Optimization of anti-proliferative activity using a screening approach with a series of bis-heterocyclic G-quadruplex ligands

Using a phenotypic screening and SAR optimization approach, a phenyl-bis-oxazole derivative has been identified with anti-proliferative activity, optimized with the use of a panel of cancer cell lines. The lead compound was synthesized by means of a short and effective two-step synthesis using Pd-catalyzed direct arylation. The compound stabilizes several quadruplex DNA sequences including a human telomeric DNA and one from the promoter of the HSP90 gene, although the structure-activity relationships of the series are not obviously related to the quadruplex binding.