[(1S,2S,4R,7E,9S,11S)-4,8-dimethyl-12-methylidene-13-oxo-3,14-dioxatricyclo[9.3.0.02,4]tetradec-7-en-9-yl] 2,4-bis(trifluoromethyl)benzoate | 1486479-66-6

• 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: [(1S,2S,4R,7E,9S,11S)-4,8-dimethyl-12-methylidene-13-oxo-3,14-dioxatricyclo[9.3.0.02,4]tetradec-7-en-9-yl] 2,4-bis(trifluoromethyl)benzoate
• CAS: 1486479-66-6
• 化学式: C₂₄H₂₂F₆O₅
• 分子量: 504.426
• InChiKey: ZHMQQYPYNLWKTR-SPFWDDOMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  35
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  65.1
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  parthenolide 在 4-二甲氨基吡啶 、 sodium phosphite 、 phosphite dehydrogenase 、 cytochrome P₄₅₀ monooxygenase from Bacillus megaterium V₇₈A, F₈₁S, A₈₂V, F₈₇A, P₁₄₂S, T₁₇₅I, A₁₈₀T, 181L, A₁₈₄V, A₁₉₇V, F₂₀₅C, S₂₂₆R, H₂₃₆Q, E₂₅₂G, R₂₅₅S, A₂₉₀V, L₃₅₃V mutant 、 烟酰胺腺嘌呤双核苷酸磷酸盐 、 三乙胺 作用下， 以 aq. phosphate buffer 、 二氯甲烷 为溶剂， 反应 14.0h， 生成 [(1S,2S,4R,7E,9S,11S)-4,8-dimethyl-12-methylidene-13-oxo-3,14-dioxatricyclo[9.3.0.02,4]tetradec-7-en-9-yl] 2,4-bis(trifluoromethyl)benzoate
  参考文献：
  名称：

  Discovery of Potent Parthenolide-Based Antileukemic Agents Enabled by Late-Stage P450-Mediated C—H Functionalization

  摘要：

  The sesquiterpene lactone parthenolide has recently attracted considerable attention owing to its promising antitumor properties, in particular in the context of stem-cell cancers including leukemia. Yet, the lack of viable synthetic routes for re-elaborating this complex natural product has represented a fundamental obstacle toward further optimization of its pharmacological properties. Here, we demonstrate how this challenge could be addressed via selective, late-stage sp(3) C-H bond functionalization mediated by P450 catalysts with tailored site-selectivity. Taking advantage of our recently introduced tools for high-throughput P450 fingerprinting and fingerprint-driven P450 reactivity prediction, we evolved P450 variants useful for carrying out the highly regioselective hydroxylation of two aliphatic sites (C9 and C14) in parthenolide carbocyclic backbone. By chemoenzymatic synthesis, a panel of novel C9- and C14-modified parthenolide analogs were generated in order to gain initial structure-activity insights on these previously inaccessible sites of the molecule. Notably, some of these compounds were found to possess significantly improved antileukemic potency against primary acute myeloid leukemia cells, while exhibiting low toxicity against normal mature and progenitor hematopoietic cells. By identifying two 'hot spots' for improving the anticancer properties of parthenolide, this study highlights the potential of P450-mediated C-H functionalization as an enabling, new strategy for the late-stage manipulation of bioactive natural product scaffolds.

  DOI：

  10.1021/cb400626w

文献信息

• 10.1021/cb400626
  作者：Kolev, Joshua N.、O'Dwyer, Kristen M.、Jordan, Craig T.、Fasan, Rudi

  DOI：10.1021/cb400626

  日期：——
• Discovery of Potent Parthenolide-Based Antileukemic Agents Enabled by Late-Stage P450-Mediated C—H Functionalization
  作者：Joshua N. Kolev、Kristen M. O’Dwyer、Craig T. Jordan、Rudi Fasan

  DOI：10.1021/cb400626w

  日期：2014.1.17

  The sesquiterpene lactone parthenolide has recently attracted considerable attention owing to its promising antitumor properties, in particular in the context of stem-cell cancers including leukemia. Yet, the lack of viable synthetic routes for re-elaborating this complex natural product has represented a fundamental obstacle toward further optimization of its pharmacological properties. Here, we demonstrate how this challenge could be addressed via selective, late-stage sp(3) C-H bond functionalization mediated by P450 catalysts with tailored site-selectivity. Taking advantage of our recently introduced tools for high-throughput P450 fingerprinting and fingerprint-driven P450 reactivity prediction, we evolved P450 variants useful for carrying out the highly regioselective hydroxylation of two aliphatic sites (C9 and C14) in parthenolide carbocyclic backbone. By chemoenzymatic synthesis, a panel of novel C9- and C14-modified parthenolide analogs were generated in order to gain initial structure-activity insights on these previously inaccessible sites of the molecule. Notably, some of these compounds were found to possess significantly improved antileukemic potency against primary acute myeloid leukemia cells, while exhibiting low toxicity against normal mature and progenitor hematopoietic cells. By identifying two 'hot spots' for improving the anticancer properties of parthenolide, this study highlights the potential of P450-mediated C-H functionalization as an enabling, new strategy for the late-stage manipulation of bioactive natural product scaffolds.