Structure-activity relationships among daunorubicin and adriamycin analogs

Structural characteristics of Adriamycin and daunorubicin analogs are discussed in terms of three antitumor activity classifications: compounds with potency and efficacy equivalent to or superior to the parent antibiotics, compounds displaying high efficacy but with decreased potency, and compounds in which a key structural change has destroyed all in vivo antitumor activity. It is first concluded that analogs possessing efficacy and potency comparable to the parent antibiotics are quite similar to the parents in structural terms, ie, their hydrophilic character, functional groups, and stereochemistry. Within this group there is suggestive evidence that altered electronic character of the aglycones may be associated with improved cardiotoxicity characteristics. The second general conclusion is that high efficacy accompanied by decreased potency is compatible with a much wider array of structural variants than is high efficacy accompanied by high potency. Thus, analogs with substantially higher or lower lipophilicity than the parent antibiotics, as well as those with an array of ionic characteristics differing from the parents, retained significant efficacy. These characteristics are compatible with the concept of multiple mechanisms of action for the anthracycline antibiotics. In general, structural changes in the sugar side chain are appreciably more compatible with retention of in vivo antitumor efficacy than are changes in the aglycone, both in terms of functional groups and stereochemistry.