(±)-(3R,8aS)-5-methyl-3-(pentadecyloxy)-8,8a-dihydrofuro[3,4-e][1,3,2]dioxaphosphepin-6(1H)-one 3-oxide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: (±)-(3R,8aS)-5-methyl-3-(pentadecyloxy)-8,8a-dihydrofuro[3,4-e][1,3,2]dioxaphosphepin-6(1H)-one 3-oxide
• 英文别名: (3R,8aS)-5-methyl-3-oxo-3-pentadecoxy-8,8a-dihydro-1H-furo[3,4-e][1,3,2]dioxaphosphepin-6-one
• 化学式: C₂₂H₃₉O₆P
• 分子量: 430.522
• InChiKey: BHKGHKHKDXVQJF-AFJIDDCJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  29
• 可旋转键数：
  15
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  71.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  溴代十五烷 、 3-methoxy-5-methyl-3-oxo-8,8a-dihydro-1H-furo[3,4-e][1,3,2]dioxaphosphepin-6-one 在 四丁基碘化铵 作用下， 以 1,4-二氧六环 为溶剂， 以9.5 mg的产率得到(±)-(3R,8aR)-5-methyl-3-(pentadecyloxy)-8,8a-dihydrofuro[3,4-e][1,3,2]dioxaphosphepin-6(1H)-one 3-oxide
  参考文献：
  名称：

  Rat hormone sensitive lipase inhibition by cyclipostins and their analogs

  摘要：

  Cyclipostins are bicyclic lipophilic phosphate natural products. We report here that synthesized individual diastereomers of cyclipostins P and R have nanomolar IC(50)s toward hormone sensitive lipase (HSL). The less potent diastereomers of these compounds have 10-fold weaker IC(50)s. The monocyclic phosphate analog of cyclipostin P is nearly as potent as the bicyclic natural product. Bicyclic phosphonate analogs of both cyclipostins exhibit IC(50)s similar to those of the weaker diastereomer phosphates (about 400 nM). The monocyclic phosphonate analog of cyclipostin P has similar potency. A series of monocyclic phosphonate analogs in which a hydrophobic tail extends from the lactone side of the ring are considerably poorer inhibitors, with IC(50)s around 50 mu M. Finally cyclophostin, a related natural product inhibitor of acetylcholinesterase (AChE) that lacks the hydrocarbon tail of cyclipostins, is not active against HSL. These results indicate a critical SAR for these compounds, the hydrophobic tail. The smaller lactone ring is not critical to activity, a similarity shared with cyclophostin and AChE. The HSL kinetics of inhibition for the cyclipostin P trans diastereomer were examined in detail. The reaction is irreversible with a K-I of 40 nM and a rate constant for inactivation of 0.2 min(-1). These results are similar to those observed for cyclophostin and AChE. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.01.028

文献信息

• Rat hormone sensitive lipase inhibition by cyclipostins and their analogs
  作者：Elena Vasilieva、Supratik Dutta、Raj K. Malla、Benjamin P. Martin、Christopher D. Spilling、Cynthia M. Dupureur

  DOI：10.1016/j.bmc.2015.01.028

  日期：2015.3

  Cyclipostins are bicyclic lipophilic phosphate natural products. We report here that synthesized individual diastereomers of cyclipostins P and R have nanomolar IC(50)s toward hormone sensitive lipase (HSL). The less potent diastereomers of these compounds have 10-fold weaker IC(50)s. The monocyclic phosphate analog of cyclipostin P is nearly as potent as the bicyclic natural product. Bicyclic phosphonate analogs of both cyclipostins exhibit IC(50)s similar to those of the weaker diastereomer phosphates (about 400 nM). The monocyclic phosphonate analog of cyclipostin P has similar potency. A series of monocyclic phosphonate analogs in which a hydrophobic tail extends from the lactone side of the ring are considerably poorer inhibitors, with IC(50)s around 50 mu M. Finally cyclophostin, a related natural product inhibitor of acetylcholinesterase (AChE) that lacks the hydrocarbon tail of cyclipostins, is not active against HSL. These results indicate a critical SAR for these compounds, the hydrophobic tail. The smaller lactone ring is not critical to activity, a similarity shared with cyclophostin and AChE. The HSL kinetics of inhibition for the cyclipostin P trans diastereomer were examined in detail. The reaction is irreversible with a K-I of 40 nM and a rate constant for inactivation of 0.2 min(-1). These results are similar to those observed for cyclophostin and AChE. (C) 2015 Elsevier Ltd. All rights reserved.