Doxorubicin and Related Compounds. II. Structure-Activity Considerations

Abstract

In the last ten years several anthracycline glycosides related to doxorubicin have been obtained by semisynthesis, partial synthesis, total synthesis, biosynthesis and tested for “in vitro” and “in vivo” antitumor activity in our laboratories with the aim of developing new anticancer agents endowed with higher antitumor activity, larger spectrum of activity and lower toxicity in respect to the parent compound. The establishment of structure-activity relationships is an essential part of such program. It is now possible to operate a retrospective investigation on data collected in these investigations in order to perform deductions concerning the said relationships. In part I of this study (1) the importance of DNA as the main cellular receptor of the antitumor anthracyclines and some physico-chemical properties of the intercalation complex formed in solution between these compounds and DNA have been described. In particular, these properties have been used for the classification of thirty daunorubicin and doxorubicin analogues according to their affinity for DNA. We shall naw discuss the correlations of biological activity in different experimental systems with the chemical structure of these analogues on the basis of the said classification. The experimental systems used are the effect on the colony forming ability of HeLa cells “in vitro” and that on mice bearing transplantable tumors such as the L 1210, P 388 and Gross leukemias. All activity data reported in this paper are derived from internal reports concerning the experiments performed at Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, by A. Di Marco, A.M. Casazza and G. Pratesi.