Parallel Solution Phase Synthesis and Preliminary Biological Activity of a 5'-Substituted Cytidine Analog Library.,ACS Combinatorial Science

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Parallel Solution Phase Synthesis and Preliminary Biological Activity of a 5'-Substituted Cytidine Analog Library.
ACS Combinatorial Science Pub Date : 2019-08-19 , DOI: 10.1021/acscombsci.9b00072
Omar Moukha-Chafiq ₁ , Robert C Reynolds ₂ , Jacob C Wilson ₃ , Timothy S Snowden ₃

Affiliation

A 109-membered library of 5'-substituted cytidine analogs was synthesized, via funding through the NIH Roadmap Initiative and the Pilot Scale Library (PSL) Program. Reaction core compounds contained -NH2 (2) and -COOH (44 and 93) groups that were coupled to a diversity of reactants in a parallel, solution phase format to produce the target library. The assorted reactants included -NH2, -CHO, -SO2Cl, and -COOH functional groups, and condensation with the intermediate core materials 2 and 44 followed by acidic hydrolysis produced 3-91 in good yields and high purity. Linkage of the amino terminus of d-phenylalanine methyl ester to the free 5'-COOH of 44 and NaOH treatment led to core library -COOH precursor 93. In a libraries from libraries approach, compound 93 served as the vital building block for our unique library of dipeptidyl cytidine analogs 94-114 through amide coupling of the -COOH group with numerous commercial amines followed by acidic deprotection. Initial screening of the complete final library through the MLPCN program revealed a modest number of hits over diverse biological processes. These hits might be considered as starting points for hit-to-lead optimization and development studies.

中文翻译：

5'-取代的胞苷类似物文库的平行溶液相合成和初步生物活性。

通过美国国立卫生研究院路线图计划和中试规模库（PSL）计划的资助，合成了一个由109个成员组成的5'-取代胞苷类似物库。反应核心化合物包含-NH2（2）和-COOH（44和93）基团，这些基团以平行溶液相的形式与多种反应物偶联，生成目标库。所分类的反应物包括-NH 2，-CHO，-SO 2 Cl和-COOH官能团，并且与中间核材料2和44缩合，然后进行酸性水解，以良好的产率和高纯度产生了3-91。d-苯丙氨酸甲酯的氨基末端与44和NaOH处理的游离5'-COOH的连接产生了核心库-COOH前体93。化合物93是我们独特的二肽基胞苷类似物94-114文库的重要组成部分，它通过-COOH基团与众多商业胺的酰胺偶联，然后进行酸性脱保护作用。通过MLPCN程序对完整的最终文库进行的初步筛选显示，在不同的生物学过程中命中数不多。这些命中可以被认为是命中率领先的优化和开发研究的起点。

更新日期：2019-07-31

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