3-(tetrazol-5-yl)thymidine | 1425377-07-6

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: 3-(tetrazol-5-yl)thymidine
• 英文别名: 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-3-(2H-tetrazol-5-yl)pyrimidine-2,4-dione
• CAS: 1425377-07-6
• 化学式: C₁₁H₁₄N₆O₅
• 分子量: 310.269
• InChiKey: BHECPIRLBWKOIC-XLPZGREQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  145
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-(tetrazol-5-yl)thymidine 、 1-碘代丙烷 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 24.0h， 以71%的产率得到1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-3-(2-propyltetrazol-5-yl)pyrimidine-2,4-dione
  参考文献：
  名称：

  Synthesis of N3-substituted carboranyl thymidine bioconjugates and their evaluation as substrates of recombinant human thymidine kinase 1

  摘要：

  Four different libraries of overall twenty three N3-substituted thymidine (dThd) analogues, including eleven 3-carboranyl thymidine analogues (3CTAs), were synthesized. The latter are potential agents for Boron Neutron Capture Therapy (BNCT) of cancer. Linker between the dThd scaffold and the m-carborane cluster at the N3-position of the 3CTAs contained amidinyl-(3e and 3f), guanidyl-(7e-7g), tetrazolylmethyl-(9b1/2-9d1/2), or tetrazolyl groups (11b1/2-11d1/2) to improve human thymidine kinase 1 (hTK1) substrate characteristics and water solubilities compared with 1st generation 3CTAs, such as N5 and N5-2OH. The amidinyl- and guanidyl-type N3-substitued dThd analogues (3a-3f and 7a -7g) had hTK1 phosphorylation rates of <30% relative to that of dThd, the endogenous hTK1 substrate, whereas the tetrazolyl-type N3-substitued dThd analogues (9a, 9b1/2-9d1/2 and 11a, 11b1/2-11d1/2) had relative phosphorylation rates (rPRs) of >40%. Compounds 9a, 9b1/2-9d1/2 and 11a, 11b1/2 -11d1/2 were subjected to in-depth enzyme kinetics studies and the obtained rk(cat)/K-m (k(cat)/K-m relative to that of dThd) ranged from 2.5 to 26%. The tetrazolyl-type N3-substitued dThd analogues 9b1/2 and 11d1/2 were the best substrates of hTK1 with rPRs of 52.4% and 42.5% and rk(cat)/K-m values of 14.9% and 19.7% respectively. In comparison, the rPR and rk(cat)/K-m values of N5-2OH in this specific study were 41.5% and 10.8%, respectively. Compounds 3e and 3f were >1900 and >1500 times, respectively, better soluble in PBS (pH 7.4) than N5-2OH whereas solubilities for 9b1/2-9d1/2 and 11b1/2-11d1/2 were only 1.3-13 times better. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.11.041
• 作为产物：
  描述：

  3',5'-(di-tert-butyldimethylsilyl)thymidine 在 sodium azide 、 三乙胺 、 三氟乙酸 、 zinc dibromide 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 异丙醇 、 丙酮 为溶剂， 反应 11.0h， 生成 3-(tetrazol-5-yl)thymidine
  参考文献：
  名称：

  Synthesis of N3-substituted carboranyl thymidine bioconjugates and their evaluation as substrates of recombinant human thymidine kinase 1

