(+)-octahydro-3,6α-dimethyl-3,12-epoxy-9β-(3'-(p-trifluoromethylphenyl)propyl)-12H-pyrano[4,3j]-1,2-benzodioxepin | 467223-67-2

• 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
• 英文名称: (+)-octahydro-3,6α-dimethyl-3,12-epoxy-9β-(3'-(p-trifluoromethylphenyl)propyl)-12H-pyrano[4,3j]-1,2-benzodioxepin
• 英文别名: (1R,4S,5R,8S,9R,12R,13R)-1,5-dimethyl-9-[3-[4-(trifluoromethyl)phenyl]propyl]-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecane
• CAS: 467223-67-2
• 化学式: C₂₄H₃₁F₃O₄
• 分子量: 440.503
• InChiKey: WPISCARJLQMKSA-YEMUDNHFSA-N

物化性质

• 熔点：
  79-80 °C
• 沸点：
  470.7±45.0 °C(predicted)
• 密度：
  1.25±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  36.9
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (+)-octahydro-3,6α-dimethyl-3,12-epoxy-9β-(3'-(p-trifluoromethylphenyl)propyl)-12H-pyrano[4,3j]-1,2-benzodioxepin 在 palladium on activated charcoal 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 7.0h， 以42%的产率得到(+)-octahydro-3,6α-dimethyl-3,12-epoxy-9β-(3'-(p-trifluoromethylphenyl)propyl)-12H-pyrano[4,3j]-1,2-benzoxepin
  参考文献：
  名称：

  Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 8. Design, Synthesis, and CoMFA Studies toward the Development of Artemisinin-Based Drugs against Leishmaniasis and Malaria

  摘要：

  Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.

  DOI：

  10.1021/jm030181q
• 作为产物：
  描述：

  青蒿素 在 三乙基硅烷 、 偶氮二异丁腈 、 三正丁基氢锡 、 二异丁基氢化铝 、 间氯过氧苯甲酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 二氯甲烷 、 苯 为溶剂， 反应 11.17h， 生成 (+)-octahydro-3,6α-dimethyl-3,12-epoxy-9β-(3'-(p-trifluoromethylphenyl)propyl)-12H-pyrano[4,3j]-1,2-benzodioxepin
  参考文献：
  名称：

  Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 7. Direct Modification of (+)-Artemisinin and In Vivo Antimalarial Screening of New, Potential Preclinical Antimalarial Candidates

  摘要：

  On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9beta-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. Several of the new compounds 7 and 10-14 were synthesized, employing the key synthetic intermediate 23. In a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisinin analogues. Under a new approach, we developed A one step reaction for the interconversion of artemisinin 1 into artemisitene 22 that did not employ selenium-based reagents and found that 2-arylethyliodides would undergo facile radical-induced conjugate addition to the exomethylene lactone of 22 in good yield. The lactone carbonyls, were removed sequentially by diisobutylaluminum hydride reduction followed directly by a second reduction (BF3-etherate/Et3SiH) to afford the desired corresponding pyrans. Six additional halogen-substituted aromatic side chains were installed via 22 furnishing the bioassay candidates 15-20. The analogues were examined for in vitro antimalarial activity in the W-2 and D-6 clones of Plasmodium falciparum and were additionally tested. in vivo in Plasmodium berghei- and/or Plasmodium yoelii-infected mice. Several of the compounds emerged as highly potent orally active candidates without obvious toxicity, Of these, two were chosen for pharmacokinetic evaluation, 14 and 17.

  DOI：

  10.1021/jm020142z

文献信息

• Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 8. Design, Synthesis, and CoMFA Studies toward the Development of Artemisinin-Based Drugs against Leishmaniasis and Malaria
  作者：Mitchell A. Avery、Kannoth M. Muraleedharan、Prashant V. Desai、Achintya K. Bandyopadhyaya、Marise M. Furtado、Babu L. Tekwani

  DOI：10.1021/jm030181q

  日期：2003.9.1

  Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.
• Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 7. Direct Modification of (+)-Artemisinin and In Vivo Antimalarial Screening of New, Potential Preclinical Antimalarial Candidates
  作者：Mitchell A. Avery、Maria Alvim-Gaston、Jeffrey A. Vroman、Baogen Wu、Arba Ager、Wallace Peters、Brian L. Robinson、William Charman

  DOI：10.1021/jm020142z

  日期：2002.9.1

  On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9beta-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. Several of the new compounds 7 and 10-14 were synthesized, employing the key synthetic intermediate 23. In a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisinin analogues. Under a new approach, we developed A one step reaction for the interconversion of artemisinin 1 into artemisitene 22 that did not employ selenium-based reagents and found that 2-arylethyliodides would undergo facile radical-induced conjugate addition to the exomethylene lactone of 22 in good yield. The lactone carbonyls, were removed sequentially by diisobutylaluminum hydride reduction followed directly by a second reduction (BF3-etherate/Et3SiH) to afford the desired corresponding pyrans. Six additional halogen-substituted aromatic side chains were installed via 22 furnishing the bioassay candidates 15-20. The analogues were examined for in vitro antimalarial activity in the W-2 and D-6 clones of Plasmodium falciparum and were additionally tested. in vivo in Plasmodium berghei- and/or Plasmodium yoelii-infected mice. Several of the compounds emerged as highly potent orally active candidates without obvious toxicity, Of these, two were chosen for pharmacokinetic evaluation, 14 and 17.