Chemical Genetics research programmes require libraries of small molecules which span large tracts of biologically-relevant chemical space. Natural products necessarily reside in such chemical space, since they bind both biosynthetic enzymes and target macromolecules. However, natural product partners are not available for most protein targets. Chemical Genetics has spawned diversity-oriented synthesis (DOS), in which libraries of diverse molecules are assembled in up to ca. five steps. The systematic variation of ligand scaffold is particularly challenging, though, despite recent advances in DOS, the diversity of chemical libraries has not yet approached that of natural products because the ligand scaffolds are insufficiently varied. This proposal will focus on the development of new methodology for the synthesis of skeletally diverse alkaloid-like compounds. A multicomponent reaction will be used to define an initial scaffold. A suite of 'scaffold switching' transformations will be developed to allow the initial scaffolds to be transformed into final scaffolds. The methods will be applied to the synthesis of at least 100 alkaloid-like compounds based on at least 10 distinct scaffolds. The library of compounds will be made available, using robotics at Leeds, to European cell biologists for screening in cell- and protein-based assays. The diversity and natural product-like nature means that it is likely to span large tracts of biologically relevant chemical space.
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