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

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 -NH () and -COOH ( and ) groups that were coupled to a diversity of reactants in a parallel, solution phase format to produce the target library. The assorted reactants included -NH, -CHO, -SOCl, and -COOH functional groups, and condensation with the intermediate core materials and followed by acidic hydrolysis produced - in good yields and high purity. Linkage of the amino terminus of d-phenylalanine methyl ester to the free 5'-COOH of and NaOH treatment led to core library -COOH precursor . In a libraries from libraries approach, compound served as the vital building block for our unique library of dipeptidyl cytidine analogs - 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.