Solid-Phase Total Synthesis of Cherimolacyclopeptide E and Discovery of More Potent Analogues by Alanine Screening

Cherimblacyclopeptide E (1) is a cyclic hexapeptide obtained from Annona cherimola, reported to be cytotoxic against the KB (human nasopharyngeal carcinoma) cell line. The solid phase total syntheses of this cyclic peptide and its analogues were accomplished by employing FMOC/tert-butyl-protected amino acids and the Kenner sulfonamide safety catch linker. The synthetic peptide 1 was found to be weakly cytotoxic against four Cell lines (MOLT 4, Jurkat T lymphoma, MDA-MB-231, and KB). Analogues 3 and 7, where glycine at positions 2 and 6 of the parent compound was replaced by Ala, exhibited enhanced cytotoxicity against KB (3, IC50 6.3 mu M; 7, IC50 7.8 mu M) and MDA-MB-231 breast cancer cells (3, IC50 10.2 mu M; 7, IC50 7.7 mu M), thereby suggesting possible selective targeting of these cancer cells by these peptides. The spectral data of Synthetic peptide 1 was found to be similar to that reported for the natural product. However, a striking difference in biological activity was noted, which warrants the re-evaluation of the original natural product for purity and the existence of conformational differences.