benzoic acid (3aS,4R,6R,6aR)-6-(2-chloro-6-(3-iodo-benzylamino)-purin-9-yl)-2,2-dimethyl-tetrahydro-thieno[3,4-d][1,3]dioxol-4-ylmethyl ester | 596103-11-6

• 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-(3-iodo-benzylamino)-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-(3-iodo-benzylamino)purin-9-yl]-2,2-dimethyl-tetrahydro-thieno[3,4-d][1,3]dioxol-4-yl-methyl ester；Benzoic acid (3aS,4R,6R,6aR)-6-[2-chloro-6-(3-iodo-benzylamino)purin-9-yl]-2,2-dimethyl-tetrahydro-thieno[3,4-d][1,3]dioxol-4-ylmethyl ester；[(3aR,4R,6R,6aS)-4-[2-chloro-6-[(3-iodophenyl)methylamino]purin-9-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrothieno[3,4-d][1,3]dioxol-6-yl]methyl benzoate
• CAS: 596103-11-6
• 化学式: C₂₇H₂₅ClIN₅O₄S
• 分子量: 677.95
• InChiKey: QWMOUGCCFAEJGL-UMCMBGNQSA-N

物化性质

• 沸点：
  732.3±70.0 °C(Predicted)
• 密度：
  1.75±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  39
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 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-(3-iodo-benzylamino)-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 、 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)silyl]oxy]-5-[2-chloro-6-[(3-iodophenyl)methylamino]purin-9-yl]thiolane-2-carboxylic acid
  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 、 三氟甲磺酸三甲基硅酯 、 溶剂黄146 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 乙酸乙酯 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 48.42h， 生成 benzoic acid (3aS,4R,6R,6aR)-6-(2-chloro-6-(3-iodo-benzylamino)-purin-9-yl)-2,2-dimethyl-tetrahydro-thieno[3,4-d][1,3]dioxol-4-ylmethyl ester
  参考文献：
  名称：

  Structure−Activity Relationships of 2-Chloro-N⁶-substituted-4‘-thioadenosine-5‘-uronamides as Highly Potent and Selective Agonists at the Human A₃ Adenosine Receptor

  摘要：

  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.

  DOI：

  10.1021/jm050595e

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.
• Structure–activity relationships of 2-chloro-N6-substituted-4′-thioadenosine-5′-N,N-dialkyluronamides as human A3 adenosine receptor antagonists
  作者：Lak Shin Jeong、Hyuk Woo Lee、Hea Ok Kim、Dilip K. Tosh、Shantanu Pal、Won Jun Choi、Zhan-Guo Gao、Amit R. Patel、Wanda Williams、Kenneth A. Jacobson、Hee-Doo Kim

  DOI：10.1016/j.bmcl.2008.01.070

  日期：2008.3

  On the basis of potent and selective A(3) adenosine receptor (AR) antagonist, 2-chloro-N-6-(3-iodobenzyl)-4'-thioadenosine-5'-N,N-dimethyluronamide, structure-activity relationships were studied for a series of 5'-N,N-dialkyluronamide derivatives, synthesized from D-gulonic gamma-lactone. From this study, it was revealed that removal of the hydrogen bond-donating ability of the 5'-uronamide was essential for the pure A(3)AR antagonism. 5'-N,N-Dimethyluronamide derivatives exhibited higher binding affinity than larger 5'-N,N-dialkyl or 5'-N,N-cycloalkylamide derivatives, indicating that steric factors are crucial in binding to the human A(3)AR. A N-6-(3-bromobenzyl) derivative 6c (K-i = 9.32 nM) exhibited the highest binding affinity at the human A3AR with very low binding affinities to other AR subtypes. (c) 2008 Elsevier Ltd. All rights reserved.
• 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.