Bio-Inspired Dual Selective BCL-2/c-MYC G-Quadruplex Binders: Design, Synthesis and Anticancer Activity of Drug-like Imidazo[2,1-i]purine Derivatives.

In the search for new drug-like selective G-quadruplex binders, a bio-inspired design focused on the use of nucleobases as synthons in a multicomponent reaction has been herein proved to be viable and successful. Hence, a new class of multi-functionalized imidazo[2,1-i]purine derivatives, easily synthesized with a convergent approach, allowed the identification of the first dual BCL2/c-MYC gene promoter G-quadruplex ligand. Biophysical studies involving CD melting experiments, MST measurements, NMR titrations, and computational docking calculations, as well as biological investigations including cytotoxicity and apoptotic assays, and qPCR and Western Blot analyses, have been carried out to assess the potency and to characterize the binding mode of the newly identified lead compound. The absence of toxicity towards normal cells, together with the small molecular weight (≅ 500), the water solubility, the ease of functionalization, and the selectivity profile are promising and desirable features to develop G...