Bifunctional antitumor compounds: interaction of adriamycin with metallocene dichlorides.
In order to synthesize bifunctional antitumor compounds, the interactions of adriamycin with metallocene dichlorides, Cp2MCl2, where M = Zr, Ti, V, have been studied. Using absorption, fluorescence, and circular dichroism measurements, we have shown that adriamycin is able to coordinate to the three metal ions. The interaction of Cp2ZrCl2 and Cp2VCl2 with adriamycin leads to compounds of 1:2 metal:drug stoichiometry, whereas the interaction of Cp2TiCl2 with adriamycin leads to two types of compounds of 1:2 and 1:1 stoichiometry. The Zr-adriamycin complex, which is unable to dissociate, even at a pH lower than 1, does not display antitumor activity against P-388 leukemia. However Ti-adriamycin complexes, which are more susceptible to dissociation in acidic media, exhibit antitumor activity that compares with that of the free drug. These complexes, unlike adriamycin, do not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase. In addition, the presence of metal ions promote the binding of the drug to DNA and erythrocyte ghosts.
Moustatih
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Laboratoire de Chimie Bioinorganique (UA CNRS 198), Bobigny, France.
Fiallo
M M
MM
Garnier-Suillerot
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D000818:Animals; D002942:Circular Dichroism; D003432:Cross-Linking Reagents / Q000138:chemical synthesis; D004247:DNA / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism*; D004910:Erythrocyte Membrane / Q000378:metabolism; D006801:Humans; D051379:Mice; D009942:Organometallic Compounds / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
D003432:Cross-Linking Reagents; D009942:Organometallic Compounds; C013108:metallocene; D013481:Superoxides; D004317:Doxorubicin; D004247:DNA