482d
|
RELEASE OF THE CYANO MOIETY IN THE CRYSTAL STRUCTURE OF N-CYANOMETHYL-N-(2-METHOXYETHYL)-DAUNOMYCIN COMPLEXED WITH D(CGATCG)
OverviewOverview
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.
About this StructureAbout this Structure
482D is a Protein complex structure of sequences from [1] with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Release of the cyano moiety in the crystal structure of N-cyanomethyl-N-(2-methoxyethyl)-daunomycin complexed with d(CGATCG)., Saminadin P, Dautant A, Mondon M, Langlois D'estaintot B, Courseille C, Precigoux G, Eur J Biochem. 2000 Jan;267(2):457-64. PMID:10632715
Page seeded by OCA on Tue Jan 29 21:45:15 2008