Synthesis of Antitumor Bicyclic Hexapeptide RA-VII Analogues Possessing an Aromatic Amino Acid at Residue 2

J Org Chem. 2024 Nov 15;89(22):16936-16946. doi: 10.1021/acs.joc.4c01924. Epub 2024 Oct 30.

Abstract

RA-III acetate was treated with Lawesson's reagent to afford [Tyr-3-Ψ(CS-NH)-Ala-4]RA-III acetate. Treatment of this product with Hg(OAc)2/Li2CO3 and then methanol gave an oxazole intermediate. Acid-catalyzed arylation of the methylene carbon atom on the oxazole ring and subsequent partial hydrolysis of the oxazole ring in the resultant compounds afforded RA-VII analogues having an aromatic amino acid at residue 2. [5-Fluoro-d-Trp-2]RA-VII showed IC50 values of 0.038 and 0.077 μM against the HL-60 and HCT-116 cell lines, respectively.

MeSH terms

  • Amino Acids, Aromatic / chemical synthesis
  • Amino Acids, Aromatic / chemistry
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • HCT116 Cells
  • HL-60 Cells
  • Humans
  • Molecular Structure
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Amino Acids, Aromatic
  • Oligopeptides
  • Peptides, Cyclic