(-)-1-[(1S,2S,4R)-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-β-L-ribofuranosyl]thymine | 479035-93-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (-)-1-[(1S,2S,4R)-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-β-L-ribofuranosyl]thymine
• 英文别名: 1-[(2S,3S,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-fluoro-3-phenylselanylthiolan-2-yl]-5-methylpyrimidine-2,4-dione
• CAS: 479035-93-3
• 化学式: C₃₂H₃₅FN₂O₃SSeSi
• 分子量: 653.751
• InChiKey: NZSBZIZRLFQOIO-YEOMKBMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.12
• 重原子数：
  41
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  83.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (-)-1-[(1S,2S,4R)-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-β-L-ribofuranosyl]thymine 在 间氯过氧苯甲酸 、 吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 以76%的产率得到(+)-1-[(1S,4R)-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2,3-didehydro-2-fluoro-4-thio-β-L-ribofuranosyl]thymine
  参考文献：
  名称：

  Synthesis, Anti-HIV Activity, and Molecular Mechanism of Drug Resistance of l-2‘,3‘-Didehydro-2‘,3‘-dideoxy-2‘-fluoro-4‘-thionucleosides

  摘要：

  beta-L-2',3'-Didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides (beta-L-2'-F-4'-S-d4Ns) have been synthesized and evaluated against HIV-1 in primary human lymphocytes. The key intermediate 8, which was prepared from 2,3-O-isopropylidene-L-glyceraldehyde 1 in 13 steps, was condensed with various pyrimidine and purine bases followed by elimination and deprotection to give the target compounds, beta-L-2'-F-4'-S-d4Ns (17-20 and 27-30). The antiviral activity of the newly synthesized compounds was evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which the cytosine 17, 5-fluorocytosine 18, and adenine 27 derivatives showed potent anti-HIV activities (EC50 = 0.12, 0.15, and 1.74 muM, respectively) without significant cytotoxicity up to 100 muM in human PBM, CEM, and Vero cells. The cytosine derivative 17 (beta-L-2'-F-4'-S-d4C), however, showed cross-resistance to a 3TC-resistant variant (HIV-1(M184V)). Molecular modeling studies suggest that the pattern of antiviral activity, similar to that of beta-L-2'-F-d4N, stemmed from their conformational and structural similarities. The isosteric substitution of sulfur for 4'-oxygen was well tolerated in the catalytic site of HIV-1 reverse transcriptase in the wild-type virus. However, the steric hindrance between the sugar moiety of the unnatural L-nucleoside and the side chains of VaI184 of M184V RT in 3TC-resistant mutant HIV strains destabilizes the RT-nucleoside triphosphate complex, which causes the cross-resistance to 3TC (M184V mutant).

  DOI：

  10.1021/jm020376i
• 作为产物：
  描述：

  (2R,4R)-(-)-4-tert-butyldiphenylsilyloxymethyl-2-fluoro-γ-thiobutyrolactone 在 4-二甲氨基吡啶 、 TEA 、 二异丁基氢化铝 、 六甲基二硅氮烷 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 27.0h， 生成 (-)-1-[(1S,2S,4R)-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-β-L-ribofuranosyl]thymine
  参考文献：
  名称：

  Synthesis, Anti-HIV Activity, and Molecular Mechanism of Drug Resistance of l-2‘,3‘-Didehydro-2‘,3‘-dideoxy-2‘-fluoro-4‘-thionucleosides

  摘要：

  beta-L-2',3'-Didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides (beta-L-2'-F-4'-S-d4Ns) have been synthesized and evaluated against HIV-1 in primary human lymphocytes. The key intermediate 8, which was prepared from 2,3-O-isopropylidene-L-glyceraldehyde 1 in 13 steps, was condensed with various pyrimidine and purine bases followed by elimination and deprotection to give the target compounds, beta-L-2'-F-4'-S-d4Ns (17-20 and 27-30). The antiviral activity of the newly synthesized compounds was evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which the cytosine 17, 5-fluorocytosine 18, and adenine 27 derivatives showed potent anti-HIV activities (EC50 = 0.12, 0.15, and 1.74 muM, respectively) without significant cytotoxicity up to 100 muM in human PBM, CEM, and Vero cells. The cytosine derivative 17 (beta-L-2'-F-4'-S-d4C), however, showed cross-resistance to a 3TC-resistant variant (HIV-1(M184V)). Molecular modeling studies suggest that the pattern of antiviral activity, similar to that of beta-L-2'-F-d4N, stemmed from their conformational and structural similarities. The isosteric substitution of sulfur for 4'-oxygen was well tolerated in the catalytic site of HIV-1 reverse transcriptase in the wild-type virus. However, the steric hindrance between the sugar moiety of the unnatural L-nucleoside and the side chains of VaI184 of M184V RT in 3TC-resistant mutant HIV strains destabilizes the RT-nucleoside triphosphate complex, which causes the cross-resistance to 3TC (M184V mutant).

  DOI：

  10.1021/jm020376i

文献信息

• Synthesis, Anti-HIV Activity, and Molecular Mechanism of Drug Resistance of <scp>l</scp>-2‘,3‘-Didehydro-2‘,3‘-dideoxy-2‘-fluoro-4‘-thionucleosides
  作者：Hyunah Choo、Youhoon Chong、Yongseok Choi、Judy Mathew、Raymond F. Schinazi、Chung K. Chu

  DOI：10.1021/jm020376i

  日期：2003.1.1

  beta-L-2',3'-Didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides (beta-L-2'-F-4'-S-d4Ns) have been synthesized and evaluated against HIV-1 in primary human lymphocytes. The key intermediate 8, which was prepared from 2,3-O-isopropylidene-L-glyceraldehyde 1 in 13 steps, was condensed with various pyrimidine and purine bases followed by elimination and deprotection to give the target compounds, beta-L-2'-F-4'-S-d4Ns (17-20 and 27-30). The antiviral activity of the newly synthesized compounds was evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which the cytosine 17, 5-fluorocytosine 18, and adenine 27 derivatives showed potent anti-HIV activities (EC50 = 0.12, 0.15, and 1.74 muM, respectively) without significant cytotoxicity up to 100 muM in human PBM, CEM, and Vero cells. The cytosine derivative 17 (beta-L-2'-F-4'-S-d4C), however, showed cross-resistance to a 3TC-resistant variant (HIV-1(M184V)). Molecular modeling studies suggest that the pattern of antiviral activity, similar to that of beta-L-2'-F-d4N, stemmed from their conformational and structural similarities. The isosteric substitution of sulfur for 4'-oxygen was well tolerated in the catalytic site of HIV-1 reverse transcriptase in the wild-type virus. However, the steric hindrance between the sugar moiety of the unnatural L-nucleoside and the side chains of VaI184 of M184V RT in 3TC-resistant mutant HIV strains destabilizes the RT-nucleoside triphosphate complex, which causes the cross-resistance to 3TC (M184V mutant).