1-(2,3-dideoxy-3-L-alanylamino-β-D-erythro-pentofuranosyl)thymine | 125483-18-3

• 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-L-alanylamino-β-D-erythro-pentofuranosyl)thymine
• 英文别名: 3'-N-(L-alanyl)-3'-amino-3'-deoxythymidine；2',3'-dideoxy-3'-L-alanylamino-thymidine；Ala-aT；3'-N-(L-alanyl)amino-2',3'-dideoxy-5-methyluridine；(2S)-2-amino-N-[(2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]propanamide
• CAS: 125483-18-3
• 化学式: C₁₃H₂₀N₄O₅
• 分子量: 312.326
• InChiKey: GCJZIXQWEHRNHN-AXTSPUMRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  134
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3'-氨基-2',3'-双脱氧胸苷 在 N-羟基丁二酰亚胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.08h， 生成 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

文献信息

• Derivatives of 2'-deoxyuridine substituted in the 5-,3'-or 5'-position
  申请人：Institut de Recherches Chimiques et Biologiques Appliquees (I.R.C.E.B.A.)

  公开号：US05212161A1

  公开（公告）日：1993-05-18

  The present invention relates to novel derivatives of 2'-deoxyuridine substituted in the 5-, 3'- or 5'-position by .alpha.-aminoacyl groups, to a process for their preparation and the drugs in which they are present. These derivatives have the following general formula: ##STR1## in which R is selected from an alkyl or alkenyl radical having from 1 to 4 carbon atoms, an aryl radical or a halogen, it being possible for said alkyl, alkenyl and aryl radicals to contain at least one halogen substituent, and a radical of the formula --NH--R.sub.1, in which R.sub.1 is an amino acid residue or a peptide residue containing from 2 to 6 amino acids; and R' and R" are selected from a hydroxyl radical and a radical of the formula --NH--R.sub.1, in which R.sub.1 is as defined above, with the proviso that R' and R" are not simultaneously --NH--R.sub.1 and that, when R is --NH--R.sub.1, R' and R" are simultaneously a hydroxyl group. Application: treatment of cancers and viral infections.

  本发明涉及2'-去氧尿苷的新颖衍生物，其在5-、3'-或5'-位置被α-氨基酰基团取代，以及其制备过程和所含药物。这些衍生物具有以下通用公式： 其中R从含有1至4个碳原子的烷基或烯基基团、芳基基团或卤素中选择，其中所述烷基、烯基和芳基基团可能含有至少一个卤素取代基，以及公式--NH--R.sub.1中的基团，其中R.sub.1是含有2至6个氨基酸的氨基酸残基或肽残基；R'和R"从羟基基团和公式--NH--R.sub.1中选择，其中R.sub.1如上定义，但R'和R"不能同时为--NH--R.sub.1，当R为--NH--R.sub.1时，R'和R"同时为一个羟基团。应用：治疗癌症和病毒感染。
• Nucleoside–amino acid conjugates: An alternative route to the design of ribonuclease A inhibitors
  作者：Joy Debnath、Swagata Dasgupta、Tanmaya Pathak

  DOI：10.1016/j.bmc.2009.06.002

  日期：2009.7

  Nucleoside-amino acid conjugates have been employed to inhibit the ribonucleolytic activity of ribonuclease A (RNase A) and affect the protonation/deprotonation equilibrium of its active site histidine residues. Agarose gel and precipitation assays indicate inhibition of RNase A activity by these molecules with a possible role of the polar side chains of the amino acids in RNase A inhibition. Kinetic experiments demonstrated that the mode of inhibition is competitive in nature with inhibition constants (K-i) in the micromolar range. The nucleoside-serine conjugate occupies the active site of RNase A and preferential perturbs the pK(a) value of His-119 by its 'free amino group' as found from H-1 NMR studies. Docking studies revealed that the free amino groups of the most active compounds are within hydrogen bonding distance of His-119 in inhibitor-RNase A complexes. (C) 2009 Elsevier Ltd. All rights reserved.
• 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.
• MORINIERE, JEAN-LUC;FAUIQUES, MICHELLE;ROUSSEAU, CLAUDE;DANREE, BERNARD;M+
  作者：MORINIERE, JEAN-LUC、FAUIQUES, MICHELLE、ROUSSEAU, CLAUDE、DANREE, BERNARD、M+

  DOI：——

  日期：——
• NOUVEAUX DERIVES DE LA DEOXY-2'-URIDINE SUBSTITUEE EN POSITION 5, 3' ou 5' PAR DES GROUPEMENTS ALPHA-AMINO ACYLES, PROCEDE POUR LEUR OBTENTION ET MEDICAMENTS LES CONTENANT
  申请人：INSTITUT DE RECHERCHES CHIMIQUES ET BIOLOGIQUES APPLIQUEES (I.R.C.E.B.A.) Société à responsabilité limitée dite:

  公开号：EP0448550B1

  公开（公告）日：1994-08-10