1H-imidazo[4,5-f][1,10]phenanthroline carbohydrate conjugates: synthesis, DNA interactions and cytotoxic activity

Abstract

Here we present a novel family of carbohydrate conjugates based on the 2-aryl-imidazo[4,5-f][1,10]phenanthroline core modified with carbohydrates (carb-APIPs). The hybrid compounds were prepared by direct treatment of the unprotected carbohydrate with 2-(4-aminophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (APIP). The N-glycosylation reactions with the monosaccharides tested afforded stereoselectively the more stable N-beta-glycopyranosylamines that, in solution, underwent a dynamic equilibrium leading to anomeric mixtures with a small participation of the alfa isomer. DNA interaction experiments with telomeric G-quadruplex DNA included DNA FRET melting assays, circular dichroism, and equilibrium dialysis and revealed that the novel carb-APIPs bind the G-quadruplex structure with high affinity. Interestingly, the presence of the carbohydrate confers good selectivity towards the telomeric quadruplex structure, as suggested by competition DNA FRET melting assays. Besides the extended aromatic surface that allows pi-stacking interactions, the carbohydrate part of the conjugate may contribute to groove binding recognition, as indicated by viscosity experiments. In addition, the novel carb-APIPs showed significant cytotoxic properties in PC3 and HeLa cells and, to a lesser extent, in MCF7 cells and normal human fibroblasts (HFF1).