The isolation, total synthesis and structure elucidation of chlorofusin, a natural product inhibitor of the p53–MDM2 protein–protein interaction

• Published in: Natural product reports Vol. 26; no. 4; pp. 465 - 477
• Main Authors: Clark, Ryan C., Lee, Sang Yeul, Searcey, Mark, Boger, Dale L.
• Format: Journal Article
• Language: English
• Published: England 01.01.2009
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; biological assessment; Drug Design; Fusarium - chemistry; Molecular Structure; neoplasms; Neoplasms - drug therapy; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - isolation & purification; Peptides, Cyclic - pharmacology; protein-protein interactions; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - metabolism; stereochemistry; therapeutics; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0265-0568; 1460-4752; 1460-4752
• DOI: 10.1039/b821676b

Inhibitors of key protein-protein interactions are emerging as exciting therapeutic targets for the treatment of cancer. One such interaction between MDM2 (HDM2) and p53, that silences the tumour suppression activities of p53, was found to be inhibited by the recently isolated natural product chlorofusin. Synthetic studies on this complex natural product summarized herein have served to reassign its chromophore relative stereochemistry, assign its absolute stereochemistry, and provided access to a series of key analogues and partial structures for biological evaluation.