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 | 142102-79-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 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
• 中文别名: N-环己基-2-甲基-10-羰基-1,7-二氮杂二环[4.4.0]癸-2,4,6,8-四烯-9-甲酰胺
• 英文名称: TSAO-m3T
• 英文别名: 2,4(1H,3H)-pyrimidinedione, 1-[(5R,6R,8R,9R)-4-amino-9-[t-butyldimethylsilyloxy]-6-[t-butyldimethylsilyloxymethyl]-2,2-dioxido-1,7-dioxa-2-thiaspiro[4,4]non-3-en-8-yl]-3,5-dimethyl-；[1-[2',5'-bis-O-(tert-butyldimethylsilyl)-3'-deoxy-β-D-ribofuranosyl]-3-N-methylthymine]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)；TSAO-m³T；{1-[2',5'-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-methylthymine}-3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide)；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]-3,5-dimethylpyrimidine-2,4-dione
• CAS: 142102-79-2
• 化学式: C₂₅H₄₅N₃O₈SSi₂
• 分子量: 603.885
• InChiKey: KZKYYGSZDVZKNJ-XDSPWSPCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.06
• 重原子数：
  39
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.76
• 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-[(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 在 ammonium cerium(IV) nitrate 、 碘 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 1.0h， 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''-amino-3''-iodo-1'',2''-oxathiole-2'',2''-dioxide)
  参考文献：
  名称：

  通过有效的钯催化交叉偶联方法合成具有抗HIV-1和抗HIV-2活性的3''-取代的TSAO衍生物。

  摘要：

  已经探索了用于在TSAO衍生物的螺部分的3'位置上引入几个官能团的各种合成研究。其中，3''-碘-TSAO衍生物与不同锡烷的Stille交叉偶联为磺内酯螺环部分3''-位通过碳-碳键形成的直接和选择性官能化提供了有效而直接的途径。评估合成的化合物对细胞培养物中HIV-1和HIV-2复制的抑制作用。在3''位置引入溴，尤其是碘，赋予了最高的抗HIV-1活性。相反，（未）取代的乙烯基，炔基，苯基或噻吩基在该位置的存在显着降低了抗HIV-1活性。出奇，3'-链烯基取代的TSAO衍生物中的几种在亚毒性浓度下也具有抗HIV-2活性，这一发现对于NNRTIs非常罕见，而对于TSAO衍生物则从未见过。最后，根据我们最近提出的TSAO衍生物与HIV-1逆转录酶两个亚基之间的相互作用的分子模型，讨论了一些3''-取代的TSAO衍生物的抗HIV-1活性。

  DOI：

  10.1021/jm020820h
• 作为产物：
  描述：

  5-O-benzoyl-3-C-cyano-1,2-O-isopropylidene-3-O-mesyl-α-D-ribofuranose 在 吡啶 、 4-二甲氨基吡啶 、 ammonium sulfate 、 三氟甲磺酸三甲基硅酯 、 氨 、 potassium carbonate 、 caesium carbonate 、 六甲基二硅氮烷 、 三氟乙酸 作用下， 以 甲醇 、 丙酮 、 乙腈 为溶剂， 反应 40.0h， 生成 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
  参考文献：
  名称：

  TSAO类似物。1- [2'，5'-双-O-（叔丁基二甲基甲硅烷基）-β-D-呋喃呋喃糖基] -3'-螺-5'-（4''-）的立体特异性合成和抗HIV-1活性氨基-1''，2''-草硫醇2''，2''-二氧化物）嘧啶和嘧啶修饰的核苷。

  摘要：

  抗HIV-1药物[1- [2'，5'-双-O-（叔丁基二甲基甲硅烷基）-β-D-呋喃呋喃糖基]-胸腺嘧啶]的新铅的几种类似物-3'-spiro-5'在胸腺嘧啶部分的N-3，O-4和C-5位修饰的'-（4''-氨基-1''，2''-草硫醇2''，2''-二氧化物）（TSAO），已经制备并评估为HIV-1复制的抑制剂。描述了一种新的立体选择性合成方法。1,2-二-O-乙酰基-5-O-苯甲酰基-3-C-氰基-3-O-甲磺酰基-D-呋喃呋喃糖与嘧啶碱的反应，然后用Cs2CO3处理，得到立体选择性的β-D-呋喃呋喃糖基-3'-螺核苷。2′，5′-O-脱酰并随后用叔丁基二甲基甲硅烷基氯处理得到TSAO衍生物。仅那些在C-5'和C-2'均具有tBDMSi基团的类似物 核糖部分的位置显示出有效的抗HIV-1活性。活性范围为0.060μM至1.0μM。在胸腺嘧啶环的N-3处引入烷基或烯基官能团可显着降低细胞

  DOI：

  10.1021/jm00094a009

文献信息

• 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。
• 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.
• 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.
• 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.
• TSAO Derivatives: Highly Specific Inhibitors of Human Immunodeficiency Virus Type-1 (HIV-1) Replication
  作者：Maria Camarasa、Maria Péarez-Péarez、Sonsoles Velázquez、Ana San-Féalix、Rosa Alvarez、Simon Ingate、Maria Luisa Jimeno、Anna Karlsson、Erik De Clercq、Jan Balzarini

  DOI：10.1080/15257779508012432

  日期：1995.5.1

  TSAO derivatives represent a unique class of nucleosides that are specifically targeted at HIV-1 RT. This overview is focussed on the chemical synthesis, the conformational studies, the antiviral and metabolic properties of TSAO derivatives, as well as their mechanism of antiviral action and the molecular basis of the vapid selection of resistant HIV-1 strains that emerge in cell culture in the presence of TSAO derivatives.