A theoretical study of the comparative binding affinities of daunomycin derivatives to a double-stranded oligomeric DNA. Proposal for new high affinity derivatives.

Theoretical computations were performed on the comparative binding affinities of daunomycin (DM, 1) and seven derivatives related to the double-stranded oligonucleotide d(CGATCG)2. The compounds investigated were 4-demethoxy DM (2), and its beta-anomer (3), 4-demethoxy-7,9-bis-epi DM (4) and its beta anomer (5), a derivative with glucosamine instead of daunosamine (6), and two additional hypothetical DM derivatives in which the cationic NH3+ group of the daunosamine moiety is replaced by either a CH2--NH3+ group (7) or a CH2CH2NH3+ group (8), so as to indicate the effect on the binding affinity of interposing one- or two-methylene groups between the sugar and the cationic charge. The conformational angles of the hexanucleotide are fixed in values found in the representative crystal structure of the d(CGTACG)2-DM complex. The intermolecular drug-hexanucleotide interaction energies and the conformational energy changes of the drug upon binding are computed and optimized in the framework of the SIBFA procedure (sum of interactions between fragments computed ab initio), which uses empirical formulas based on ab initio SCF computations. The overall binding affinity ordering of compounds 1-6 compares satisfactorily with the ordering of available experimental affinity constants. The binding affinities of compounds 7 and 8, for which no experimental results seem to be available yet, are predicted to be significantly higher than those of the parent compound DM, with the greatest affinity found for 7. Because of the overall correlation between binding affinity of anthracyclines to DNA and their antitumor activity, these last two compounds deserve an exploration of their chemotherapeutic efficiency.