Solid-Phase Combinatorial Synthesis and Biological Evaluation of Destruxin e Analogues

Masahito Yoshida, Yoshitaka Ishida, Kenta Adachi, Hayato Murase, Hiroshi Nakagawa, Takayuki Doi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The solid-phase combinatorial synthesis of cyclodepsipeptide destruxin E has been demonstrated. The combinatorial synthesis of cyclization precursors 8 was achieved by using a split and pool method on SynPhase Lanterns. The products were successfully macrolactonized in parallel in the solution phase by using 2-methyl-6-nitrobenzoic anhydride and 4-(dimethylamino)pyridine N-oxide to afford macrolactones 9, and the subsequent formation of an epoxide in the side chain gave 18 member destruxin E analogues 6. Biological evaluation of analogues 6 indicated that the N-MeAla residue was crucial to the induction of morphological changes in osteoclast-like multinuclear cells (OCLs). Based on structure-activity relationships, azido-containing analogues 15 were then designed for use as a molecular probe. The synthesis and biological evaluation of analogues 15 revealed that 15 b, in which the Ile residue was replaced with a Lys(N3) residue, induced morphological changes in OCLs at a sufficient concentration, and modification around the Ile residue would be tolerated for attachment of a chemical tag toward the target identification of destruxin E (1). Forced to change: The 18 member analogues of destruxin E (see scheme) were successfully synthesized. Biological evaluation of these analogues indicated that the N-MeAla residue was crucial for inducing morphological changes in osteoclast-like multinuclear cells (OCLs). Molecular probes were then prepared by replacing the Ile residue with a Lys(N3) residue for target identification in OCLs.

Original languageEnglish
Pages (from-to)18417-18430
Number of pages14
JournalChemistry - A European Journal
Volume21
Issue number50
DOIs
Publication statusPublished - 2015 Dec 7

Keywords

  • combinatorial chemistry
  • molecular probes
  • peptides
  • solid-phase synthesis
  • structure-activity relationships

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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