[1-[2',5'-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-(methyl)thymine]-3'-spiro-5''-[4''-(3-benzoylureido)-1'',2''-oxathiole-2'',2''-dioxide] | 378748-06-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-(methyl)thymine]-3'-spiro-5''-[4''-(3-benzoylureido)-1'',2''-oxathiole-2'',2''-dioxide]
• 英文别名: 4''-benzoyl-ureido-TSAO-m3T；N-[[(5R,6R,8R,9R)-9-[tert-butyl(dimethyl)silyl]oxy-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-8-(3,5-dimethyl-2,4-dioxopyrimidin-1-yl)-2,2-dioxo-1,7-dioxa-2lambda6-thiaspiro[4.4]non-3-en-4-yl]carbamoyl]benzamide；N-[[(5R,6R,8R,9R)-9-[tert-butyl(dimethyl)silyl]oxy-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-8-(3,5-dimethyl-2,4-dioxopyrimidin-1-yl)-2,2-dioxo-1,7-dioxa-2λ6-thiaspiro[4.4]non-3-en-4-yl]carbamoyl]benzamide
• CAS: 378748-06-2
• 化学式: C₃₃H₅₀N₄O₁₀SSi₂
• 分子量: 751.018
• InChiKey: MOPSDZXNUDMGOE-CBGHTPRCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.24
• 重原子数：
  50
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  178
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-(methyl)thymine]-3'-spiro-5''-[4''-(3-benzoylureido)-1'',2''-oxathiole-2'',2''-dioxide] 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 0.08h， 以72%的产率得到[1-(β-D-ribofuranosyl)-3-N-methylthymine]-3'-spiro-5''-[4''-(3-benzoylureido)-1'',2''-oxathiole-2'',2''-dioxide]
  参考文献：
  名称：

  4′′-Benzoylureido-TSAO Derivatives as Potent and Selective Non-Nucleoside HCMV Inhibitors. Structure−Activity Relationship and Mechanism of Antiviral Action

  摘要：

  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.

  DOI：

  10.1021/jm800050t
• 作为产物：
  描述：

  1-[(5R,6R,7R,9R)-4-氨基-6-(叔丁基-二甲基硅烷基)氧基-9-[(叔丁基-二甲基硅烷基)氧基甲基]-2,2-二氧代-1,8-二氧杂-2lambda6-硫杂螺[4.4]壬-3-烯-7-基]-3,5-二甲基嘧啶-2,4-二酮 、 苯甲酰异氰酸脂 在 sodium hydride 作用下， 以 乙腈 为溶剂， 以90%的产率得到[1-[2',5'-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-(methyl)thymine]-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

文献信息

• Novel [2‘,5‘-Bis-<i>O-</i>(<i>tert-</i>butyldimethylsilyl)-β-<scp>d</scp>-ribofuranosyl]- 3‘-spiro-5‘ ‘-(4‘ ‘-amino-1‘ ‘,2‘ ‘-oxathiole-2‘ ‘,2‘ ‘-dioxide) Derivatives with Anti-HIV-1 and Anti-Human-Cytomegalovirus Activity
  作者：Sonia de Castro、Esther Lobatón、María-Jesús Pérez-Pérez、Ana San-Félix、Alessandra Cordeiro、Graciela Andrei、Robert Snoeck、Erik De Clercq、Jan Balzarini、María-José Camarasa、Sonsoles Velázquez

  DOI：10.1021/jm040868q

  日期：2005.2.1

  New [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide) (TSAO) derivatives substituted at the 4"-amino group of the spiro moiety with different carbonyl functionalities have been designed and synthesized. Various synthetic procedures, on the scarcely studied reactivity of the 3'-spiroaminooxathioledioxide moiety, have been explored. The compounds were evaluated for their inhibitory effect on both wild-type and TSAO-resistant HIV-1 strains, in cell culture. The presence of a methyl ester (10) or amide groups (12) at the 4"-position conferred the highest anti-HIV-1 activity, while the free oxalyl acid derivative (11) was 10- to 20-fold less active against the virus. In contrast, the presence at this position of (un)substituted ureido or acyl groups markedly diminished or annihilated the anti-HIV-1 activity. Surprisingly, some of the target compounds also showed inhibition of human cytomegalovirus (HCMV) replication at subtoxic concentrations. This has never been observed previously for TSAO derivatives. In particular, compound 26 represents the first TSAO derivative with dual anti-HIV-1 and -HCMV activity.
• “SECOND GENERATION” OF TSAO COMPOUNDS DIRECTED AGAINST HIV-1 TSAO-RESISTANT STRAINS
  作者：E. Lobatón、S. Velázquez、M. J. Pérez-Pérez、M. L. Jimeno、A. San-Félix、E. De Clercq、J. Balzarini、M. J. Camarasa

  DOI：10.1081/ncn-100002356

  日期：2001.3.31

  A "second generation" of TSAO molecules directed against TSAO-resistant strains have been prepared. The presence of two neighboring carbonyl groups at the 4 " position of the 3'-spiro moiety seems to be important for the anti-HIV-1 activity against both wild type and TSAO-resistant strains. NMR conformational studies in solution and theoretical calculations of the novel compounds have also been carried out.