Stereochemical requirements in the antitumor anthracyclines.

Abstract

The synthesis, DNA binding data and early biological evaluation of 9-deacetyldaunorubicin [NSC 268708, (5)] and the corresponding C-9 epimer [NSC 268709, (6)] were reported. The present findings are interesting regarding the dependence of the DNA-binding properties on the stereochemistry at the C-9 asymmetric center and the relationships of these properties with antitumor efficacy. As the main biochemical effects of anthracycline antibiotics are concerned with nucleic acid synthesis and the binding of these drugs to DNA is considered responsible for their interference with template DNA function, the interaction of 5 and 6 with native DNA was studied by equilibrium dialysis and low shear viscosimetry. The results were compared with those obtained for daunorubicin and doxorubicin. The Kapp values of both deacetyl derivatives are lower than those of daunorubicin and doxorubicin. The Kapp value of 6 indicates that in this derivative the .beta.-orientation of the C-9 OH group is less favorable to its interaction with the 1st DNA phosphate away from the intercalation site. These results are confirmed by those obtained by low shear viscosimetry which show a similar trend. Preliminary activity data of 5 and 6 are reported. The 2 epimers showed a different efficacy as antitumor agents in laboratory animals, the 9(S) compound showing a higher selectivity of inhibition of tumor development in comparison with the toxic effects in the host. In the antitumor anthracyclines stereochemistry at the C-9 center is an important molecular requirement for optimal pharmacological activity. In the C-9 deacetyl derivatives described here, the effect of stereochemistry on pharmacological activity parallels that on DNA complexing ability.