Allosteric, chiral-selective drug binding to DNA

The binding interactions of (-)-daunorubicin (WP900), a newly synthesized e nantiomer of the anticancer drug (+)-daunorubicin, with right- and left-han ded DNA, have been studied quantitatively by equilibrium dialysis, fluoresc ence spectroscopy, and circular dichroism. (+)-Daunorubicin binds selective ly to right-handed DNA, whereas the enantiomeric WP900 ligand binds selecti vely to left-handed DNA. Further, binding of the enantiomeric pair to DNA i s clearly chirally selective, and each of the enantiomers was found to act as an allosteric effector of DNA conformation. Under solution conditions th at initially favored the left-handed conformation of [poly(dGdC)](2), (+)-d aunorubicin allosterically converted the polynucleotide to a right-handed i ntercalated form. In contrast, under solution conditions that initially fav ored the right-handed conformation of [poly(dGdC)](2), WP900 converted the polynucleotide to a left-handed form. Molecular dynamics studies by using t he AMBER force field resulted in a stereochemically feasible model for the intercalation of WP900 into left-handed DNA. The chiral selectivity observe d for the DNA binding of the daunorubicin/WP900 enantiomeric pair is far gr eater than the selectivity previously reported for a variety of chiral meta l complexes. These results open a new avenue for the rational design of pot ential anticancer agents that target left-handed DNA.