A series of β-secretase peptidomimetic inhibitors with Leu＊Ala hydroxyethylene dipeptide isostere were synthesized and their β-secretase inhibitory activities were measured. The most potent compound N9 showed an inhibitory rate of 59.66% （10 mg/mL）. Compound N9 might be further modified by means of computational chemical methodology.
Based upon the crystal structure of a previously reported fragment hit that binds to Corresponding author. β-secretase, a novel series of non-peptidic small-molecule β-secretase inhibitors, namely hexahydropyrimidin-5-ols, along with two series of their analogues, were rationally designed through structural modification. The CADD study was performed and revealed good expectation. Inhibitory activities of the corresponding structural cores were tested, which provided further support for our design approach.
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.
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%）.
