Abstract
G-quadruplex DNA plays important regulatory roles in the maintenance of telomere length and transcriptions inhibition of such oncogenes as c-myc, and thus has become an attractive target for the development of anti-cancer therapeutic agents. Poly-oxazole macrocycles are a promising new class of G-quadruplex binding ligands. Herein is described the synthesis of a tetraoxazole peptide macrocycle and an epimerization product. The synthetic unit was prepared by cyclization-oxidation of a diserine with one hydroxyl protected. Two-cycle coupling of the unit gave a linear tetraoxazole amide. The targeted molecule and the epimerization product were obtained after macrocyclization of the linear precursor and following removal of the protecting benzyl groups. With structural similarities to the most potent G-quadruplex stabilizer telomestatin, these two molecules might potentially be used to probe the biological significance of G-quadruplex' in vivo.
Highlights
G-quadruplex stabilization by small molecules is a promising strategy to develop anticancer therapeutic drugs.[1]
Telomestatin 1, (Figure 1) a natural product isolated from Streptomyces anulatus 3533-SV4, is the most potent G-quadruplex stabilizer identified[3] and widely used to probe the in vivo significance of G-quadruplex.[4]
Molecular modeling studies suggest that the exceptional activity of telomestatin may be attributed to the π-π stacking interaction between the oxazole rings and the end G-tetrads of G-quadruplex.[5]
Summary
G-quadruplex stabilization by small molecules is a promising strategy to develop anticancer therapeutic drugs.[1]. Some poly-oxazole macrocycles have emerged as a promising new class of anticancer agents that target G-quadruplex DNA.[8] Here, we report the synthesis of a tetraoxazole peptide macrocycle 2a and an epimerization product 2b. With structural similarities with telomestatin, these two molecules might potentially be used to probe G-quadruplex biological significance in vivo.
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