1-[(1R,3R,4R,5R)-6-amino-4-[tert-butyl(dimethyl)silyl]oxy-8,8-dioxo-1-(triisopropylsilyloxymethyl)-2,9-dioxa-8$l^{6}-thiaspiro[4.4]non-6-en-3-yl]-3,5-dimethyl-pyrimidine-2,4-dione | 879082-21-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-[(1R,3R,4R,5R)-6-amino-4-[tert-butyl(dimethyl)silyl]oxy-8,8-dioxo-1-(triisopropylsilyloxymethyl)-2,9-dioxa-8$l^{6}-thiaspiro[4.4]non-6-en-3-yl]-3,5-dimethyl-pyrimidine-2,4-dione
• 英文别名: 1-[(5R,6R,8R,9R)-4-amino-9-[tert-butyl(dimethyl)silyl]oxy-2,2-dioxo-6-[tri(propan-2-yl)silyloxymethyl]-1,7-dioxa-2λ6-thiaspiro[4.4]non-3-en-8-yl]-3,5-dimethylpyrimidine-2,4-dione
• CAS: 879082-21-0
• 化学式: C₂₈H₅₁N₃O₈SSi₂
• 分子量: 645.965
• InChiKey: XJYXWXMRBSNBPK-UBUPGXEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.23
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  146
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  1-[(1R,3R,4R,5R)-6-amino-4-[tert-butyl(dimethyl)silyl]oxy-8,8-dioxo-1-(triisopropylsilyloxymethyl)-2,9-dioxa-8$l^{6}-thiaspiro[4.4]non-6-en-3-yl]-3,5-dimethyl-pyrimidine-2,4-dione 、 苯甲酰异氰酸脂 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 以67%的产率得到[1-[2'-O-(tert-butyldimethylsilyl)-5'-O-(triisopropylsilyl)-β-D-ribofuranosyl]-3-N-methylthymine]-3'-spiro-5''-[4''-(3-benzoylureido)-1'',2''-oxathiole-2'',2''-dioxide]
  参考文献：
  名称：

  Novel Non-Nucleoside Human Cytomegalovirus Inhibitors Based Upon Tsao Nucleoside Derivatives: Structure-Activity Relationships

  摘要：

  TSAO derivatives area unique group of potent and highly specific inhibitors of HIV-1 replication. We have recently reported 4"-ureido TSAO derivatives that are devoid of anti-HIV-1 activity, but inhibit human cytomegalovirus with an activity comparable to that of Ganciclovir. We herein report the synthesis and biological evaluation of novel 4"-ureido TSAO derivatives in order to evaluate the structural features required for anti-HCMV activity. Interestingly, these studies revealed that the compounds may inhibit HCMV at the DNA polymease step via a non-nucleaside mechanism.

  DOI：

  10.1080/15257770701490431
• 作为产物：
  描述：

  三异丙基氯硅烷 、 1-[4-amino-9-(tert-butyl-dimethyl-silanyloxy)-6-hydroxymethyl-2,2-dioxo-1,7-dioxa-2λ⁶-thia-spiro[4.4]non-3-en-8-yl]-3,5-dimethyl-1H-pyrimidine-2,4-dione 在 4-二甲氨基吡啶 作用下， 以 乙腈 为溶剂， 反应 10.0h， 以50%的产率得到1-[(1R,3R,4R,5R)-6-amino-4-[tert-butyl(dimethyl)silyl]oxy-8,8-dioxo-1-(triisopropylsilyloxymethyl)-2,9-dioxa-8$l^{6}-thiaspiro[4.4]non-6-en-3-yl]-3,5-dimethyl-pyrimidine-2,4-dione
  参考文献：
  名称：

  5'-的前所未有的不稳定性ø -叔从3'-螺-5'丁基二甲硅烷基组' - （4' ' -酰基-1' '2' '-oxathiole-2''，2' “二氧化物）通过4''-酰氨基残基的邻近基团参与的核苷衍生物

  摘要：

  叔胺的温和去甲硅烷基化的稀有例子先前已经描述了丁基二甲基甲硅烷基（TBDMS）醚基团通过相邻基团的参与。在这里，我们将详细研究在DMSO溶液中5'-TBDMS基团对4''-酰基氨基TSAO衍生物的不寻常不稳定性的发现。报道了具有不同羰基官能度的各种4''-取代的TSAO衍生物在不同溶剂中的合成和比较化学稳定性研究。还已在TSAO分子的5'-位进行了修饰，以深入了解发生脱甲硅烷基化的结构要求。还研究了溶剂的作用。此外，已经进行了NMR和理论研究，以进一步了解构象，几何，和/或可能在5'-TBDMS组的“自发”释放中起作用的电子参数。提出了涉及4''-酰基氨基的相邻基团参与的甲硅烷基水解机理。

