The synthesis of macrocyclic molecules related to telomestatin

Abstract

G-quadruplex DNA represents an attractive target for the development of anti-cancer therapeutic agents as it plays important roles in transcriptional regulation and the maintenance of telomeric length. Oxazole-containing macrocycles such as telomestatin are considered to be a promissing new class of G-quadruplex binding ligands. In this work, poly-oxazole building blocks were synthesized to prepare a tetraoxazole peptide macrocycle in good yield. The macrocycle was obtained by employing standard peptide coupling conditions using a convergent solution phase approach. The synthetic unit of the oxazole amino acid containing compound was prepared by cyclodehydration/oxidation of protected serine and phenylalanine. Two-cycle coupling of the unit gave a linear tetraoxazole amide. The final macrocyclization was accomplished by using O-[(1-cyano-2-ethoxy-2-oxoethylidene)amino]-oxytri(pyrrolidin-1-yl) phosphonium hexafluorophosphate (PyOxP) and the product (45% yield) was characterized by 1H NMR. Finally, the Cu (II) coordination chemistry of the tetraoxazole macrocycle was investigated by spectrophotometric titration.