(S)-2-(((9H-fluorenyl-methoxy)carbonyl)amino)-4-(diethoxyphosphoryl)-4,4-difluorobutanoic acid | 1428630-39-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: (S)-2-(((9H-fluorenyl-methoxy)carbonyl)amino)-4-(diethoxyphosphoryl)-4,4-difluorobutanoic acid
• 英文别名: (2S)-4-(diethyl phosphono)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4,4-difluorobutanoic acid；(2S)-4-diethoxyphosphoryl-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4,4-difluorobutanoic acid
• CAS: 1428630-39-0
• 化学式: C₂₃H₂₆F₂NO₇P
• 分子量: 497.433
• InChiKey: SVIJKUUVTWVGNC-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.23
• 重原子数：
  34.0
• 可旋转键数：
  11.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  111.16
• 氢给体数：
  2.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (S)-2-(((9H-fluorenyl-methoxy)carbonyl)amino)-4-(diethoxyphosphoryl)-4,4-difluorobutanoic acid 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity

  摘要：

  Many protein-protein interactions in cells are mediated by functional domains that recognize and bind to motifs containing phosphorylated serine and threonine residues. To create small molecules that inhibit such interactions, we developed methodology for the synthesis of a prodrug that generates a phosphoserine peptidomimetic in cells. For this study, we synthesized a small molecule inhibitor of 14-3-3 proteins that incorporates a nonhydrolyzable difluoromethylenephosphoserine prodrug moiety. The prodrug is cytotoxic at low micromolar concentrations when applied to cancer cells and induces caspase activation resulting in apoptosis. The prodrug reverses the 14-3-3-mediated inhibition of FOXO3a resulting from its phosphorylation by Akt1 in a concentration-dependent manner that correlates well with its ability to inhibit cell growth. This methodology can be applied to target a variety of proteins containing phosphoserine and other phosphoamino acid binding domains.

  DOI：

  10.1016/j.chembiol.2012.05.011
• 作为产物：
  描述：

  二氟甲基膦酸二乙酯 在 盐酸 、 六甲基磷酰三胺 、 4-二甲氨基吡啶 、 Jones reagent 、 水 、 magnesium 、 N,N-二异丙基乙胺 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 丙酮 为溶剂， 生成 (S)-2-(((9H-fluorenyl-methoxy)carbonyl)amino)-4-(diethoxyphosphoryl)-4,4-difluorobutanoic acid
  参考文献：
  名称：

  Synthesis of a Phosphoserine Mimetic Prodrug with Potent 14-3-3 Protein Inhibitory Activity

  摘要：

  Many protein-protein interactions in cells are mediated by functional domains that recognize and bind to motifs containing phosphorylated serine and threonine residues. To create small molecules that inhibit such interactions, we developed methodology for the synthesis of a prodrug that generates a phosphoserine peptidomimetic in cells. For this study, we synthesized a small molecule inhibitor of 14-3-3 proteins that incorporates a nonhydrolyzable difluoromethylenephosphoserine prodrug moiety. The prodrug is cytotoxic at low micromolar concentrations when applied to cancer cells and induces caspase activation resulting in apoptosis. The prodrug reverses the 14-3-3-mediated inhibition of FOXO3a resulting from its phosphorylation by Akt1 in a concentration-dependent manner that correlates well with its ability to inhibit cell growth. This methodology can be applied to target a variety of proteins containing phosphoserine and other phosphoamino acid binding domains.

  DOI：

  10.1016/j.chembiol.2012.05.011

文献信息

• Exploratory studies on CA-15L, an anti-HIV active HIV-1 capsid fragment
  作者：Kohei Tsuji、Kofi Baffour-Awuah Owusu、Takuya Kobayakawa、Rongyi Wang、Masayuki Fujino、Moemi Kaneko、Naoki Yamamoto、Tsutomu Murakami、Hirokazu Tamamura

  DOI：10.1016/j.bmc.2020.115488

  日期：2020.6

  Utilizing overlapping fragment peptide libraries covering the whole sequence of an HIV-1 capsid (CA) protein with the addition of an octa-arginyl moiety, we had previously found several peptides with anti-HIV-1 activity. Herein, among these potent CA fragment peptides, CA-15L was examined because this peptide sequence overlaps with Helix 7, a helix region of the CA protein, which may be important for

  利用覆盖了HIV-1衣壳（CA）蛋白整个序列的重叠片段肽库，并添加了一个八-精氨酸部分，我们以前发现了几种具有抗HIV-1活性的肽。在此，在这些有效的CA片段肽中，检查了CA-15L，因为该肽序列与CA蛋白的螺旋区螺旋7重叠，这对于CA蛋白的寡聚化可能是重要的。合成了具有亲水性残基的CA-15L替代物及其衍生物，其中氨基酸序列被一个或多个残基向C末端移动，并评估了其抗HIV活性。此外，合成了其取代Ser149残基的衍生物，并评估了它们的抗HIV活性，因为Ser149可能在CA蛋白寡聚体的降解步骤中被磷酸化。发现了几种活性化合物，它们可能成为新的抗HIV药物和阐明CA功能的新工具。
• Synthesis of α,α-Difluorinated Phosphonate pSer/pThr Mimetics via Rhodium-Catalyzed Asymmetric Hydrogenation of β-Difluorophosphonomethyl α-(Acylamino)acrylates
  作者：Hong-Xue Chen、Jie Kang、Rong Chang、Yun-Lai Zhang、Hua-Zhen Duan、Yan-Mei Li、Yong-Xiang Chen

  DOI：10.1021/acs.orglett.8b01151

  日期：2018.6.1

  for α,α-difluorinated phosphonate mimetics of phosphoserine/phosphothreonine utilizing rhodium-catalyzed asymmetric hydrogenation was developed. The dehydrogenated substrate β-difluorophosphonomethyl α-(acylamino)acrylates were first prepared from protected serine/threonine followed by asymmetric hydrogenation using the rhodium–DuPhos catalytic system to generate the chiral center(s). These important

  提出了利用铑催化的不对称加氢合成磷酸丝氨酸/磷酸苏氨酸的α，α-二氟代膦酸酯模拟物的简便方法。脱氢的底物β-二氟膦酰基甲基α-（酰基氨基）丙烯酸酯首先由受保护的丝氨酸/苏氨酸制备，然后使用铑-DuPhos催化系统进行不对称氢化以生成手性中心。这些重要的膦酸酯结构单元已成功地掺入抗磷酸酶的肽中，与亲本pSer / pThr肽相比，其显示出与14-3-3ζ蛋白相似的抑制作用。