1425510-91-3Relevant academic research and scientific papers
Synthetic progress in cMyc-Max oncoprotein miniaturization: Semi-online monitoring gives solid-phase access to hydrophobic b(-HLH-)ZIP peptidosteroid tweezers
Verzele, Dieter,Madder, Annemieke
, p. 673 - 687 (2013)
Miniature versions of basic leucine zipper (bZIP) and basic helix-loop-helix zipper (b-HLH-ZIP) transcription factors are promising tools for molecular dissection of the genetic information in a post-genomic context. Despite the opportunities of genome interfering agents based on certain oncogenic zipper proteins, structural mimicry of transcription factors is a delicate undertaking, and experimental fine-tuning through bottom-up organic chemistry could benefit from solid-phase/library approaches. Involved in a variety of human pathologies, we became interested in the miniaturization of the cMyc-Max b-HLH-ZIP oncoprotein, and herein elaborate on our synthetic progress in that direction. A bile acid scaffold was successfully employed as artificial dimerization interface in this new type of transcription factor model. Orthogonality of the applied Alloc/Boc/Fmoc chemistries allowed the synthesis of both homo- and heterodimeric peptidosteroid conjugates, covalently restricted with defined geometrical properties. Recognition peptides were assembled through standard Fmoc/tBu solid-phase peptide synthesis (SPPS) chemistry, assisted by automated procedures for consecutive chain elongation on solid support. Invaluable to monitor present strategy, a photocleavable linker allowed rapid, yet detailed analysis of side chain protected peptide intermediates, liberated from the sampled resin, by reverse-phase HPLC and MALDI-TOF-MS. By decorating each scaffold position with two basic region peptides in a 2 × 2 design, a first generation of unprecedented b(-HLH-)ZIP peptidosteroids was efficiently obtained. As such, a versatile methodology amenable to library generation is presented. Decoration of a bile acid scaffold with two recognition peptides in a 2 × 2 solid-phase design brought us one step closer towards an unprecedented model of the oncogenic cMyc-Max transcription factor. Feasible by monitoring the stepwise synthesis of our b(-HLH-)ZIP peptidosteroids through a photocleavable linker strategy, a versatile methodology amenable to library generation is presented. Copyright
