Solid-phase synthesis of the cyclic peptide portion of chlorofusin, an inhibitor of p53-MDM2 interactions.
The first solid-phase synthesis of the chlorofusin peptide is described. The synthesis involved side-chain immobilization of N(alpha)-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. [structure: see text]
Malkinson
John P
JP
Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
Zloh
Mire
M
Kadom
Mohanad
M
Errington
Rachel
R
Smith
Paul J
PJ
Searcey
Mark
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D010766:Phosphorylation; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D009687:Nuclear Proteins; D010456:Peptides, Cyclic; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C434864:chlorofusin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2