COMPARISON OF DNA-SEQUENCE SELECTIVITY OF ANTHRACYCLINE ANTIBIOTICS AND THEIR 3'-HYDROXYLATED ANALOGS

The sequence selectivity of three anthracyclines and their 3' hydroxyl ated analogs (in which an OH replaces NH3+ in the daunosamine at neutr al pH) was examined in DNase I footprinting experiments on a 158-bp DN A fragment. We found that chemical modification of the daunosamine at C3' has more drastic consequences for sequence selectivity than chemic al modification at C4 and C14 of the aglycone moiety, All anthracyclin es and hydroxylated derivatives selectively recognize the triplet PyAP y. The importance of NH3+ in stabilizing the interaction was evidenced . First of all, comparable protection patterns require 5 times more hy droxyanthracycline than regular anthracycline. Furthermore, it is only after the replacement of NH3+ by OH that an additional protection sit e - GGC - appears. GGC is the site of best selectivity of the hydroxya nthracyclines. Anthracyclines can be considered both intercalators (ag lycone moiety) and minor groove binders (sugar moiety), Since intercal ating drugs show a slight preference for GC base pairs, we suggest hyd roxylated 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 w ill interact with the sugar-phosphate chain.