Molecular structure of the halogenated anti-cancer drug iododoxorubicin complexed with d(TGTACA) and d(CGATCG)

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Abstract
4′-Deoxy-4′-iododoxorubicln, a halogenated anthracycllne derivative, is an anticancer agent currently under Phase II clinical trials. In precllnlcal 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 lipophillclty of this compound as compared to related anthracycllne 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 substltuent does not alter the geometry of intercalation as compared to previously solved anthracycllne 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.