title: Solid-phase synthesis of smac peptidomimetics incorporating triazoloprolines and biarylalanines.
abstract: Apoptotic induction mechanisms are of crucial importance for the general homeostasis of multicellular organisms. In cancer the apoptotic pathways are downregulated, which, at least partly, is due to an abundance of inhibitors of apoptosis proteins (IAPs) that block the apoptotic cascade by deactivating proteolytic caspases. The Smac protein has an antagonistic effect on IAPs, thus providing structural clues for the synthesis of new pro-apoptotic compounds. Herein, we report a solid-phase approach for the synthesis of Smac-derived tetrapeptide libraries. On the basis of a common (N-Me)AVPF sequence, peptides incorporating triazoloprolines and biarylalanines were synthesized by means of Cu(I)-catalyzed azide-alkyne cycloaddition and Pd-catalyzed Suzuki cross-coupling reactions. Solid-phase procedures were optimized to high efficiency, thus accessing all products in excellent crude purities and yields (both typically above 90%). The peptides were subjected to biological evaluation in a live/dead cellular assay which revealed that structural decorations on the AVPF sequence indeed are highly important for cytotoxicity toward HeLa cells.
authors: Department of Chemistry, Technical University of Denmark.
authors: Sebastian T
authors: ST
authors: Le Quement
authors: Mette
authors: M
authors: Ishoey
authors: Mette T
authors: MT
authors: Petersen
authors: Jacob
authors: J
authors: Thastrup
authors: Grith
authors: G
authors: Hagel
authors: Thomas E
authors: TE
authors: Nielsen
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry*; D000480:Alkynes / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D002384:Catalysis; D003300:Copper / Q000737:chemistry; D006841:Hydrocarbons, Aromatic / Q000737:chemistry; D051034:Inhibitor of Apoptosis Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010165:Palladium / Q000737:chemistry; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques / Q000379:methods*; D014230:Triazoles / Q000737:chemistry
chemical_list: D000480:Alkynes; D001386:Azides; D006841:Hydrocarbons, Aromatic; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D057786:Peptidomimetics; C532637:SMAC peptide; D014230:Triazoles; D010165:Palladium; D003300:Copper; D011392:Proline; D000409:Alanine