Design, synthesis, and bioactivities of tasiamide B derivatives as cathepsin D inhibitors.Cathepsin D (Cath D) is overexpressed and hypersecreted by malignant tumors and involved in the progress of tumor invasion, proliferation, metastasis, and apoptosis.  Cath D has been considered as a potential target to treat cancer.  Our previous studies revealed that tasiamide B derivatives TB-9 and TB-11 exhibited high potent inhibition against Cath D and other aspartic proteases, but their molecular weights are still high, and the role of each residue is unknown yet.  Based on this, two series of tasiamide B derivatives have been designed, synthesized, and evaluated for their inhibitory activity against Cath D/Cath E/BACE1.  Enzymatic assays revealed that the target compound 1 with lower molecule weight showed good inhibitory activity against Cath D with IC50 of 3.29 nM and satisfactory selectivity over Cath E (72-fold) and BACE1 (295-fold), which could be a valuable template for the design of highly potent and selective Cath D inhibitors.
C