The binding properties of two antitumor ruthenium(III) complexes to apotransferrin.
The interaction of two ruthenium(III) complexes exhibiting high anticancer activity, namely trans-indazolium(bisindazole)tetrachlororuthenate(III) (ru-ind) and trans-imidazolium(bisimidazole)tetrachlororuthenate(III) (ru-im), with human serum apotransferrin has been investigated through spectroscopic and chromatographic techniques with the ultimate goal of preparing adducts with good selectivity for cancer cells. Whereas the binding of ru-im to human serum apotransferrin takes several hours, ru-ind, the less toxic complex, gives rise to a well defined 2:1 complex within a few minutes. We have ascertained that ru-ind binding occurs around the iron binding sites; binding does not occur in the absence of bicarbonate, and this anion dictates the kinetic and mechanistic characteristics of protein binding of ru-ind. The two ruthenium(III) complexes do not behave as iron(III) complexes, e.g. Fe(EDTA) or Fe(nitrilotriacetate), which lose their respective ligands when binding apotransferrin, but the N-heterocycles remain attached to the metal in the protein-bound species. Reversion of binding is obtained by acidification in the presence of chelators such as citrate or ATP. In comparison with cisplatin and its deactivation by serum proteins, our results indicate that other metal complexes such as ru-ind could use transferrin as a drug delivery system. Furthermore, the rapid protein binding of ru-ind seems to be related to a lower toxicity while still exhibiting high antitumor activity.
Kratz
F
F
Department of Chemistry, University of Florence, Italy.
Hartmann
M
M
Keppler
B
B
Messori
L
L
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001059:Apoproteins / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism; D007191:Indazoles / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012428:Ruthenium / Q000737:chemistry* / Q000378:metabolism; D013053:Spectrophotometry; D014168:Transferrin / Q000737:chemistry* / Q000378:metabolism
D000970:Antineoplastic Agents; D001059:Apoproteins; D007093:Imidazoles; D007191:Indazoles; D009942:Organometallic Compounds; D014168:Transferrin; C028284:apotransferrin; C073527:imidazolium-tetrachlorobisimidazole ruthenium(III); C068847:indazolium-tetrachlorobisindazoleruthenate(III); D012428:Ruthenium