Design,synthesis And Bioactivities Of Peptidic Cathepsin D Inhibitors

Cathepsin D(Cath D)is overexpressed and hyper-secreted 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.Tasiamide B,a linear peptide isolated from the marine cyanobacteria Symploca sp.,was proved as a good template for the development of aspartic proteases inhibitors.Our research group finished the total synthesis and stereochemical reassignment of tasiamide B and then prepared series of its derivatives.TB-9 and TB-11,two respective compounds among them,exhibited highly potent inhibitory against Cath D and other aspartic proteases(Cath E and BACE1).However,their high molecular weight leads to the poor membrane permeability probably.What's more,the role of each residue is unknown yet.Based on this,21 compounds of three series have been designed,in order to enhance the membrane permeability and explore the core structure.These target compounds were prepared by using segment condensation strategy.1)A series of 14 target compounds(A-1?A-14)were designed and prepared.Amino acid units of TB-9 and TB-11 were truncated one-by-one at the C-terminus,in which Val-N-Me-Gln-Ahppa fragment was retained and methyl ester or free carboxyl group at the C-terminal.2)B series of 5 target compounds(B-1-B-5)were designed and 4 among them were prepared successlfully.B-1 was obtained by hydrolyzing methyl ester from TB-9.B-2-B-4 were prepared,in which phenylalanine unit was replaced with tyrosine unit and methyl ester or free carboxyl group at C-terminal.3)CPP can carry a variety of macromolecular substances into cells freely,due to its potent membrane permeability.On the base of this,C series of 2 bioconjugate inhibitors were desig/:ned and synthesized.C-1(or C-2)was obtained by combining B-1(or B-3)and CPP with a flexible linker.This Master's dissertation descri'bes the design,synthesis and bioactivities of peptidic cathepsin D inhibitors.Three series of compounds have been designed,synthesized and evaluated.Enzymatic assays revealed that proline residue can be truncated at the C-terminus,but other hydrophobic amino acid residues must be retained.The methyl ester derivatives had slightly improved in activity and selectivity against Cath D than corresponding carboxylic acid.What's more,compounds with aromatic ring at the N-terminus were crucial for the inhibitory potency against Cath D.Phe was replaced with Tyr to obtain a new Cath D inhibitor with high activity and selectivity.C series of 2 bioconjugate inhibitors can successfully penetrate the membrane and target the lysosome,and improved the cell activity compared to prototype inhibitor.