(diethoxyphosphoryl) methyl nosylate | 35449-96-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (diethoxyphosphoryl) methyl nosylate
• 英文别名: Diaethoxyphosphinylmethyl-m-nitrobenzolsulfonat；(Di-ethoxyphosphinyl)-methyl-m-nitrophenylsulfonat
• CAS: 35449-96-8
• 化学式: C₁₁H₁₆NO₈PS
• 分子量: 353.29
• InChiKey: CHGMUTWPHLCMTG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.52
• 重原子数：
  22.0
• 可旋转键数：
  9.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  122.04
• 氢给体数：
  0.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  (diethoxyphosphoryl) methyl nosylate 、 ((3aR,4R,6R,6aR)-6-(6-chloro-4-(2',3'-dihydrospiro[azetidine-3,1'-inden]-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol 在 magnesium 2-methylpropan-2-olate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以95%的产率得到diethyl ((((3aR,4R,6R,6aR)-6-(6-chloro-4-(2',3'-dihydrospiro[azetidine-3,1'-inden]-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)phosphonate
  参考文献：
  名称：

  A Novel CD73 Inhibitor SHR170008 Suppresses Adenosine in Tumor and Enhances Anti-Tumor Activity with PD-1 Blockade in a Mouse Model of Breast Cancer

  摘要：

  Introduction: CD73 and adenosine support growth-promoting neovascularization, metastasis, and survival in cells, and promote anti-PD-1 mAb therapy-induced immune escape. Consequently, developing a CD73 inhibitor as monotherapy and a potential beneficial combination partner with immune-checkpoint inhibitors needs investigation. Methods: CD73 inhibitors were evaluated in vitro with soluble and membrane-bound CD73 enzymes, as well as its PD biomarker responses in human peripheral blood mononuclear cells (PBMC) by flow cytometry and ELISA. The binding modes of the molecules were analyzed via molecular modeling. The anti-tumor activity and synergistic effect of SHR170008 in combination with anti-PD-1 mAb were evaluated in a syngeneic mouse breast cancer model. Results: SHR170008 was discovered during the initial structural modifications on the link between the ribose and the α-phosphate of AMPCP, which significantly improved the stability of the compound confirmed by the metabolite identification study. Further modifications on the adenine base of AMPCP improved the potency due to forming stronger interactions with CD73 protein. It exhibited potent inhibitory activities on soluble and endogenous membrane-bound CD73 enzymes, and induced IFNγ production, reversed AMP-suppressed CD25+ and CD8+/CD25+ expression, and enhanced granzyme B production on CD8+ T cells in human PBMC. SHR170008 showed dose-dependent anti-tumor efficacy with suppression of adenosine in the tumors in EMT6 mouse breast tumor model. The increase of adenosine in tumor tissue by anti-PD-1 mAb alone was suppressed by SHR170008 in the combination groups. Simultaneous inhibition of CD73 and PD-1 neutralization synergistically enhanced antitumor immunity and biomarkers in response, and exposures of SHR170008 were correlated with the efficacy readouts. Conclusion: Our findings suggest that CD73 may serve as an immune checkpoint by generating adenosine, which suppresses the antitumor activity of anti-PD-1 mAb, and inhibition of CD73 may be a potential beneficial combination partner with immune-checkpoint inhibitors to improve their therapeutic outcomes in general.

  DOI：

  10.2147/ott.s326178
• 作为产物：
  描述：

  羟甲基膦酸二乙酯 、 3-硝基苯磺酰氯 在 氢氧化钾 作用下， 以 乙醚 为溶剂， 生成 (diethoxyphosphoryl) methyl nosylate
  参考文献：
  名称：

  Vizgert,R.V.; Voloshin,M.P., Journal of general chemistry of the USSR, 1971, vol. 41, p. 2009 - 2011

  摘要：

  DOI：