Understanding the Guanidine‐Like Cationic Moiety for Optimal Binding into the DNA Minor Groove

Abstract

Based on our previous positive results with bis-guanidine-like diaromatic compounds as DNA minor groove binders, we propose a new family: bis-2-amino-1,4,5,6-tetrahydropyrimidines. According to calculated parameters, these dicationic systems would have a more suitable size and lipophilicity for binding into the minor groove than previous series. Moreover, their DFT-optimised structures and docking into an AT oligomer model show that they would bind in the minor groove with good strength and without energy penalty. Hence, we prepared compounds 4 a-c and evaluated their binding to ssDNA and poly(dA-dT)2 by thermal denaturation experiments. The results showed that 4 a (CO) and 4 d (NH) were the best DNA binders. Compared to the previous series, 4 a-d are better binders than bis-guanidiniums but poorer than bis-2-aminoimidazolinium derivatives. Moreover, circular dichroism experiments using ssDNA and poly(dA-dT)2 confirmed binding into the minor groove. Based on our computational design as well as biophysical studies, we have been able to determine that the optimal interaction of guanidine-like dications in the minor grove occurs with bis-2-aminoimidazolinium systems.