  DOI：

  10.1021/jo0520588

文献信息

• Novel Non-Nucleoside Human Cytomegalovirus Inhibitors Based Upon Tsao Nucleoside Derivatives: Structure-Activity Relationships
  作者：Sonia de Castro、Graziela Andrei、Robert Snoeck、Jan Balzarini、María-José Camarasa、Sonsoles Velázquez

  DOI：10.1080/15257770701490431

  日期：2007.11.26

  TSAO derivatives area unique group of potent and highly specific inhibitors of HIV-1 replication. We have recently reported 4"-ureido TSAO derivatives that are devoid of anti-HIV-1 activity, but inhibit human cytomegalovirus with an activity comparable to that of Ganciclovir. We herein report the synthesis and biological evaluation of novel 4"-ureido TSAO derivatives in order to evaluate the structural features required for anti-HCMV activity. Interestingly, these studies revealed that the compounds may inhibit HCMV at the DNA polymease step via a non-nucleaside mechanism.
• 4′′-Benzoylureido-TSAO Derivatives as Potent and Selective Non-Nucleoside HCMV Inhibitors. Structure−Activity Relationship and Mechanism of Antiviral Action
  作者：Sonia de Castro、M. Teresa Peromingo、Lieve Naesens、Graciela Andrei、Robert Snoeck、Jan Balzarini、Sonsoles Velázquez、María-José Camarasa

  DOI：10.1021/jm800050t

  日期：2008.9.25

  Analogues of the 4"-benzoyl-ureido-TSAO derivative (1) modified at different positions have been prepared and evaluated against wild-type strains of HCMV and murine cytomegalovirus (MCMV) in cell culture. In addition, the activity of the most active derivatives against several drug-resistant HCMV mutants has been determined. A stringent structure-antiviral activity relationship was observed for the 4"-benzoylureido-TSAO derivatives for which the concomitant presence of a highly lipophilic substituent at both 2'- and 5'-positions was required to fully preserve the antihuman cytomegalovirus efficacy. Time-of-addition studies and HCMV immediately early and early gene expression studies revealed a target at the time of viral DNA synthesis, although direct inhibition of HCMV-encoded DNA polymerase could not be observed in cell-free assays. Lack of cross-resistance against a broad variety of mutant HCMV strains points to an antiviral target that is different from those drugs that are currently approved for clinical use.
• Unprecedented Lability of the 5‘-<i>O</i>-<i>tert</i>-Butyldimethylsilyl Group from 3‘-Spiro-5‘ ‘-(4‘ ‘-acylamino-1‘ ‘,2‘ ‘-oxathiole-2‘ ‘,2‘ ‘-dioxide) Nucleoside Derivatives via Neighboring Group Participation of the 4‘ ‘-Acylamino Residue
  作者：Sonia de Castro、Angel Lozano、María-Luisa Jimeno、María-Jesús Pérez-Pérez、Ana San-Félix、María-José Camarasa、Sonsoles Velázquez

  DOI：10.1021/jo0520588

  日期：2006.2.1

  detail, the discovery of the unusual lability of the 5‘-TBDMS group on 4‘ ‘-acylamino TSAO derivatives in DMSO solution. The synthesis and comparative chemical stability studies in different solvents of a variety of 4‘ ‘-substituted TSAO derivatives bearing different carbonyl functionalities are reported. Modifications have also been performed at the 5‘-position of the TSAO molecule to gain insight into

  叔胺的温和去甲硅烷基化的稀有例子先前已经描述了丁基二甲基甲硅烷基（TBDMS）醚基团通过相邻基团的参与。在这里，我们将详细研究在DMSO溶液中5'-TBDMS基团对4''-酰基氨基TSAO衍生物的不寻常不稳定性的发现。报道了具有不同羰基官能度的各种4''-取代的TSAO衍生物在不同溶剂中的合成和比较化学稳定性研究。还已在TSAO分子的5'-位进行了修饰，以深入了解发生脱甲硅烷基化的结构要求。还研究了溶剂的作用。此外，已经进行了NMR和理论研究，以进一步了解构象，几何，和/或可能在5'-TBDMS组的“自发”释放中起作用的电子参数。提出了涉及4''-酰基氨基的相邻基团参与的甲硅烷基水解机理。