Screening solution-phase combinatorial libraries using pulsed ultrafiltration electrospray mass spectrometry
Screening solution-phase combinatorial libraries using pulsed ultrafiltration electrospray mass spectrometry
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DOI：
10.1021/jm960729b
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发表时间：
1997-12-05
影响因子：
7.3
通讯作者：
Venton, DL
中科院分区：
文献类型：
--
作者：
Zhao, YZ;vanBreemen, RB;Venton, DL
描述了met bud，其中在一锅反应中合成同系物家族，无需分离或纯化，并且使用基于脉冲超滤/电喷雾质谱（PUF/ESMS）的竞争性结合测定来筛选反应混合物，以暂时鉴定对靶受体具有最高亲和力的那些衍生物。作为测试该方法的模型系统，我们进行了一个合成方案，旨在制备一系列腺苷脱氨酶抑制剂赤-9（2-羟基-3-壬基）腺嘌呤（EHNA）的类似物，作为非立体异构混合物。与不含蛋白质的对照相比，对粗反应混合物进行脉冲超滤筛选，检测到对应于 EHNA 型衍生物及其三个线性烷基同系物的质子化分子，但没有显示异丁基或苄基 EHNA 衍生物的质子化分子，表明后者是无活性的。为了验证这一结论，我们制备了 E/THNA、线性同系物和苄基衍生物（均作为非对映体混合物），并生物测定了它们的腺苷脱氨酶抑制指数 ([I]/[S](0.5))。单独合成的类似物的生物测定结果与 PUF 实验中观察到的相对离子增强所预测的结果非常一致。因此，PUF 协议可用作快速为化学家寻找候选药物提供指导的通用方法。
A met bud Is described whereby a family of homologues is synthesized in a one-pot reaction, without isolation or purification, and the reaction mixture is screened using a competitive binding assay based on pulsed ultrafiltration/electrospray mass spectrometry (PUF/ESMS) to tentatively identify those derivatives hatting the highest affinity for a target receptor. As a model system to test this approach, a synthetic scheme designed to prepare a series of analogues of the adenosine deaminase inhibitor erythro-9(2-hydroxy-3-nonyl)adenine (EHNA), as dia-stereomeric mixtures, was carried out. Pulsed ultrafiltration screening of the crude reaction mixture against controls without protein detected protonated molecules corresponding to EHNA-type derivatives and three of its linear, alkyl homologues but did not show protonated molecules for an isobutyl or benzylic EHNA derivative, suggesting the latter was inactive. To verify this conclusion, we prepared E/THNA, the linear homologues, and the benzylic derivative (each as a diastereomeric mixture) and bioassayed them for their adenosine deaminase inhibition index ([I]/[S](0.5)). The bioassay results for the individually synthesized analogues were in good agreement with that predicted by the observed relative ion enhancement in the PUF experiments. Thus, the PUF protocol might be used as a general method to quickly provide direction to the chemist in search of drug candidates.