[(2R,3S,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-2-[[(4-methoxyphenyl)-diphenylmethoxy]methyl]oxolan-3-yl] acetate | 1053608-92-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: [(2R,3S,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-2-[[(4-methoxyphenyl)-diphenylmethoxy]methyl]oxolan-3-yl] acetate
• CAS: 1053608-92-6
• 化学式: C₃₁H₂₉FN₂O₇
• 分子量: 560.579
• InChiKey: FFLCCZXLDSZERI-UPRLRBBYSA-N

物化性质

• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  41
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  [(2R,3S,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-2-[[(4-methoxyphenyl)-diphenylmethoxy]methyl]oxolan-3-yl] acetate 在 溶剂黄146 作用下， 反应 0.33h， 生成 β-5-Fluor-3'-acetyl-2'-desoxy-uridin
  参考文献：
  名称：

  Synthesis and Biological Activity of Aromatic Amino Acid Phosphoramidates of 5-Fluoro-2‘-deoxyuridine and 1-β-Arabinofuranosylcytosine:  Evidence of Phosphoramidase Activity

  摘要：

  The amino acid phosphoramidate diesters of FUdR (2) and Ara-C (6), 5-fluoro-2'-deoxy-5'-uridyl N-(1-carbomethoxy-2-phenylethyl)phosphor (5a), 5-fluoro-2'-deoxy-5'-uridyl N-(1-carbomethoxy-2-indolylethyl)phosphoramidate (5b), 1-beta-arabinofuranosylcytosine 5'-N-(1-carbomethoxy-2-phenylethyl)phosphoramidate (8a), and 1-beta-arabinofuranosylcytosine 5'-N-(1-carbomethoxy-2-indolylethyl)phosphoramidate (8b), were synthesized and tested for their antitumor activity against L1210 mouse lymphocytic leukemia cells and CCRF-CEM human T-cell lymphoblastic leukemia cells. Ara-C phosphoramidates 8a,b were found to be inactive at a concentration of 100 mu M, while the FUdR conjugates 5a,b exhibited IC50 values within a range of 0.30-0.40 mu M. Stability studies revealed that >99% of the phosphoramidates remained intact after incubation for >2 days in 20% calf or 20% human serum. Intracellular thymidylate synthase (TS) inhibition studies revealed that treatment of L1210 and CCRF-CEM cells with 5a or 5b resulted in significant inhibition of TS in intact and permeabilized cells, while treatment of L929 TK- cells with these compounds did not result in inhibition of TS activity in intact cells. However, permeabilization of L929 TK- cells enhanced the activity of 5a,b toward intracellular TS by 900- and 1500-fold, respectively. In addition, incubation of cell-free extracts of CEM cells with radiolabeled 5b resulted in the rapid production of FUdR 5'-monophosphate and a lag in the generation of FUdR. Consequently, it is proposed that the metabolism of the phosphoramidate diesters of FUdR in proliferating tissue proceeds through two separate enzymatic steps involving P-N bond cleavage by an unknown phosphoramidase followed by P-O bond cleavage by phosphatases such as 5'-nucleotidase.

  DOI：

  10.1021/jm9603680
• 作为产物：
  描述：

  4-甲氧基三苯基氯甲烷 在 吡啶 作用下， 反应 52.0h， 生成 [(2R,3S,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-2-[[(4-methoxyphenyl)-diphenylmethoxy]methyl]oxolan-3-yl] acetate
  参考文献：
  名称：

  Synthesis and Biological Activity of Aromatic Amino Acid Phosphoramidates of 5-Fluoro-2‘-deoxyuridine and 1-β-Arabinofuranosylcytosine:  Evidence of Phosphoramidase Activity

  摘要：

  The amino acid phosphoramidate diesters of FUdR (2) and Ara-C (6), 5-fluoro-2'-deoxy-5'-uridyl N-(1-carbomethoxy-2-phenylethyl)phosphor (5a), 5-fluoro-2'-deoxy-5'-uridyl N-(1-carbomethoxy-2-indolylethyl)phosphoramidate (5b), 1-beta-arabinofuranosylcytosine 5'-N-(1-carbomethoxy-2-phenylethyl)phosphoramidate (8a), and 1-beta-arabinofuranosylcytosine 5'-N-(1-carbomethoxy-2-indolylethyl)phosphoramidate (8b), were synthesized and tested for their antitumor activity against L1210 mouse lymphocytic leukemia cells and CCRF-CEM human T-cell lymphoblastic leukemia cells. Ara-C phosphoramidates 8a,b were found to be inactive at a concentration of 100 mu M, while the FUdR conjugates 5a,b exhibited IC50 values within a range of 0.30-0.40 mu M. Stability studies revealed that >99% of the phosphoramidates remained intact after incubation for >2 days in 20% calf or 20% human serum. Intracellular thymidylate synthase (TS) inhibition studies revealed that treatment of L1210 and CCRF-CEM cells with 5a or 5b resulted in significant inhibition of TS in intact and permeabilized cells, while treatment of L929 TK- cells with these compounds did not result in inhibition of TS activity in intact cells. However, permeabilization of L929 TK- cells enhanced the activity of 5a,b toward intracellular TS by 900- and 1500-fold, respectively. In addition, incubation of cell-free extracts of CEM cells with radiolabeled 5b resulted in the rapid production of FUdR 5'-monophosphate and a lag in the generation of FUdR. Consequently, it is proposed that the metabolism of the phosphoramidate diesters of FUdR in proliferating tissue proceeds through two separate enzymatic steps involving P-N bond cleavage by an unknown phosphoramidase followed by P-O bond cleavage by phosphatases such as 5'-nucleotidase.

  DOI：

  10.1021/jm9603680