Evolved diversification of a modular natural product pathway: Apratoxins F and G, two cytotoxic cyclic depsipeptides from a palmyra collection of Lyngbya bouillonii

Kevin Tidgewell, Niclas Engene, Tara Byrum, Joseph Media, Takayuki Doi, Fred A. Valeriote, William H. Gerwick

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

A collection of Lyngbya bouillonii from Palmyra Atoll in the Central Pacific, a site several thousand kilometers distant from all previous collections of this chemically prolific species of cyanobacterium, was found to contain two new cancer cell cytotoxins of the apratoxin family. The structures of the new compounds, apratoxins F and G, were determined by 1D and 2D NMR techniques in combination with mass spectrometric methods. Stereochemistry was explored by using chromatographic analyses of the hydrolytically released fragments in combination with NMR and optical rotation comparisons with known members of the apratoxin family. Apratoxins F and G add fresh insights into the SAR of this family because they incorporate an N-methyl alanine residue at a position where all prior apratoxins have possessed a proline unit, yet they retain high potency as cytotoxins to H-460 cancer cells with IC50 values of 2 and 14 nM, respectively. Additional assays using zone inhibition of cancer cells and clonogenic cells give a comparison of the activities of apratoxin F to apratoxin A. Additionally, the clonogenic studies in combination with maximum tolerated dose (MTD) studies provided insights as to dosing schedules that should be used for in vivo studies, and preliminary in vivo evaluation validated the predicted in vivo efficacy for apratoxin A. These new apratoxins are illustrative of a mechanism (the modification of an NRPS adenylation domain specificity pocket) for evolving a biosynthetic pathway so as to diversify the suite of expressed secondary metabolites.

Original languageEnglish
Pages (from-to)1458-1466
Number of pages9
JournalChemBioChem
Volume11
Issue number10
DOIs
Publication statusPublished - 2010 Jul 5

Keywords

  • Anticancer
  • Cyanobacteria
  • Natural products
  • Structure elucidation
  • Structure-activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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