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

Farzana Shaheen, Tania S. Rizvi, Syed G. Musharraf, A. Ganesan, Kai Xiao, Jared B. Townsend, Kit Lam, M. Iqbal Choudhary

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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.

Original languageEnglish (US)
Pages (from-to)1882-1887
Number of pages6
JournalJournal of Natural Products
Volume75
Issue number11
DOIs
StatePublished - 2012

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ASJC Scopus subject areas

  • Complementary and alternative medicine
  • Molecular Medicine
  • Organic Chemistry
  • Analytical Chemistry
  • Pharmaceutical Science
  • Pharmacology
  • Drug Discovery

Cite this

Shaheen, F., Rizvi, T. S., Musharraf, S. G., Ganesan, A., Xiao, K., Townsend, J. B., Lam, K., & Choudhary, M. I. (2012). Solid-phase total synthesis of cherimolacyclopeptide e and discovery of more potent analogues by alanine screening. Journal of Natural Products, 75(11), 1882-1887. https://doi.org/10.1021/np300266e