Solid-phase total synthesis of (-)-apratoxin a and its analogues and their biological evaluation

Takayuki Doi, Yoshitaka Numajiri, Takashi Takahashi, Motoki Takagi, Kazuo Shin-Ya

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Two approaches for the solid-phase total synthesis of apratoxinA and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer-support, macrolactamization of 10, followed by thiazoline formation, provided apratoxinA. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid-phase peptide synthesis by using amino acids 13-15 and 18. The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxinA, and O-methyl tyrosine can be replaced by 7-azidoheptyl tyrosine without loss of activity. The 1,3-dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring. Solid Approach: Two routes for the solid-phase total synthesis of apratoxinA have been described. On the basis of this method, its analogues were synthesized and their biological activity has been evaluated.

Original languageEnglish
Pages (from-to)180-188
Number of pages9
JournalChemistry - An Asian Journal
Volume6
Issue number1
DOIs
Publication statusPublished - 2011 Jan 3

Keywords

  • cytotoxicity
  • peptides
  • solid-phase synthesis
  • structure-activity relationships
  • total synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Solid-phase total synthesis of (-)-apratoxin a and its analogues and their biological evaluation'. Together they form a unique fingerprint.

  • Cite this