Carbocyclic analogues of netropsin and distamycin: DNA-binding properties and inhibition of DNA topoisomerases

Abstract

Inhibition of DNA topoisomerase and DNA-binding properties of a series of benzene-containing and C-terminus-modified analogues of distamycin and netropsin are described. These analogues contain two or three benzene units, respectively. Dibenzene analogues did not inhibit the topoisomerases, I and II. In this case, relaxation of DNA was inhibited with tribenzene analogues. Data from the ethidium displacement assay showed that these compounds were able to bind in the minorgroove binding mode in AT sequences of DNA. Molecular modelling experiments were performed to rationalize the lower binding affinity of tribenzene analogues of distamycin and netropsin, 3 and 4, compared to dibenzene analogues, 1 and 2. The superior DNA-binding afforded by 1 and 2 in comparison to 3 and 4 results from their more effective penetration into the minor groove of DNA and smaller perturbation of molecular structure upon complex formation.