Solution-phase parallel synthesis of acyclic nucleoside libraries of purine, pyrimidine, and triazole acetamides.
Solution-phase parallel synthesis of acyclic nucleoside libraries of purine, pyrimidine, and triazole acetamides.
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DOI：
10.1021/co500067c
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发表时间：
2014-09-08
影响因子：
--
通讯作者：
Reynods, Robert C.
中科院分区：
文献类型：
--
作者：
Pathak, Ashish K.;Pathak, Vibha;Reynods, Robert C.
关键词：
分子多样性在利用高通量筛选技术针对表型或基于酶的靶标的现代药物发现中起着关键作用。在NIH路线图倡议的中试规模库计划的主持下，我们在此产生并报告了181个嘌呤、嘧啶和1，2，4-三唑-N-乙酰胺类似物的多样化库，这些类似物以平行高通量溶液相反应形式制备。以HATU为偶联试剂，将一组不同的胺与几种核酸的N-乙酸反应，合成了不同的无环核苷N-乙酰胺类似物。这些反应使用24孔反应块和自动试剂分配平台在惰性气氛下进行。目标化合物在自动纯化系统上使用固体样品加载预填充柱和预填充硅胶柱进行纯化。所有化合物均通过NMR和HRMS表征，并在提交至NIH的分子库小分子储存库（MLSMR）之前通过HPLC分析纯度。通过分子库探针生产中心网络（MLPCN）计划的初步筛选，表明几个类似物显示出多样和有趣的生物活性。
Molecular diversity plays a pivotal role in modern drug discovery against phenotypic or enzyme-based targets using high throughput screening technology. Under the auspices of the Pilot Scale Library Program of the NIH Roadmap Initiative, we produced and report herein a diverse library of 181 purine, pyrimidine, and 1,2,4-triazole-N-acetamide analogues which were prepared in a parallel high throughput solution-phase reaction format. A set of assorted amines were reacted with several nucleic acid N-acetic acids utilizing HATU as the coupling reagent to produce diverse acyclic nucleoside N-acetamide analogues. These reactions were performed using 24 well reaction blocks and an automatic reagent-dispensing platform under inert atmosphere. The targeted compounds were purified on an automated purification system using solid sample loading prepacked cartridges and prepacked silica gel columns. All compounds were characterized by NMR and HRMS, and were analyzed for purity by HPLC before submission to the Molecular Libraries Small Molecule Repository (MLSMR) at NIH. Initial screening through the Molecular Libraries Probe Production Centers Network (MLPCN) program, indicates that several analogues showed diverse and interesting biological activities.
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