{1-[2',5'-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-(3-hydroxypropyl)thymine}-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) | 347916-41-0

• 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-(3-hydroxypropyl)thymine}-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)
• 英文别名: 1-[(5R,6R,8R,9R)-4-amino-9-[tert-butyl(dimethyl)silyl]oxy-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-1,7-dioxa-2lambda6-thiaspiro[4.4]non-3-en-8-yl]-3-(3-hydroxypropyl)-5-methylpyrimidine-2,4-dione；1-[(5R,6R,8R,9R)-4-amino-9-[tert-butyl(dimethyl)silyl]oxy-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-1,7-dioxa-2λ6-thiaspiro[4.4]non-3-en-8-yl]-3-(3-hydroxypropyl)-5-methylpyrimidine-2,4-dione
• CAS: 347916-41-0
• 化学式: C₂₇H₄₉N₃O₉SSi₂
• 分子量: 647.938
• InChiKey: KQEYNZWYFCBEOF-MGUUAAOPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.91
• 重原子数：
  42
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  166
• 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-(3-hydroxypropyl)thymine}-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) 在 palladium on activated charcoal 氢气 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， -20.0~25.0 ℃ 、206.84 kPa 条件下， 反应 1.08h， 生成 [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-[3-[[(hydroxycarbonyl)hydroxyphosphonyl]oxy]propyl]thymine]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)
  参考文献：
  名称：

  Hybrids of [TSAO-T]−[Foscarnet]:  The First Conjugate of Foscarnet with a Non-nucleoside Reverse Transcriptase Inhibitor through a Labile Covalent Ester Bond

  摘要：

  This paper describes the first example of combination of non-nucleoside reverse transcriptase inhibitors such as TSAO derivatives and foscarnet (PFA) in a single molecule through a labile covalent ester bond. The essential criteria in the design of these hybrids [TSAO-T]-[PFA] was to explore if the conjugation of foscarnet with the highly lipophilic TSAO derivative may facilitate the penetration of the conjugates through the cell membrane and if the hybrids escape extracellular hydrolysis and regenerate the parent inhibitors intracellulary. Several [TSAO-T]-[PFA] conjugates proved markedly inhibitory to HIV-1. Some of them also showed potent activity against PFA-resistant HIV-1 strains but fewer had detectable inhibitory activity against TSAO-resistant HIV-1 strains. These results indicated a pivotal role of the TSAO component of the hybrid but not the PFA component in the activity of the conjugates. Moreover, stability studies of the [TSAO-T]-[PFA] conjugates demonstrated that the compounds were stable in PBS whereas some of the conjugates regenerated the parent inhibitors in extracts from CEM cells.

  DOI：

  10.1021/jm031045o
• 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-2-硫杂螺[4.4]壬-3-烯-7-基]-5-甲基嘧啶-2,4-二酮 、 3-溴-1-丙醇 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 6.0h， 以78%的产率得到{1-[2',5'-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-(3-hydroxypropyl)thymine}-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)
  参考文献：
  名称：

  Identification of a Putative Binding Site for [2‘,5‘-Bis-O-(tert-butyldimethylsilyl)-β-d-ribofuranosyl]-3‘-spiro-5‘ ‘-(4‘ ‘-amino-1‘ ‘,2‘ ‘-oxathiole-2‘ ‘,2‘ ‘-dioxide)thymine (TSAO) Derivatives at the p51−p66 Interface of HIV-1 Reverse Transcriptase

  摘要：

  A binding site for TSAO-m(3)T at the interface between the p66 and p51 subunits of HIV-1 reverse transcriptase (RT) and distinct from that of "classical" HIV-1 non-nucleoside inhibitors is proposed. The feasibility of the binding mode was assessed by carrying out nanosecond molecular dynamics simulations for the complexes of TSAO-m(3)T with reduced models of both the wildtype enzyme and a more sensitive R172A mutant. The molecular model is in agreement with a previous proposal, with known structure-activity and mutagenesis data for this unique class of inhibitors, and also with recent biochemical evidence indicating that TSAO analogues can affect enzyme dimerization. The relative importance of residues involved in dimer formation and TSAO-RT complex stabilization was assessed by a combination of surface area accessibility, molecular mechanics, and continuum electrostatics calculations. A structure-based modification introduced into the lead compound yielded a new derivative with improved antiviral activity.

