(3S)-16, 17-didehydrofalcarinol

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (3S)-16, 17-didehydrofalcarinol
• 英文别名: dehydrofalcarinol；(3S)-16,17-didehydrofalcarinol；(3S,9Z)-heptadeca-1,9,16-trien-4,6-diyn-3-ol
• 化学式: C₁₇H₂₂O
• 分子量: 242.361
• InChiKey: JRLHSTVTOOELAF-MQNTZWLQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  18
• 可旋转键数：
  9
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  20.2
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  (R)-methoxytrifluoromethylphenylacetyl chloride 、 (3S)-16, 17-didehydrofalcarinol 在 氘代吡啶 作用下， 反应 4.0h， 生成
  参考文献：
  名称：

  CRISPR-Cas9 Genome-Wide Knockout Screen Identifies Mechanism of Selective Activity of Dehydrofalcarinol in Mesenchymal Stem-like Triple-Negative Breast Cancer Cells

  摘要：

  There are no targeted therapies available for triple-negative breast cancers (TNBCs) in part because they represent a heterogeneous group of tumors with diverse oncogenic drivers. Our goal is to identify targeted therapies for subtypes of these cancers using a mechanism-blind screen of natural product extract libraries. An extract from Desmanthodium guatemalense was 4-fold more potent for cytotoxicity against MDA-MB-231 cells, which represent the mesenchymal stem-like (MSL) subtype, as compared to cells of other TNBC subtypes. Bioassay-guided fractionation led to the isolation of six polyacetylenes, and subsequent investigations of plant sources known to produce polyacetylenes yielded six additional structurally related compounds. A subset of these compounds retained selective cytotoxic effects in MSL subtype cells. Studies suggest that these selective effects do not appear to be due to PPARγ agonist activities that have previously been reported for polyacetylenes. A CRISPR-Cas9-mediated gene knockout screen was employed to identify the mechanism of selective cytotoxic activity of the most potent and selective compound, dehydrofalcarinol (1a). This genomic screen identified HSD17B11, the gene encoding the enzyme 17β-hydroxysteroid dehydrogenase type 11, as a mediator of the selective cytotoxic effects of 1a in MDA-MB-231 cells that express high levels of this protein. The Project Achilles cancer dependency database further identified a subset of Ewing sarcoma cell lines as highly dependent on HSD17B11 expression, and it was found these were also highly sensitive to 1a. This report demonstrates the value of CRISPR-Cas9 genome-wide screens to identify the mechanisms underlying the selective activities of natural products.

  DOI：

  10.1021/acs.jnatprod.0c00642
• 作为产物：
  描述：

  deca-2c,9-dien-1-ol 在 N-溴代丁二酰亚胺(NBS) 、 盐酸羟胺 、 正丁胺 、 三苯基膦 、 copper(l) chloride 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 异丙醇 为溶剂， 反应 3.52h， 生成 dehydrofalcarinol 、 (3S)-16, 17-didehydrofalcarinol
  参考文献：
  名称：

  falcarinol 型 oxylipin (3S)-16,17-didehydrofalcarinol 的全合成及其对墨西哥利什曼原虫的活性

  摘要：

  本文报道了一种获得 (3 S )-16,17-二去氢法尔卡林醇 ( 1a ) 的新合成途径，以提供体内试验所需的数量。为此目的，应用了双合成子偶联合成。一方面，通过九步得到( Z )-10-bromodeca-1,8-diene ( 10 )，另一方面，hepta-1-en-4,6-diyn-3-ol ( 11 )在一个单一步骤中获得，片段被偶联得到外消旋1，产率为27%。最后，手性色谱分离1提供了所需的对映异构体1a (27 mg)，其针对墨西哥利什曼原虫进行了测试, 证明了其高效的生物活性 (IC 50  = 0.74 μM)。

  DOI：

  10.1016/j.tet.2022.132832

文献信息

• Total synthesis of the falcarinol-type oxylipin (3S)-16,17-didehydrofalcarinol and its activity against Leishmania mexicana
  作者：Horacio Larqué、Ana G. Carrillo-Aké、Jennifer de la Vega、Sergio R. Peraza-Sánchez、Rubén M. Carballo、Abelardo Chávez-Montes、Esther del Olmo

  DOI：10.1016/j.tet.2022.132832

  日期：2022.7

  This paper reports a novel synthesis route to obtain (3S)-16,17-didehydrofalcarinol (1a) in order to provide the quantities necessary for in vivo tests. For this purpose, a two-synthon coupling synthesis was applied. On the one hand, the (Z)-10-bromodeca-1,8-diene (10) was obtained throughout nine steps, and on the other, the hepta-1-en-4,6-diyn-3-ol (11) was obtained in one single step, the fragments

  本文报道了一种获得 (3 S )-16,17-二去氢法尔卡林醇 ( 1a ) 的新合成途径，以提供体内试验所需的数量。为此目的，应用了双合成子偶联合成。一方面，通过九步得到( Z )-10-bromodeca-1,8-diene ( 10 )，另一方面，hepta-1-en-4,6-diyn-3-ol ( 11 )在一个单一步骤中获得，片段被偶联得到外消旋1，产率为27%。最后，手性色谱分离1提供了所需的对映异构体1a (27 mg)，其针对墨西哥利什曼原虫进行了测试, 证明了其高效的生物活性 (IC 50  = 0.74 μM)。
• CRISPR-Cas9 Genome-Wide Knockout Screen Identifies Mechanism of Selective Activity of Dehydrofalcarinol in Mesenchymal Stem-like Triple-Negative Breast Cancer Cells
  作者：Corena V. Grant、Shengxin Cai、April L. Risinger、Huiyun Liang、Barry R. O’Keefe、John G. Doench、Robert H. Cichewicz、Susan L. Mooberry

  DOI：10.1021/acs.jnatprod.0c00642

  日期：2020.10.23

  There are no targeted therapies available for triple-negative breast cancers (TNBCs) in part because they represent a heterogeneous group of tumors with diverse oncogenic drivers. Our goal is to identify targeted therapies for subtypes of these cancers using a mechanism-blind screen of natural product extract libraries. An extract from Desmanthodium guatemalense was 4-fold more potent for cytotoxicity against MDA-MB-231 cells, which represent the mesenchymal stem-like (MSL) subtype, as compared to cells of other TNBC subtypes. Bioassay-guided fractionation led to the isolation of six polyacetylenes, and subsequent investigations of plant sources known to produce polyacetylenes yielded six additional structurally related compounds. A subset of these compounds retained selective cytotoxic effects in MSL subtype cells. Studies suggest that these selective effects do not appear to be due to PPARγ agonist activities that have previously been reported for polyacetylenes. A CRISPR-Cas9-mediated gene knockout screen was employed to identify the mechanism of selective cytotoxic activity of the most potent and selective compound, dehydrofalcarinol (1a). This genomic screen identified HSD17B11, the gene encoding the enzyme 17β-hydroxysteroid dehydrogenase type 11, as a mediator of the selective cytotoxic effects of 1a in MDA-MB-231 cells that express high levels of this protein. The Project Achilles cancer dependency database further identified a subset of Ewing sarcoma cell lines as highly dependent on HSD17B11 expression, and it was found these were also highly sensitive to 1a. This report demonstrates the value of CRISPR-Cas9 genome-wide screens to identify the mechanisms underlying the selective activities of natural products.