Release of the cyano moiety in the crystal structure of NâcyanomethylâNâ(2âmethoxyethyl)âdaunomycin complexed with d(CGATCG)
2000
Saminadin, Pascale | Dautant, Alain | Mondon, Martine | Langlois d’Estaintot, Béatrice | Courseille, Christian | Précigoux, Gilles
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 crossâlinks in drug DNA complexes. The present study concerns NâcyanomethylâNâ(2âmethoxyethyl)âdaunomycin (CMDa), a synthetic analogue of cyanomorpholinoâdaunomycin. 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 (ΔTmâ=â7.5â°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 1.5âà resolution. The complex crystallizes in the space group P41212 and is similar to other anthracyclineâhexanucleotide complexes. In the crystal state, the observed densities indicate the formation of NâhydroxymethylâNâ(2âmethoxyethyl)âdaunomycin (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 drugâDNA 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.
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