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

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 /Li ₂ CO ₃ 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 IC ₅₀ values of 0.038 and 0.077 μM against the HL-60 and HCT-116 cell lines, respectively.