Abstract

The binding of antimalarial 8-aminoquinolines (including primaquine and pentaquine), some of their potential metabolites, and chloroquine to DNA, RNA, and various polydeoxyribo- and polyribonucleotides has been studied by equilibrium dialysis and direct spectrophotometry. The extent of binding of primaquine, pentaquine, and chloroquine to native calf thymus DNA, as measured by equilibrium dialysis, does not vary in the range of pH 6.0-8.0. A major portion of each 6-hydroxy derivative of the 8-aminoquinolines binds to DNA, although, in the two examples studied, the extent of binding is somewhat less than for the corresponding 6-methoxy parent compound. Removal of the protonated terminal nitrogen of the 8-diamino side chain decreases the binding of the 8-aminoquinolines to very low levels. The structure and composition of polynucleotides affect their binding of the 8-aminoquinolines and chloroquine. Data from equilibrium dialysis show that the extent of binding of 8-aminoquinolines is greatest to native and denatured DNA, followed, in order, by soluble RNA and purine-containing polyribonucleotides (poly rI, poly rA, poly rG), poly rU, and poly rC. The nucleotide sequence and composition also affect the polynucleotide-induced decrease in the absorbance of an aminoquinoline. Thus, double-stranded homopolymers like poly dAdT and poly dGdC cause only a slight decrease (less than 3%) in the absorbance of pentaquine, but the double-stranded alternating copolymer poly dAT causes a major decrease (more than 35%; similar to the decrease caused by native DNA) in the absorbance of the same aminoquinoline. Extensive binding of an aminoquinoline to a polynucleotide may occur without a marked concomitant decrease in the absorbance of the aminoquinoline. In equilibrium dialysis experiments, the presence of primaquine does not decrease the binding of chloroquine to native calf thymus DNA, even at a molar ratio of primaquine to chloroquine of 8:1. However, chloroquine decreases the binding of primaquine to native DNA. Although there is an apparent interaction between the ring systems of bound primaquine and the nucleic acid bases, primaquine does not appear to intercalate into the DNA structure to a sufficient extent to be detectable by an increase in the viscosity of native DNA.