NAP-TSAO-T | 672307-67-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: NAP-TSAO-T
• 英文别名: [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-(3-aminopropyl)thymine]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)；1-[(1R,3R,4R,5R)-6-amino-4-[tert-butyl(dimethyl)silyl]oxy-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-8,8-dioxo-2,9-dioxa-8$l^{6}-thiaspiro[4.4]non-6-en-3-yl]-3-(3-aminopropyl)-5-methyl-pyrimidine-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-aminopropyl)-5-methylpyrimidine-2,4-dione
• CAS: 672307-67-4
• 化学式: C₂₇H₅₀N₄O₈SSi₂
• 分子量: 646.953
• InChiKey: GPEIGMRODCSUDE-MGUUAAOPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.88
• 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：
  172
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  NAP-TSAO-T 在 palladium on activated charcoal 氢气 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、172.37 kPa 条件下， 反应 26.0h， 生成 [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-N-[3-N'-[valyl-phenylalanylamino]propyl]thymine]-3'-spiro-5''-[4''-amino-1'',2''-oxathiole-2'',2''-dioxide]
  参考文献：
  名称：

  Design and Discovery of a Novel Dipeptidyl-peptidase IV (CD26)-Based Prodrug Approach

  摘要：

  Here we describe a novel type of enzyme-based prodrug approach in which a dipeptide moiety is linked to a nonpeptidic therapeutic drug through an amide bond which is specifically cleaved by the dipeptidyl-peptidase IV ( DPP IV/CD26) enzyme activity present in plasma and on the surface of certain cells. DPP IV has high substrate selectivity for peptides with a proline ( or an alanine) at the penultimate amino acid position at the N-terminus but tolerates a wide range of natural amino acids at the amino terminal end. A variety of dipeptidyl amide prodrugs of anti-HIV TSAO molecules were synthesized and evaluated for their ability to act as substrates for the enzyme. Our data revealed that DPP IV/CD26 can efficiently recognize such prodrugs as substrates, releasing the parent compound. Moreover, it is possible to modify the half-life and the lipophilicity of the prodrugs by changing the nature of the dipeptide. All conjugates have shown marked in vitro antiviral activities irrespective the the nature of the terminal and/or the penultimate amino acid moiety.

  DOI：

  10.1021/jm0606490
• 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 在 palladium on activated charcoal 氢气 、 potassium carbonate 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 6.5h， 生成 NAP-TSAO-T
  参考文献：
  名称：

  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

  摘要：

  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).

  DOI：

  10.1021/jm050437n

文献信息

• [EN] PRODRUGS CLEAVABLE BY CD26<br/>[FR] PROMEDICAMENTS POUVANT ETRE CLIVES A MOYEN DE CD26
  申请人：LEUVEN K U RES & DEV

  公开号：WO2004098644A1

  公开（公告）日：2004-11-18

  The present invention provides a new prodrug technology and new prodrugs in order to increase the solubility, to modulate plasma protein binding or to enhance the biovailability of a drug. In the present invention the prodrugs are conjugates of a therapeutic compound and a peptide (eg tetrapeptide or hexapeptide) wherein the conjugate is cleavable by dipeptidyl-peptidases, more preferably by CD26, also known as DPPIV (dipeptidyl aminodipeptidase IV). The present invention furthermore provides a method of producing said prodrugs, to enhance brain and lymphatic delivery of drugs and/or to extend drug half-lives in plasma.

  本发明提供了一种新的前药技术和新的前药，以增加药物的溶解度，调节血浆蛋白结合或增强药物的生物利用度。在本发明中，前药是治疗化合物和肽（例如四肽或六肽）的结合物，其中结合物可被二肽肽酶（更优选为CD26，也称为DPPIV，即二肽氨二肽酶IV）水解。本发明还提供了一种生产所述前药的方法，以增强药物在大脑和淋巴系统中的传递，并/或延长药物在血浆中的半衰期。
• Novel N-3 Substituted TSAO-T Derivatives: Synthesis and Anti-HIV-Evaluation
  作者：María-Cruz Bonache、Ernesto Quesada、Chih-Wei Sheen、Jan Balzarini、Nicolas Sluis-Cremer、María Jesús Pérez-Pérez、María-José Camarasa、Ana San-Félix

  DOI：10.1080/15257770801943990

  日期：2008.4.4

  Novel derivatives of the anti-HIV-1 agent, TSAO-T, bearing at the N-3 position alkylating groups or photoaffinity labels were prepared and evaluated for their anti-HIV activity. All of these compounds demonstrated pronounced anti-HIV-1 activity and inhibited HIV-1 RT; however, we were unable to detect stable covalent linkages between inhibitor and enzyme. In addition, compounds with an alcohol functional group connected to the N-3 position through a cis or trans double bond have been prepared. These compounds have been useful to study how the conformational restriction of the linker affects in the interaction between the N-3 substituent and the HIV-1 RT enzyme.
• 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).
• Design and Discovery of a Novel Dipeptidyl-peptidase IV (CD26)-Based Prodrug Approach
  作者：Carlos García-Aparicio、María-Cruz Bonache、Ingrid De Meester、Ana San-Félix、Jan Balzarini、María-José Camarasa、Sonsoles Velázquez

  DOI：10.1021/jm0606490

  日期：2006.8.1

  Here we describe a novel type of enzyme-based prodrug approach in which a dipeptide moiety is linked to a nonpeptidic therapeutic drug through an amide bond which is specifically cleaved by the dipeptidyl-peptidase IV ( DPP IV/CD26) enzyme activity present in plasma and on the surface of certain cells. DPP IV has high substrate selectivity for peptides with a proline ( or an alanine) at the penultimate amino acid position at the N-terminus but tolerates a wide range of natural amino acids at the amino terminal end. A variety of dipeptidyl amide prodrugs of anti-HIV TSAO molecules were synthesized and evaluated for their ability to act as substrates for the enzyme. Our data revealed that DPP IV/CD26 can efficiently recognize such prodrugs as substrates, releasing the parent compound. Moreover, it is possible to modify the half-life and the lipophilicity of the prodrugs by changing the nature of the dipeptide. All conjugates have shown marked in vitro antiviral activities irrespective the the nature of the terminal and/or the penultimate amino acid moiety.