N-alkylated oligoamide alpha-helical proteomimetics.
Generic approaches for the design and synthesis of small molecule inhibitors of protein-protein interactions (PPIs) represent a key objective in modern chemical biology. Within this context, the alpha-helix mediated PPIs have received considerable attention as targets for inhibition using small molecules, foldamers and proteomimetics. This manuscript describes a novel N-alkylated aromatic oligoamide proteomimetic scaffold and its solid-phase synthesis--the first time such an approach has been used for proteomimetics. The utility of these scaffolds as proteomimetics is exemplified through the identification of potent microM inhibitors of the p53-hDM2 helix mediated PPI--a key oncogenic target.
Campbell
Frederick
F
School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, United Kingdom.
Plante
Jeffrey P
JP
Edwards
Thomas A
TA
Warriner
Stuart L
SL
Wilson
Andrew J
AJ
D000478:Alkylation; D000595:Amino Acid Sequence; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D020543:Proteome / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism
C433227:CNBP protein, human; D009757:Nylons; D020543:Proteome; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53