1-(2,3-dideoxy-3-(N-t-butyloxycarbonyl-L-alanylamino)-β-D-erythro-pentofuranosyl)thymine | 142410-22-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: 1-(2,3-dideoxy-3-(N-t-butyloxycarbonyl-L-alanylamino)-β-D-erythro-pentofuranosyl)thymine
• 英文别名: 1-[2,3-dideoxy-3-(N-t-butyloxycarbonyl-L-alanylamino)-β-D-erythro-pentofuranosyl]thymine；tert-butyl N-[(2S)-1-[[(2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]amino]-1-oxopropan-2-yl]carbamate
• CAS: 142410-22-8
• 化学式: C₁₈H₂₈N₄O₇
• 分子量: 412.443
• InChiKey: XXVDIZRYEGHFAT-WUHRBBMRSA-N

物化性质

• 密度：
  1.33±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  146
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-(2,3-dideoxy-3-(N-t-butyloxycarbonyl-L-alanylamino)-β-D-erythro-pentofuranosyl)thymine 在 三氟乙酸 作用下， 反应 0.08h， 以49%的产率得到1-(2,3-dideoxy-3-L-alanylamino-β-D-erythro-pentofuranosyl)thymine
  参考文献：
  名称：

  抗生素嘌呤霉素作为3'-氨基-3'-脱氧胸苷的潜在前药的类似物

  摘要：

  据报道，在DMF中使用二环己基碳二亚胺和N-羟基琥珀酰亚胺使L-和D-3'-氨基-2'，3'-二脱氧核苷2-5与N -BOC保护的氨基酸6和13缩合，得到N -BOC保护的酰氨aminonucleosides 7- 9和14中51-81％的产率。用三氟乙酸脱保护后，相应的未保护的新的嘌呤霉素10-12和15类似物以43-56％的产率获得。使用HIV（HTLV-III B染色）感染的MT-4细胞作为靶标系统，这些化合物未显示任何显着的抗病毒活性。

  DOI：

  10.1002/jhet.5570290102
• 作为产物：
  描述：

  3'-氨基-2',3'-双脱氧胸苷 、 Boc-L-丙氨酸 N-丁二酰亚胺酯 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 1-(2,3-dideoxy-3-(N-t-butyloxycarbonyl-L-alanylamino)-β-D-erythro-pentofuranosyl)thymine
  参考文献：
  名称：

  Compensatory effects of the human nucleoside transporters on the response to nucleoside-derived drugs in breast cancer MCF7 cells

  摘要：

  Nucleoside transporters (NTs) are involved in the cytotoxicity and transcriptomic response induced by nucleoside analogues. A relationship between the expression of nucleoside transporters and response to therapy has been demonstrated in solid tumours, although the pattern of such expression is highly variable. Thus, a question is whether the transporter expression pattern rather than specific NT proteins might better explain the ability of tumour cells to respond to nucleoside-derived drug therapy. In this study we used the breast cancer cell lines MCF7 and MCF7-hCNT1 (stably transfected with hCNT1) to determine whether hCNT1 expression can complement hENT1 functional loss in the cytotoxicity and transcriptomic response triggered by nucleoside analogues. Expression of hCNT1 slightly increased cell sensitivity to 5'-deoxy-5-fluorouridine (5'-DFUR). inhibition of the endogenous equilibrative activity blocked 5'-DFUR cytotoxicity in MCF7 cells, but not in MCF7-hCNT1 cells. Moreover, under equilibrative transport inhibition conditions, induction of some transcriptional targets of 5'-DFUR was blocked in MCF7 cells, whereas ENT-inhibition had no effect on the transcriptional response to 5'-DFUR in MCF7-hCNT1 cells. To confirm the role of hCNT1 in 5'-DFUR treatment, a panel of nucleoside derivatives suitable for hCNT1-inhibition was obtained. The molecule T-Ala inhibited hCNT1-mediated transport. Furthermore, the cytotoxic action of 5'-DFUR and the transcriptional changes produced by this nucleoside analogue were partially inhibited by T-Ala in MCF7-hCNT1 cells. These results show a link between NT function and the pharmacogenomic response to nucleoside analogues and further support the hypothesis that the expression pattern rather than specific transporters determines the cytotoxic effect of nucleoside derivatives. (c) 2007 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2007.10.005

