STRUCTURE, DNA MINOR-GROOVE BINDING, AND BASE-PAIR SPECIFICITY OF ALKYL-LINKED AND ARYL-LINKED BIS(AMIDINOBENZIMIDAZOLES) AND BIS(AMIDINOINDOLES)

A series of bis(amidinobenzimidazoles) and bis(amidinoindoles) with va ried linking chains connecting the aromatic groups and various modific ations to the basic amidino groups have been prepared. The calf thymus (CT) DNA and nucleic acid homopolymer [poly(dA).poly(dT), poly(dA-dT) .poly-(dA-dT), and poly(dG-dC).poly(dG-dC)] binding properties of thes e compounds have been studied by thermal denaturation (DELTAT(m)) and viscosity. The compounds show a greater affinity for poly(dA).poly(dT) and poly(dA-dT).poly(dA-dT) than for poly(dG-dC).poly(dG-dC). Viscome tric titrations indicate that the compounds do not bind by intercalati on. Molecular modeling studies and the biophysical data suggest that t he molecules bind to the minor groove of CT DNA and homopolymers. Anal ysis of the shape of the molecules is consistent with this mode of nuc leic acid binding. Compounds with an even number of methylenes connect ing the benzimidazole rings have a higher affinity for DNA than those with an odd number of methylenes. Molecular modeling calculations that determine the radius of curvature of four defined groups in the molec ule show that the shape of the molecule, as a function of chain length , affects the strength of nucleic acid binding. Electronic effects fro m cationic substituents as well as hydrogen bonding from the imidazole nitrogens also contribute to the nucleic acid affinity. The bis(amidi noindoles) show no structurally associated differential in nucleic aci d base pair specificity or affinity.