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Solid-phase total synthesis of cherimolacyclopeptide E and discovery of more potent analogues by alanine screening.

Authors
  • F, Shaheen
  • Ts, Rizvi
  • Sg, Musharraf
  • A, Ganesan
  • Kai Xiao
  • Jb, Townsend
  • Kit S. Lam
  • Mi, Choudhary
Type
Published Article
Journal
Journal of Natural Products
Publisher
American Chemical Society
Volume
75
Issue
11
Pages
1882–1887
Identifiers
DOI: 10.1021/np300266e
Source
Kit Lam Lab
License
Unknown

Abstract

Cherimolacyclopeptide 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 μM; 7, IC50 7.8 μM) and MDA-MB-231 breast cancer cells (3, IC50 10.2 μM; 7, IC50 7.7 μM), 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.

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