Discovery of 7-(Prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A2A Adenosine Receptor: Prediction from Molecular Modeling
摘要:
We describe the identification of 7-(prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A(2A) adenosine receptor (A(2A)AR). Molecular-modeling indicated that the (S)-2-hydroxymethylene-pyrrolidine could mimic the interactions of agonists' ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A(2A)AR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties.
噻唑并[5,4- d ]嘧啶是重要的一类具有多种生物活性的杂环化合物。在本文中,我们报告了使用可回收的KF /氧化铝催化剂高效合成噻唑并[5,4- d ]嘧啶的方法。4,6-二氯-5-氨基嘧啶在20 mol%KF /氧化铝存在下与异硫氰酸酯反应生成噻唑并[5,4- d]嘧啶类化合物,收率极高,无需任何色谱纯化。该方法操作简单,快速并且催化剂可以重复使用而没有任何明显的活性损失。在8种癌细胞系中测试了这些化合物的抗增殖活性,这些细胞系包括肺癌(NCI-H322和A549),表皮(A431),成胶质细胞瘤(T98G),胰腺(MIAPaCa-2),前列腺(PC-3),人白血病(HL-60)和乳腺癌(T47D)细胞。N,N'-二乙氨基取代的类似物2-(4-氯苯基氨基)-7-二乙氨基噻唑并[5,4- d ]嘧啶4k在肺(NCI-H322和A549),表皮(A431)中显示抗增殖活性和具有IC 50的
Single-Step Syntheses of 2-Amino-7-chlorothiazolo[5,4-<i>d</i>]pyrimidines: Intermediates for Bivalent Thiazolopyrimidines
作者:Jian Liu、Raymond J. Patch、Carsten Schubert、Mark R. Player
DOI:10.1021/jo0517702
日期:2005.11.1
A single-step process for the preparation of 2-amino-7-chlorothiazolo[5,4-d]pyrimidines, 2, was achieved by the reaction of the commercially available 4,6-dichloro-5-aminopyrimidine 1 with isothiocyanates. This mild reaction accommodates a variety of functionalized isothiocyanates and proceeds in good to excellent yields. The utility of such intermediates is exemplified by subsequent reaction with alkyl or arylamine nucleophiles to afford novel, differentially functionalized 2,7-diaminothiazolo[5,4-d]pyrimidines, 3.