benzoic acid (3aS,4R,6R,6aR)-6-(2-chloro-6-methylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-thieno[3,4-d][1,3]dioxol-4-ylmethyl ester | 596103-12-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: benzoic acid (3aS,4R,6R,6aR)-6-(2-chloro-6-methylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-thieno[3,4-d][1,3]dioxol-4-ylmethyl ester
• 英文别名: benzoic acid (3aS,4R,6R,6aR)-6-(2-chloro-6-methylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-thieno[3,4-d][1,3]dioxol-4-yl-methyl ester；[(3aR,4R,6R,6aS)-4-[2-chloro-6-(methylamino)purin-9-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrothieno[3,4-d][1,3]dioxol-6-yl]methyl benzoate
• CAS: 596103-12-7
• 化学式: C₂₁H₂₂ClN₅O₄S
• 分子量: 475.956
• InChiKey: ZQAKAGDPFBTQQM-SCFUHWHPSA-N

物化性质

• 沸点：
  618.9±65.0 °C(Predicted)
• 密度：
  1.58±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  126
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  benzoic acid (3aS,4R,6R,6aR)-6-(2-chloro-6-methylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-thieno[3,4-d][1,3]dioxol-4-ylmethyl ester 在 重铬酸吡啶 、 sodium methylate 、 potassium carbonate 、 溶剂黄146 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 (2S,3S,4R,5R)-3,4-bis(tert-butyl-dimethyl-silanyloxy)-5-(2-chloro-6-methylaminopurin-9-yl)tetrahydro-thiophene-2-carboxylic acid methylamide
  参考文献：
  名称：

  D-4′-THIOADENOSINE DERIVATIVES AS HIGHLY POTENT AND SELECTIVE AGONISTS AT THE HUMAN A₃ ADENOSINE RECEPTOR

  摘要：

  4'-Thionucleoside derivatives as potent and selective A(3) adenosine receptor agonists were synthesized, starting from D-gulono-gamma-lactone via D-thioribosyl acetate as a key intermediate, among which the 2-chloro-N-6-methyladenosine-5'-methyluronamide showed the most potent and selective binding affinity (K-i = 0.28 +/- 0.09 nM) at the human A(3) adenosine receptor.

  DOI：

  10.1081/ncn-200061827
• 作为产物：
  描述：

  2,3:5,6-di-O-isopropylidene-D-gulitol 在 吡啶 、 lead(IV) acetate 、 sodium sulfide 、 sodium tetrahydroborate 、 ammonium sulfate 、 溶剂黄146 、 间氯过氧苯甲酸 、 六甲基二硅氮烷 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 75.42h， 生成 benzoic acid (3aS,4R,6R,6aR)-6-(2-chloro-6-methylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-thieno[3,4-d][1,3]dioxol-4-ylmethyl ester
  参考文献：
  名称：

  N⁶-Substituted D-4‘-Thioadenosine-5‘-methyluronamides:  Potent and Selective Agonists at the Human A₃ Adenosine Receptor

  摘要：

  4'-Thio analogues 3-5 of Cl-IB-MECA (2) (K-i = 1.0 +/- 0.2 nM at the human A(3) adenosine receptor) were synthesized from D-gulono-gamma-lactone via 4-thioribosyl acetate 14 as the key intermediate. All synthesized 4-thionucleosides exhibited higher binding affinity to the human A(3) adenosine receptor than Cl-IB-MECA, among which 4 showed the most potent binding affinity (K-i = 0.28 +/- 0.09 nM). 4 was also selective for A(3) vs human A(1) and human A(2A) receptors by 4800- and 36000-fold, respectively.

  DOI：

  10.1021/jm034098e

文献信息

• Purine nucleosides
  申请人：Jeong Shin Lak

  公开号：US20050256143A1

  公开（公告）日：2005-11-17

  Disclosed are purine nucleoside compounds that are selective to A 3 adenosine receptors and are useful for the treatment of cancer and inflammatory diseases. The compounds are shown by the following general formula (I), including isomers thereof: wherein X is sulfur or oxygen; R 1 is hydrogen, alkyl, benzyl, halobenzyl, or phenylalkyl; R 2 is hydrogen, halogen, alkoxy, alkenyl, alkynyl, alkylthio, or thio; R 3 and R 3′ are hydrogen, hydroxyalkyl, alkoxycarbonyl, or alkylaminocabonyl, whereas R 3 and R 3 ′ do not have identical substituents simultaneously; and R 4 is hydrogen or alkyl. Also disclosed are a pharmaceutical composition comprising a compound of formula (I), an isomer, or its pharmacologically acceptable salt as an active ingredient and a method for preventing or treating various diseases, state, or condition, including asthma, inflammation, cerebral ischemia, heart diseases, and cancer.

