A series of acyclic analogs of natural product Syringolin A （SylA） were designed and synthesized during our synthetic efforts for SylA. These acyclic analogs were prepared through a seven-step linear strategy, with total yields varying from 20%-34% for one type of analogs and 12%-18% for the other. These compounds bear a common structure of peptidyl vinyl amide, which reacts irreversibly with the proteasomal active site ThrlO^γ through Michael-type 1,4-addition. Therefore, these acyclic analogs may function the same way as SylA, as potential 20S proteasome inhibitors.
Aim To synthesize protected aminoalkyl sulfinyl dilactones which were useful as the synthetic intermediates or the Cterminal pharmacophores of potential peptidomimetic proteasome inhibitors. Methods Organic reactions such as reduction, oxidation, olcfmation, and dihydroxylation were used. Results A convenient synthetic procedure to afford a series of aminoalkyl sulfinyl.dilactones was presented, which would be useful in the synthesis of five- or six-member sulfmyl dilactones. Conclusion Four aminoalkyl sulfmyl dilactones connecting different α-amino acids were synthesized.
Aim To discuss in depth the synthesis of hydroxyethylene dipeptide-based β-secretase inhibitors; Methods Organic reactions such as nucleophilic addition and substitution assisted by organometallic agents, catalytic hydrogenation, and classic peptide coupling were used to synthesize peptidomimetic β-secretase inhibitors. Results Ideal reaction conditions and potential problems were investigated, and one of the designed β-secretase inhibitors 13 （as a model） was synthesized successfully; Conclusion This approach might be used to build up the β-secretase inhibitor library and to search for new molecular candidates.
Peptidyl epoxyketones were potential antitumor agents due to their 20S proteasome inhibitory activities. Based on their structures and special inhibitory mechanism, a series of compounds were designed by linking the epoxyketone moiety （the Cterminal pharmacophore） and the peptide backbones. To make these compounds, we used a novel method to prepare the terminal α,β-unsaturated ketone, the crucial intermediate, from Weinreb amide with satisfactory yield （62%-65%）.
To find a reasonable way to prepare the designed CPP32 inhibitors. Method Ugifour-component condensation reaction was used to synthesize peptide mimic CPP32 inhibitors; ResultsA key isocyanide component (aspartate-derived isocyanide 3) and one of the designed CPP32inhibitors 4 (as a template) were synthesized; Conclusion The CPP32 inhibitor 4 was synthesized bythe newly developed procedure, which is an Ugi four-component condensation reaction based onaspartate-derived isocyanide 3. This method can be used to build up the CPP32 inhibitor library.
