Design, synthesis, and bioactivities of tasiamide B derivatives as cathepsin D inhibitors. (7th February 2019) - Li, Zhi
Abstract : 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 derivativesTB‐9 andTB‐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 compound1 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. Abstract : Two novel 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 3.29nM and satisfactory selectivity over Cath E (72‐fold) and BACE 1 (295‐fold), which could be a valuable template for the design of highly potent and selective Cath D inhibitors.