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(N)-甲撑卡巴核苷的 2-二炔基衍生物:可点击的 A(3)腺苷受体选择性激动剂。

2-Dialkynyl derivatives of (N)-methanocarba nucleosides: 'Clickable' A(3) adenosine receptor-selective agonists.

机构信息

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892, United States.

出版信息

Bioorg Med Chem. 2010 Jan 15;18(2):508-17. doi: 10.1016/j.bmc.2009.12.018. Epub 2009 Dec 11.

Abstract

We modified a series of (N)-methanocarba nucleoside 5'-uronamides to contain dialkyne groups on an extended adenine C2 substituent, as synthetic intermediates leading to potent and selective A(3) adenosine receptor (AR) agonists. The proximal alkyne was intended to promote receptor recognition, and the distal alkyne reacted with azides to form triazole derivatives (click cycloaddition). Click chemistry was utilized to couple an octadiynyl A(3)AR agonist to azido-containing fluorescent, chemically reactive, biotinylated, and other moieties with retention of selective binding to the A(3)AR. A bifunctional thiol-reactive crosslinking reagent was introduced. The most potent and selective novel compound was a 1-adamantyl derivative (K(i) 6.5nM), although some of the click products had K(i) values in the range of 200-400nM. Other potent, selective derivatives (K(i) at A(3)AR innM) were intended as possible receptor affinity labels: 3-nitro-4-fluorophenyl (10.6), alpha-bromophenacyl (9.6), thiol-reactive isothiazolone (102), and arylisothiocyanate (37.5) derivatives. The maximal functional effects in inhibition of forskolin-stimulated cAMP were measured, indicating that this class of click adducts varied from partial to full A(3)AR agonist compared to other widely used agonists. Thus, this strategy provides a general chemical approach to linking potent and selective A(3)AR agonists to reporter groups of diverse structure and to carrier moieties.

摘要

我们对一系列(N)-甲撑卡巴核苷 5'-尿苷酸进行了修饰,在扩展的腺嘌呤 C2 取代基上引入二炔基团,作为合成中间体,得到了强效和选择性的 A(3) 腺苷受体 (AR) 激动剂。近端炔烃旨在促进受体识别,而远端炔烃与叠氮化物反应形成三唑衍生物(点击环加成)。点击化学用于将八炔基 A(3)AR 激动剂与含有叠氮化物的荧光、化学反应性、生物素化和其他部分偶联,同时保留对 A(3)AR 的选择性结合。引入了双功能硫醇反应性交联试剂。最有效和选择性的新型化合物是 1-金刚烷基衍生物(K(i) 6.5nM),尽管一些点击产物的 K(i) 值在 200-400nM 范围内。其他强效、选择性衍生物(A(3)AR 的 K(i) 值为 innM)旨在作为可能的受体亲和标签:3-硝基-4-氟苯基(10.6)、α-溴苯乙酮(9.6)、硫醇反应性异噻唑啉酮(102)和芳基异硫氰酸酯(37.5)衍生物。通过抑制 forskolin 刺激的 cAMP 来测量最大功能效应,表明与其他广泛使用的激动剂相比,这类点击加合物的 A(3)AR 激动活性从部分激动剂到完全激动剂不等。因此,这种策略为将强效和选择性的 A(3)AR 激动剂与结构多样的报告基团和载体部分连接提供了一种通用的化学方法。

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