  摘要：

  Four different libraries of overall twenty three N3-substituted thymidine (dThd) analogues, including eleven 3-carboranyl thymidine analogues (3CTAs), were synthesized. The latter are potential agents for Boron Neutron Capture Therapy (BNCT) of cancer. Linker between the dThd scaffold and the m-carborane cluster at the N3-position of the 3CTAs contained amidinyl-(3e and 3f), guanidyl-(7e-7g), tetrazolylmethyl-(9b1/2-9d1/2), or tetrazolyl groups (11b1/2-11d1/2) to improve human thymidine kinase 1 (hTK1) substrate characteristics and water solubilities compared with 1st generation 3CTAs, such as N5 and N5-2OH. The amidinyl- and guanidyl-type N3-substitued dThd analogues (3a-3f and 7a -7g) had hTK1 phosphorylation rates of <30% relative to that of dThd, the endogenous hTK1 substrate, whereas the tetrazolyl-type N3-substitued dThd analogues (9a, 9b1/2-9d1/2 and 11a, 11b1/2-11d1/2) had relative phosphorylation rates (rPRs) of >40%. Compounds 9a, 9b1/2-9d1/2 and 11a, 11b1/2 -11d1/2 were subjected to in-depth enzyme kinetics studies and the obtained rk(cat)/K-m (k(cat)/K-m relative to that of dThd) ranged from 2.5 to 26%. The tetrazolyl-type N3-substitued dThd analogues 9b1/2 and 11d1/2 were the best substrates of hTK1 with rPRs of 52.4% and 42.5% and rk(cat)/K-m values of 14.9% and 19.7% respectively. In comparison, the rPR and rk(cat)/K-m values of N5-2OH in this specific study were 41.5% and 10.8%, respectively. Compounds 3e and 3f were >1900 and >1500 times, respectively, better soluble in PBS (pH 7.4) than N5-2OH whereas solubilities for 9b1/2-9d1/2 and 11b1/2-11d1/2 were only 1.3-13 times better. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.11.041

文献信息

• Synthesis of N3-substituted carboranyl thymidine bioconjugates and their evaluation as substrates of recombinant human thymidine kinase 1
  作者：Hitesh K. Agarwal、Craig A. McElroy、Elena Sjuvarsson、Staffan Eriksson、Michael V. Darby、Werner Tjarks

  DOI：10.1016/j.ejmech.2012.11.041

  日期：2013.2

  Four different libraries of overall twenty three N3-substituted thymidine (dThd) analogues, including eleven 3-carboranyl thymidine analogues (3CTAs), were synthesized. The latter are potential agents for Boron Neutron Capture Therapy (BNCT) of cancer. Linker between the dThd scaffold and the m-carborane cluster at the N3-position of the 3CTAs contained amidinyl-(3e and 3f), guanidyl-(7e-7g), tetrazolylmethyl-(9b1/2-9d1/2), or tetrazolyl groups (11b1/2-11d1/2) to improve human thymidine kinase 1 (hTK1) substrate characteristics and water solubilities compared with 1st generation 3CTAs, such as N5 and N5-2OH. The amidinyl- and guanidyl-type N3-substitued dThd analogues (3a-3f and 7a -7g) had hTK1 phosphorylation rates of <30% relative to that of dThd, the endogenous hTK1 substrate, whereas the tetrazolyl-type N3-substitued dThd analogues (9a, 9b1/2-9d1/2 and 11a, 11b1/2-11d1/2) had relative phosphorylation rates (rPRs) of >40%. Compounds 9a, 9b1/2-9d1/2 and 11a, 11b1/2 -11d1/2 were subjected to in-depth enzyme kinetics studies and the obtained rk(cat)/K-m (k(cat)/K-m relative to that of dThd) ranged from 2.5 to 26%. The tetrazolyl-type N3-substitued dThd analogues 9b1/2 and 11d1/2 were the best substrates of hTK1 with rPRs of 52.4% and 42.5% and rk(cat)/K-m values of 14.9% and 19.7% respectively. In comparison, the rPR and rk(cat)/K-m values of N5-2OH in this specific study were 41.5% and 10.8%, respectively. Compounds 3e and 3f were >1900 and >1500 times, respectively, better soluble in PBS (pH 7.4) than N5-2OH whereas solubilities for 9b1/2-9d1/2 and 11b1/2-11d1/2 were only 1.3-13 times better. (C) 2012 Elsevier Masson SAS. All rights reserved.