Molecular structure of the halogenated anti-cancer drug iododoxorubicin complexed with d(TGTACA) and d(CGATCG).
4'-Deoxy-4'-iododoxorubicin, a halogenated anthracycline derivative, is an anticancer agent currently under Phase II clinical trials. In preclinical studies, it has demonstrated significantly reduced levels of cardiotoxicity compared to currently employed anthracyclines. It also has modified pharmacological properties resulting in an altered spectrum of experimental antitumor activity. The iodine atom at the 4' position of the sugar ring reduces the basicity and enhances the lipophilicity of this compound as compared to related anthracycline drugs. We report here single crystal X-ray diffraction studies of the complexes of 4'-deoxy-4'-iododoxorubicin with the hexanucleotide duplex sequences d(TGTACA) and d(CGATCG) at 1.6 and 1.5 A, respectively. The iodine substituent does not alter the geometry of intercalation as compared to previously solved anthracycline complexes, but appears to markedly affect the solvent environment of the structures. This could have consequences for the interaction of this drug with DNA and DNA binding proteins in cells.
Berger
I
I
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
Su
L
L
Spitzner
J R
JR
Kang
C
C
Burke
T G
TG
Rich
A
A
D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry; D007364:Intercalating Agents / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*
D000903:Antibiotics, Antineoplastic; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; C053044:4'-deoxy-4'-iododoxorubicin; D004317:Doxorubicin