Solid-Phase Synthesis of the Cyclic Peptide Portion of Chlorofusin, an Inhibitor of p53-MDM2 Interactions

• Published in: Organic letters Vol. 5; no. 26; pp. 5051 - 5054
• Main Authors: Malkinson, John P, Zloh, Mire, Kadom, Mohanad, Errington, Rachel, Smith, Paul J, Searcey, Mark
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.12.2003; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Chemistry; Chemistry, Organic; Chromatography, High Pressure Liquid; Cyclization; Flow Cytometry; Fluorescent Antibody Technique; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Models, Molecular; Nuclear Proteins - antagonists & inhibitors; Peptides, Cyclic - chemical synthesis; Phosphorylation; Physical Sciences; Protein Conformation; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2; Science & Technology; Tumor Suppressor Protein p53 - antagonists & inhibitors; SUPPORT; PROTEIN; CHEMISTRY; MDM2; BINDING; CANCER; P53
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/ol0360849

The first solid-phase synthesis of the chlorofusin peptide is described. The synthesis involved side-chain immobilization of N α -Fmoc-Asp-ODmab. Synthesis of the linear peptide, initially incorporating racemic Ade8 and unsubstituted ornithine in place of the chromophore-bearing residue, was followed by cyclization on resin and peptide release to give a mixture of diastereomers. Resynthesis identified (by HPLC) the second isomer as analogous to the natural product. Initial biological assays, using an immunofluorescence method, suggest that the compounds are not cytotoxic but do not inhibit the p53/mdm2 interaction.