  揭示了对A3腺苷受体具有选择性的嘌呤核苷化合物，可用于治疗癌症和炎症性疾病。所述化合物由以下一般式（I）表示，包括其异构体：其中X为硫或氧；R1为氢、烷基、苄基、卤代苄基或苯基烷基；R2为氢、卤素、烷氧基、烯基、炔基、烷基硫基或硫基；R3和R3'为氢、羟基烷基、烷氧羰基或烷基氨羰基，其中R3和R3'不同时具有相同的取代基；R4为氢或烷基。还揭示了一种包含一种式（I）的化合物、其异构体或其药理学上可接受的盐作为活性成分的药物组合物，以及一种用于预防或治疗各种疾病、状态或症状的方法，包括哮喘、炎症、脑缺血、心脏疾病和癌症。
• N⁶-Substituted D-4‘-Thioadenosine-5‘-methyluronamides:  Potent and Selective Agonists at the Human A₃ Adenosine Receptor
  作者：Lak Shin Jeong、Dong Zhe Jin、Hea Ok Kim、Dae Hong Shin、Hyung Ryong Moon、Prashantha Gunaga、Moon Woo Chun、Yong-Chul Kim、Neli Melman、Zhan-Guo Gao、Kenneth A. Jacobson

  DOI：10.1021/jm034098e

  日期：2003.8.1

  4'-Thio analogues 3-5 of Cl-IB-MECA (2) (K-i = 1.0 +/- 0.2 nM at the human A(3) adenosine receptor) were synthesized from D-gulono-gamma-lactone via 4-thioribosyl acetate 14 as the key intermediate. All synthesized 4-thionucleosides exhibited higher binding affinity to the human A(3) adenosine receptor than Cl-IB-MECA, among which 4 showed the most potent binding affinity (K-i = 0.28 +/- 0.09 nM). 4 was also selective for A(3) vs human A(1) and human A(2A) receptors by 4800- and 36000-fold, respectively.
• Design, Synthesis, and Anti-Tumor Activity of 4′-Thionucleosides as Potent and Selective Agonists at the Human A₃Adenosine Receptor
  作者：Lak Shin Jeong、Hyuk Woo Lee、Hea Ok Kim、Ji Young Jung、Prashantha Gunaga、Sang Kook Lee、Eun-Jin Lee、Moon Woo Chun、Zhan-Guo Gao、Kenneth A. Jacobson、Hyung Ryong Moon

  DOI：10.1080/15257770701547107

  日期：2007.11.26

  On the basis of potent and selective binding affinity of Cl-IB-MECA to the human A(3) adenosine receptor, its I-thioadenosine derivatives were efficiently synthesized starting from D-gulonic gamma-lactone. Among compounds tested, 2-chloro-N-6-(3-iodobenzyl)- and 2-chloro-N-6-methyl-4'-thioadenosine-5'-methyluronamides (7a and 7b) exhibited nanomolar range of binding affinity (K-i = 0.38 nM and 0.28 nM, respectively) at the human A(3)AR. These compounds showed anti-growth effects on HL-60 leukemia cell, which resulted from the inhibition of Wnt signaling pathway.
• D-4′-THIOADENOSINE DERIVATIVES AS HIGHLY POTENT AND SELECTIVE AGONISTS AT THE HUMAN A₃ ADENOSINE RECEPTOR
  作者：Hyouk Woo Lee、Dae Hong Shin、Ji Young Jung、Hea Ok Kim、Moon Woo Chun、N. Melman、Z.-G. Gao、Kenneth A. Jacobson、Lak Shin Jeong

  DOI：10.1081/ncn-200061827

  日期：2005.4.1

  4'-Thionucleoside derivatives as potent and selective A(3) adenosine receptor agonists were synthesized, starting from D-gulono-gamma-lactone via D-thioribosyl acetate as a key intermediate, among which the 2-chloro-N-6-methyladenosine-5'-methyluronamide showed the most potent and selective binding affinity (K-i = 0.28 +/- 0.09 nM) at the human A(3) adenosine receptor.
• Structure−Activity Relationships of 2-Chloro-<i>N</i>⁶-substituted-4‘-thioadenosine-5‘-uronamides as Highly Potent and Selective Agonists at the Human A₃ Adenosine Receptor
  作者：Lak Shin Jeong、Hyuk Woo Lee、Kenneth A. Jacobson、Hea Ok Kim、Dae Hong Shin、Jeong A Lee、Zhan-Guo Gao、Changrui Lu、Heng T. Duong、Prashantha Gunaga、Sang Kook Lee、Dong Zhe Jin、Moon Woo Chun、Hyung Ryong Moon

  DOI：10.1021/jm050595e

  日期：2006.1.1

  We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes.. and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N-6-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that. similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronarnide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups. maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR.