title: Solid-phase total synthesis of cherimolacyclopeptide E and discovery of more potent analogues by alanine screening.
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.
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi , Karachi-75270, Pakistan.
authors.forename: Farzana
authors.initials: F
authors.lastname: Shaheen
authors.forename: Tania S
authors.initials: TS
authors.lastname: Rizvi
authors.forename: Syed G
authors.initials: SG
authors.lastname: Musharraf
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
authors.forename: Kai
authors.initials: K
authors.lastname: Xiao
authors.forename: Jared B
authors.initials: JB
authors.lastname: Townsend
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D000409:Alanine / Q000737:chemistry*; D000595:Amino Acid Sequence; D000596:Amino Acids; D031041:Annona / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005449:Fluorenes; D006801:Humans; D019169:Jurkat Cells; D007624:KB Cells; D008968:Molecular Conformation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D060327:Solid-Phase Synthesis Techniques; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000972:Antineoplastic Agents, Phytogenic; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D010456:Peptides, Cyclic; C506420:cherimolacyclopeptide E; D000409:Alanine