文献信息

• Analogues of the antibiotic puromycin as potential prodrugs of 3′-amino-3′-deoxythymidine
  作者：Jesper Wengel、Mohammed S. Motawia、Erik B. Pedersen、Carsten M. Nielsen

  DOI：10.1002/jhet.5570290102

  日期：1992.1

  Condensation of L- and D-3′-amino-2′,3′-dideoxynucleosides 2–5 with N-BOC-protected aminoacids 6 and 13 using dicyclohexylcarbodiimide and N-hydroxysuccinimide in DMF is reported to give the N-BOC-protected acylamino aminonucleosides 7–9 and 14 in 51–81% yield. After deprotection using trifluoroacetic acid the corresponding unprotected new analogues of puromucin 10–12 and 15 were obtained in 43–56%

  据报道，在DMF中使用二环己基碳二亚胺和N-羟基琥珀酰亚胺使L-和D-3'-氨基-2'，3'-二脱氧核苷2-5与N -BOC保护的氨基酸6和13缩合，得到N -BOC保护的酰氨aminonucleosides 7- 9和14中51-81％的产率。用三氟乙酸脱保护后，相应的未保护的新的嘌呤霉素10-12和15类似物以43-56％的产率获得。使用HIV（HTLV-III B染色）感染的MT-4细胞作为靶标系统，这些化合物未显示任何显着的抗病毒活性。
• Compensatory effects of the human nucleoside transporters on the response to nucleoside-derived drugs in breast cancer MCF7 cells
  作者：Pedro Cano-Soldado、Míriam Molina-Arcas、Berta Algueró、Ignacio Larráyoz、M. Pilar Lostao、Anna Grandas、F.Javier Casado、Marçal Pastor-Anglada

  DOI：10.1016/j.bcp.2007.10.005

  日期：2008.2

  Nucleoside transporters (NTs) are involved in the cytotoxicity and transcriptomic response induced by nucleoside analogues. A relationship between the expression of nucleoside transporters and response to therapy has been demonstrated in solid tumours, although the pattern of such expression is highly variable. Thus, a question is whether the transporter expression pattern rather than specific NT proteins might better explain the ability of tumour cells to respond to nucleoside-derived drug therapy. In this study we used the breast cancer cell lines MCF7 and MCF7-hCNT1 (stably transfected with hCNT1) to determine whether hCNT1 expression can complement hENT1 functional loss in the cytotoxicity and transcriptomic response triggered by nucleoside analogues. Expression of hCNT1 slightly increased cell sensitivity to 5'-deoxy-5-fluorouridine (5'-DFUR). inhibition of the endogenous equilibrative activity blocked 5'-DFUR cytotoxicity in MCF7 cells, but not in MCF7-hCNT1 cells. Moreover, under equilibrative transport inhibition conditions, induction of some transcriptional targets of 5'-DFUR was blocked in MCF7 cells, whereas ENT-inhibition had no effect on the transcriptional response to 5'-DFUR in MCF7-hCNT1 cells. To confirm the role of hCNT1 in 5'-DFUR treatment, a panel of nucleoside derivatives suitable for hCNT1-inhibition was obtained. The molecule T-Ala inhibited hCNT1-mediated transport. Furthermore, the cytotoxic action of 5'-DFUR and the transcriptional changes produced by this nucleoside analogue were partially inhibited by T-Ala in MCF7-hCNT1 cells. These results show a link between NT function and the pharmacogenomic response to nucleoside analogues and further support the hypothesis that the expression pattern rather than specific transporters determines the cytotoxic effect of nucleoside derivatives. (c) 2007 Elsevier Inc. All rights reserved.