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Non‐Amide‐Based Combinatorial Libraries Derived from N ‐Boc‐Iminodiacetic Acid: Solution‐Phase Synthesis of Piperazinone Libraries with Activity Against LEF‐1/ β ‐Catenin‐Mediated Transcription
Author(s) -
Boger Dale L.,
Goldberg Joel,
Satoh Shigeki,
Ambroise Yves,
Cohen Steven B.,
Vogt Peter K.
Publication year - 2000
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/1522-2675(20000809)83:8<1825::aid-hlca1825>3.0.co;2-4
Subject(s) - chemistry , iminodiacetic acid , amide , combinatorial chemistry , catenin , transcription (linguistics) , small molecule , transcription factor , dna , stereochemistry , biochemistry , wnt signaling pathway , gene , chelation , organic chemistry , linguistics , philosophy
Abstract The development of a solution‐phase approach to the rapid, parallel synthesis of highly functionalized piperazinones in only four steps starting from N ‐Boc‐iminodiacetic acid is detailed. The efforts represent the extension of the solution‐phase synthesis of combinatorial libraries from N ‐Boc‐iminodiacetic acid to non‐amide‐based libraries where simple liquid‐liquid extractions are employed to purify all reaction products. This methodology was applied to the synthesis of a diverse 150‐member library with substituents in three positions of the piperazinone core. Screening results from a luciferase reporter assay indicate that a number of library members are novel repressors of LEF‐1/ β ‐catenin‐mediated transcription, and may be effective agents against colorectal tumors. Two secondary libraries (100 members each) designed from these lead structures were synthesized and screened, providing additional active agents and insight into key structure‐activity relationships in the series. These compounds represent only the second class of small molecules which repress transcription of reporter genes containing LEF‐1 responsive elements, and the first group not based on DNA minor‐groove‐binding agents.