Doxorubicin is among the most widely used
anthracycline in
cancer chemotherapy. In an attempt to avoid the
cardiotoxicity and drug resistance of
doxorubicin therapy, several analogues were synthesized. The cyanomorpholinyl derivative is the most cytotoxic. They differ greatly from their parent compound in their
biological and pharmacological properties, inducing cross-links in
drug DNA complexes. The present study concerns N-cyanomethyl-N-(2-methoxyethyl)-daunomycin (
CMDa), a synthetic analogue of cyanomorpholino-
daunomycin. Compared to
doxorubicin,
CMDa displays a cytotoxic activity on
L1210 leukemia cells at higher concentration but is effective on
doxorubicin resistant cells. The results of fluorescence quenching experiments as well as the melting temperature (DeltaTm = 7.5 degrees C) studies are consistent with a
drug molecule which intercalates between the
DNA base pairs and stabilizes the
DNA double helix. The crystal structure of
CMDa complexed to the hexanucleotide d(CGATCG) has been determined at 1.5 A resolution. The complex crystallizes in the space group P41212 and is similar to other
anthracycline-hexanucleotide complexes. In the crystal state, the observed densities indicate the formation of N-hydroxymethyl-N-(2-methoxyethyl)-daunomycin (
HMDa) with the release of the cyano moiety without
DNA alkylation. The formation of this degradation compound is discussed in relation with other
drug modifications when binding to
DNA. Comparison with two other
drug-
DNA crystal structures suggests a correlation between a slight change in DNA conformation and the nature of the
amino sugar substituents at the N3' position located in the minor groove.