(Z)-9-{[2-(hydroxymethyl)-2-(2-phosphonoethyl)cyclopropylidene]methyl}guanine | 1170854-89-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: (Z)-9-{[2-(hydroxymethyl)-2-(2-phosphonoethyl)cyclopropylidene]methyl}guanine
• 英文别名: 2-[(2Z)-2-[(2-amino-6-oxo-1H-purin-9-yl)methylene]-1-(hydroxymethyl)cyclopropyl]ethylphosphonic acid；2-[(2Z)-2-[(2-amino-6-oxo-1H-purin-9-yl)methylidene]-1-(hydroxymethyl)cyclopropyl]ethylphosphonic acid
• CAS: 1170854-89-3
• 化学式: C₁₂H₁₆N₅O₅P
• 分子量: 341.263
• InChiKey: YRQDFNHUDXCZMV-DAXSKMNVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  163
• 氢给体数：
  5
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (Z)-9-{[2-(hydroxymethyl)-2-(2-phosphonoethyl)cyclopropylidene]methyl}guanine 在 吡啶 、 N,N'-二环己基-4-吗啉脒 、 N,N'-二环己基碳二亚胺 、 ammonium hydroxide 作用下， 以 水 为溶剂， 反应 12.0h， 以85%的产率得到2-amino-9-[(Z)-(6-hydroxy-6-oxo-7-oxa-6$l^{5}-phosphaspiro[2.5]octan-2-ylidene)methyl]-1H-purin-6-one
  参考文献：
  名称：

  Phosphonate analogues of cyclopropavir phosphates and their E-isomers. Synthesis and antiviral activity

  摘要：

  Z- and E-Phosphonate analogues 12 and 13 derived from cyclopropavir and the corresponding cyclic phosphonates 14 and 15 were synthesized and their antiviral activity was investigated. The 2,2-bis(hydroxymethylmethylenecyclopropane acetate (17) was transformed to tetrahydropyranyl acetate 18. Deacetylation gave intermediate 19 which was converted to bromide 20. Alkylation with diisopropyl methylphosphonate afforded after protecting group exchange (21 to 22) acetylated phosphonate intermediate 22. Addition of bromine gave the dibromo derivative 16 which was used in the alkylation-elimination procedure with 2-amino-6-chloropurine to give Z- and E-isomers 23 and 24. Hydrolytic dechlorination coupled with removal of all protecting groups gave the guanine phosphonates 12 and 13. Cyclization afforded the cyclic phosphonates 14 and 15. Z-Phosphonate 12 was a potent and noncytotoxic inhibitor of human and murine cytomegalovirus (HCMV and MCMV) with EC50 2.2-2.7 and 0.13 mu M, respectively. It was also an effective agent against Epstein-Barr virus (EBV, EC50 3.1 mu M). The cyclic phosphonate 14 inhibited HCMV (EC50 2.4-11.5 mu M) and MCMV (EC50 0.4 mu M) but it was ineffective against EBV. Both phosphonates 12 and 14 were as active against two HCMV Towne strains with mutations in UL97 as they were against wild-type HCMV thereby circumventing resistance due to such mutations. Z-Phosphonate 12 was a moderate inhibitor of replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) but it was a potent agent against varicella zoster virus (VZV, EC50 2.9 mu M). The cyclic phosphonate 14 lacked significant potency against these viruses. E-isomers 13 and 15 were devoid of antiviral activity. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.04.020
• 作为产物：
  描述：

  (Z)-2-amino-6-chloro-9-{[2-(2-diisopropylphosphonoethyl)-2-(acetoxymethyl)cyclopropylidene]methyl}purine 在 甲酸 、 水 、 三甲基溴硅烷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 30.0h， 以286 mg的产率得到(Z)-9-{[2-(hydroxymethyl)-2-(2-phosphonoethyl)cyclopropylidene]methyl}guanine
  参考文献：
  名称：

  Phosphonate analogues of cyclopropavir phosphates and their E-isomers. Synthesis and antiviral activity