  DOI：

  10.1021/jm001095i

文献信息

• Identification of a Putative Binding Site for [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)thymine (TSAO) Derivatives at the p51−p66 Interface of HIV-1 Reverse Transcriptase
  作者：Fátima Rodríguez-Barrios、Carlos Pérez、Esther Lobatón、Sonsoles Velázquez、Cristina Chamorro、Ana San-Félix、María-Jesús Pérez-Pérez、María-José Camarasa、Heidi Pelemans、Jan Balzarini、Federico Gago

  DOI：10.1021/jm001095i

  日期：2001.6.1

  A binding site for TSAO-m(3)T at the interface between the p66 and p51 subunits of HIV-1 reverse transcriptase (RT) and distinct from that of "classical" HIV-1 non-nucleoside inhibitors is proposed. The feasibility of the binding mode was assessed by carrying out nanosecond molecular dynamics simulations for the complexes of TSAO-m(3)T with reduced models of both the wildtype enzyme and a more sensitive R172A mutant. The molecular model is in agreement with a previous proposal, with known structure-activity and mutagenesis data for this unique class of inhibitors, and also with recent biochemical evidence indicating that TSAO analogues can affect enzyme dimerization. The relative importance of residues involved in dimer formation and TSAO-RT complex stabilization was assessed by a combination of surface area accessibility, molecular mechanics, and continuum electrostatics calculations. A structure-based modification introduced into the lead compound yielded a new derivative with improved antiviral activity.
• Improving the Antiviral Efficacy and Selectivity of HIV-1 Reverse Transcriptase Inhibitor TSAO-T by the Introduction of Functional Groups at the N-3 Position
  作者：María-Cruz Bonache、Cristina Chamorro、Sonsoles Velázquez、Erik De Clercq、Jan Balzarini、Fátima Rodríguez Barrios、Federico Gago、María-José Camarasa、Ana San-Félix

  DOI：10.1021/jm050437n

  日期：2005.10.1

  Novel derivatives of the anti-HIV-1 agent, TSAO-T, bearing at the N-3 position a variety of polar, lipophilic, or aromatic groups linked to that position through flexible polymethylene linkers of different length, were prepared and evaluated for their anti-HIV activity. Several compounds (within the series of polar bearing groups) exhibited a 2-6-fold improved antiviral potency with regard to the lead compound, TSAO-T. Moreover, some of the most active N-3 TSAO derivatives retain antiviral activity against the TSAO-T-resistant HIV-1 strain (Glu138 -> Lys). Interestingly, the N-methylcarboxamide derivative 17 was 5- to 6-fold more active (IC50: 0.56 mu M) against recombinant HIV-1 reverse transcriptase than the lead compound, thus becoming the most active TSAO derivative synthesized so far. On the other hand, the N-3 methylcarboxamide TSAO derivative 12 turned out to have the highest selectivity index yet reported for this class of compounds (around >= 12 000).
• Hybrids of [TSAO-T]−[Foscarnet]:  The First Conjugate of Foscarnet with a Non-nucleoside Reverse Transcriptase Inhibitor through a Labile Covalent Ester Bond
  作者：Sonsoles Velázquez、Esther Lobatón、Erik De Clercq、Dianna L. Koontz、John W. Mellors、Jan Balzarini、María-José Camarasa

  DOI：10.1021/jm031045o

  日期：2004.6.1

  This paper describes the first example of combination of non-nucleoside reverse transcriptase inhibitors such as TSAO derivatives and foscarnet (PFA) in a single molecule through a labile covalent ester bond. The essential criteria in the design of these hybrids [TSAO-T]-[PFA] was to explore if the conjugation of foscarnet with the highly lipophilic TSAO derivative may facilitate the penetration of the conjugates through the cell membrane and if the hybrids escape extracellular hydrolysis and regenerate the parent inhibitors intracellulary. Several [TSAO-T]-[PFA] conjugates proved markedly inhibitory to HIV-1. Some of them also showed potent activity against PFA-resistant HIV-1 strains but fewer had detectable inhibitory activity against TSAO-resistant HIV-1 strains. These results indicated a pivotal role of the TSAO component of the hybrid but not the PFA component in the activity of the conjugates. Moreover, stability studies of the [TSAO-T]-[PFA] conjugates demonstrated that the compounds were stable in PBS whereas some of the conjugates regenerated the parent inhibitors in extracts from CEM cells.