 英文别名: (9bR)-2-acetyl-3,7,9-trihydroxy-8,9b-dimethyl-6-(2-methyl-1,3-thiazol-4-yl)dibenzofuran-1-one
• 化学式: C₂₀H₁₇NO₆S
• 分子量: 399.424
• InChiKey: TYUIWHZEAXZREV-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  145
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (+)-usnic acid 在 氢溴酸 、 溴 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 168.0h， 生成 (R)-2-acetyl-3,7,9-trihydroxy-8,9b-dimethyl-6-(2-methylthiazol-4-yl)dibenzo[b,d]furan-1(9bH)-one
  参考文献：
  名称：

  Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topoteсan on in vivo tumor models

  摘要：

  The druggability of the tyrosyl-DNA phosphodiesterase 1 (Tdp1) enzyme was investigated in conjunction with topoisomerase 1 inhibition. A novel class of thiazole, aminothiazole and hydrazonothiazole usnic acid derivatives was synthesized and evaluated as Tdp1 inhibitors and their ability to sensitize tumors to topotecan, a topoisomerase inhibitor in clinical use. Of all the compounds tested, four hydrazinothiazole derivatives, 20c, 20d, 20h and 20i, inhibited the enzyme in the nanomolar range. The activity of the compounds was verified by affinity experiments as well as supported by molecular modelling. The most effective Tdp1 inhibitor, 20d, was ton-toxic and increased the effect of topotecan both in vitro and in vivo in the Lewis lung carcinoma model. Furthermore, 20d showed significant increase in the antitumor and antimetastatic effect of topotecan in mice. The results presented here justify compound 20d to be considered as a drug lead for antitumor therapy. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.10.055

文献信息

• Synthesis and activity of (+)-usnic acid and (−)-usnic acid derivatives containing 1,3-thiazole cycle against Mycobacterium tuberculosis
  作者：Olga B. Bekker、Dmitry N. Sokolov、Olga A. Luzina、Nina I. Komarova、Yuriy V. Gatilov、Sofia N. Andreevskaya、Tatiana G. Smirnova、Dmitry A. Maslov、Larisa N. Chernousova、Nariman F. Salakhutdinov、Valery. N. Danilenko

  DOI：10.1007/s00044-015-1348-2

  日期：2015.7

  New usnic acid (UA) derivatives were investigated in vitro to elucidate their potential inhibitory activities on the growth of Mycobacterium smegmatis and Mycobacterium tuberculosis. Seven pairs of enantiomers of thiazole UA derivatives were tested using the M. smegmatis strain mc(2) 155 test system, and the "structure-activity" relationship was established. The most active compounds were (+)-3 and (-)-3, and their kinase inhibitory activities were investigated. The results obtained using the Streptomyces lividans APHVIII+ and M. smegmatis APHVIII+ test systems indicated the significant protein kinase activity of these compounds and revealed the species specificity of the actions of the dextro- and levorotatory isomers. Both isomers, (+)-3 and (-)-3, possess similar inhibitory activity against M. tuberculosis H37Rv. The action of the isomers on eukaryotic cells was also investigated, and the results demonstrate that the dextrorotatory isomer (+)-3 leads to the lysis of intact macrophages to a degree higher than that obtained spontaneously and significantly higher than that obtained with the levorotatory isomer.
• Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topoteсan on in vivo tumor models
  作者：A.L. Zakharenko、O.A. Luzina、D.N. Sokolov、V.I. Kaledin、V.P. Nikolin、N.A. Popova、J. Patel、O.D. Zakharova、A.A. Chepanova、A. Zafar、J. Reynisson、E. Leung、I.K.H. Leung、K.P. Volcho、N.F. Salakhutdinov、O.I. Lavrik

  DOI：10.1016/j.ejmech.2018.10.055

  日期：2019.1

  The druggability of the tyrosyl-DNA phosphodiesterase 1 (Tdp1) enzyme was investigated in conjunction with topoisomerase 1 inhibition. A novel class of thiazole, aminothiazole and hydrazonothiazole usnic acid derivatives was synthesized and evaluated as Tdp1 inhibitors and their ability to sensitize tumors to topotecan, a topoisomerase inhibitor in clinical use. Of all the compounds tested, four hydrazinothiazole derivatives, 20c, 20d, 20h and 20i, inhibited the enzyme in the nanomolar range. The activity of the compounds was verified by affinity experiments as well as supported by molecular modelling. The most effective Tdp1 inhibitor, 20d, was ton-toxic and increased the effect of topotecan both in vitro and in vivo in the Lewis lung carcinoma model. Furthermore, 20d showed significant increase in the antitumor and antimetastatic effect of topotecan in mice. The results presented here justify compound 20d to be considered as a drug lead for antitumor therapy. (C) 2018 Elsevier Masson SAS. All rights reserved.