  摘要：

  Z- and E-Phosphonate analogues 12 and 13 derived from cyclopropavir and the corresponding cyclic phosphonates 14 and 15 were synthesized and their antiviral activity was investigated. The 2,2-bis(hydroxymethylmethylenecyclopropane acetate (17) was transformed to tetrahydropyranyl acetate 18. Deacetylation gave intermediate 19 which was converted to bromide 20. Alkylation with diisopropyl methylphosphonate afforded after protecting group exchange (21 to 22) acetylated phosphonate intermediate 22. Addition of bromine gave the dibromo derivative 16 which was used in the alkylation-elimination procedure with 2-amino-6-chloropurine to give Z- and E-isomers 23 and 24. Hydrolytic dechlorination coupled with removal of all protecting groups gave the guanine phosphonates 12 and 13. Cyclization afforded the cyclic phosphonates 14 and 15. Z-Phosphonate 12 was a potent and noncytotoxic inhibitor of human and murine cytomegalovirus (HCMV and MCMV) with EC50 2.2-2.7 and 0.13 mu M, respectively. It was also an effective agent against Epstein-Barr virus (EBV, EC50 3.1 mu M). The cyclic phosphonate 14 inhibited HCMV (EC50 2.4-11.5 mu M) and MCMV (EC50 0.4 mu M) but it was ineffective against EBV. Both phosphonates 12 and 14 were as active against two HCMV Towne strains with mutations in UL97 as they were against wild-type HCMV thereby circumventing resistance due to such mutations. Z-Phosphonate 12 was a moderate inhibitor of replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) but it was a potent agent against varicella zoster virus (VZV, EC50 2.9 mu M). The cyclic phosphonate 14 lacked significant potency against these viruses. E-isomers 13 and 15 were devoid of antiviral activity. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.04.020

文献信息

• Phosphonate analogues of cyclopropavir phosphates and their E-isomers. Synthesis and antiviral activity
  作者：Santosh B. Mhaske、Bashar Ksebati、Mark N. Prichard、John C. Drach、Jiri Zemlicka

  DOI：10.1016/j.bmc.2009.04.020

  日期：2009.6

  Z- and E-Phosphonate analogues 12 and 13 derived from cyclopropavir and the corresponding cyclic phosphonates 14 and 15 were synthesized and their antiviral activity was investigated. The 2,2-bis(hydroxymethylmethylenecyclopropane acetate (17) was transformed to tetrahydropyranyl acetate 18. Deacetylation gave intermediate 19 which was converted to bromide 20. Alkylation with diisopropyl methylphosphonate afforded after protecting group exchange (21 to 22) acetylated phosphonate intermediate 22. Addition of bromine gave the dibromo derivative 16 which was used in the alkylation-elimination procedure with 2-amino-6-chloropurine to give Z- and E-isomers 23 and 24. Hydrolytic dechlorination coupled with removal of all protecting groups gave the guanine phosphonates 12 and 13. Cyclization afforded the cyclic phosphonates 14 and 15. Z-Phosphonate 12 was a potent and noncytotoxic inhibitor of human and murine cytomegalovirus (HCMV and MCMV) with EC50 2.2-2.7 and 0.13 mu M, respectively. It was also an effective agent against Epstein-Barr virus (EBV, EC50 3.1 mu M). The cyclic phosphonate 14 inhibited HCMV (EC50 2.4-11.5 mu M) and MCMV (EC50 0.4 mu M) but it was ineffective against EBV. Both phosphonates 12 and 14 were as active against two HCMV Towne strains with mutations in UL97 as they were against wild-type HCMV thereby circumventing resistance due to such mutations. Z-Phosphonate 12 was a moderate inhibitor of replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) but it was a potent agent against varicella zoster virus (VZV, EC50 2.9 mu M). The cyclic phosphonate 14 lacked significant potency against these viruses. E-isomers 13 and 15 were devoid of antiviral activity. (C) 2009 Elsevier Ltd. All rights reserved.