Novel CADD-based peptidyl vinyl ester derivatives as potential proteasome inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 6; pp. 2198 - 2202
• Main Authors: Mou, Ke, Xu, Bo, Ma, Chao, Yang, Xiaoming, Zou, Xiaomin, Lü, Yang, Xu, Ping
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.03.2008; Elsevier
• Subjects: Animals; Antineoplastic agents; Binding mode; Bioactivity; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; CADD; Cattle; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Design; Esters - chemistry; Fluorescence; General aspects; Humans; Medical sciences; Neoplasms - drug therapy; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptidomimetic; Peptidyl vinyl ester derivatives; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - pharmacology; Proteasome inhibitor; Proteasome Inhibitors; Synthesis; Vinyl Compounds - chemical synthesis; Vinyl Compounds - chemistry; Vinyl Compounds - pharmacology; CADD; Synthesis; Peptidomimetic; Proteasome inhibitor; Binding mode; Bioactivity; Peptidyl vinyl ester derivatives; Multicatalytic endopeptidase complex; Peptides; Liver; Modeling; Ester; Structure activity relation; Vinylic compound; Molecular model; Chemical synthesis; Computer aid; Tumor cell; Human; Promyelocytic leukemia; Stomach; Enzyme; Peptidomimetic compound; Enzyme inhibitor; Epidermis; HL60 cell line; Peptidases; Cell line; KB cell line; Hydrolases
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.12.077

A binding mode of peptidyl vinyl ester derivatives with proteasome catalytic-site was reported. Basing on this model, a novel series of potential proteasome inhibitors was designed, synthesized and assayed. A series of peptidyl vinyl ester derivatives bearing three different P1 substitutions as potential proteasome inhibitors were studied. The target molecules were designed based on CADD (computer aided drug design) protocol and synthesized. Their activities toward proteasome and four human cancer cell lines (including hepatoma cell line (Bel-7402), myeloid leukemic cell line (HL-60), gastric cancer cell line (BGC-823) and nasopharyngeal cancer cell line (KB)) were tested using fluorescence assay. Two compounds showed proteasome inhibitory activities, and four compounds showed weak antiproliferative activities toward HL-60 and BGC-823.