Three tripodal ligands (1-3), three macrobicyclic cryptands (4-5), the [222] and [221] cryptands 7 and 8, and corresponding Eu(III) complexes were probed for their influence on double-stranded nucleic acids. One ligand (2) shows higher affinity to DNA as compared to RNA and another one (4) even slightly destabilizes RNA. Cryptands 7 and 8 show no detectable melting point effects; addition of the [222] cryptand 7 to Eu(III) salts has no significant effect on the nuclease activity of the free metal ion. Only the [221] cryptand 8 forms a stable complex with Eu(III) in water, leading to almost no rate decrease with the phosphodiester BNPP, in striking contrast to DNA. The histidine-containing ligand 2 exhibits an increased hydrolytic activity against BNPP and against plasmid DNA. © 2001 Elsevier Science Ltd. All rights reserved.