Synthesis of cell-permeable stapled peptide dual inhibitors of the p53-Mdm2/Mdmx interactions via photoinduced cycloaddition

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 5; pp. 1472 - 1475
• Main Authors: Madden, Michael M., Muppidi, Avinash, Li, Zhenyu, Li, Xiaolong, Chen, Jiandong, Lin, Qing
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.03.2011; Elsevier
• Subjects: Amino Acid Sequence; Antineoplastic agents; Biological and medical sciences; Cells, Cultured; Cellular uptake; Crystallography, X-Ray; Cyclization; Dipolar cycloaddition; Enzyme-Linked Immunosorbent Assay; General aspects; Inhibitors; Inhibitory Concentration 50; Light; Medical sciences; Models, Molecular; Molecular Sequence Data; Molecular Structure; Nuclear Proteins - antagonists & inhibitors; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Pharmacology. Drug treatments; Protein–protein interaction; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Stapled peptides; Cellular uptake; Inhibitors; Protein–protein interaction; Stapled peptides; Dipolar cycloaddition; 1,3-Dipolar cycloaddition; Visual imagery; Peptides; Protein-protein interaction; Cyclic peptides; Gene product; p53 Protein; Fluorescence; Molecular interaction; Photochemical reaction; mdm2 Gene; TP53 Gene; Structure activity relation; Chemical synthesis; Tumor cell; Tumor suppressor gene; Human; Cell permeability; Rodentia; Enzyme immunoassay; Uptake; Vertebrata; Mammalia; Cell line; Mouse; Animal; Inhibitor; Bone; Onc gene; ELISA assay
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.01.004

We report the first application of a photoinduced 1,3-dipolar cycloaddition reaction to ‘staple’ a peptide dual inhibitor of the p53-Mdm2/Mdmx interactions. A series of stapled peptide inhibitors were efficiently synthesized and showed excellent dual inhibitory activity in ELISA assay. Furthermore, the positively charged, stapled peptides showed enhanced cellular uptake along with modest in vivo activity.