Comparison of DNA sequence selectivity of anthracycline antibiotics and their 3'-hydroxylated analogs

Abstract

The sequence selectivity of three anthracyclines and their 3' hydroxylated analogs (in which an OH replaces NH3+ in the daunosamine at neutral pH) was examined in DNase I footprinting experiments on a 158-bp DNA fragment. We found that chemical modification of the daunosamine at C3' has more drastic consequences for sequence selectivity than chemical modification at C4 and C14 of the aglycone moiety. All anthracyclines and hydroxylated derivatives selectively recognize the triplet PyAPy. The importance of NH3+ in stabilizing the interaction was evidenced. First of all, comparable protection patterns require 5 times more hydroxyanthracycline than regular anthracycline. Furthermore, it is only after the replacement of NH3+ by OH that an additional protection site - CGC--appears. GGC is the site of best selectivity of the hydroxyanthracyclines. Anthracyclines can be considered both intercalators (aglycone moiety) and minor groove binders (sugar moiety). Since intercalating drugs show a slight preference for GC base pairs, we suggest hydroxylated anthracyclines to have a sequence specificity closer that of pure intercalators. Chemical modifications at C4 and C14 only modify the hydrogen bonding stabilization of the DNA-aglycone moiety complex: the more the anthracycline or its analog is lipophilic, the less it will interact with the sugar-phosphate chain.