Abstract
The interaction of two antitumor ruthenium(III) complexes,-Na[trans-RuCl4(DMSO)(Im)] and Na[trans-RuCl4(DMSO)(Ind)]- with human serum apotransferrin (apoTf) was investigated through a number of spectroscopic techniques such as UV-Vis absorption, CD and 1H NMR spectroscopy. Interestingly, the hydrolysis profiles of these complexes in a physiological buffer are markedly affected by the presence, in solution, of apoTf suggesting the occurrence of a specific interaction of their respective hydrolysis products with the protein. The formation of stable adducts with apotransferrin has been demonstrated by CD spectroscopy, and additional information obtained through 1H NMR of the hyperfine shifted signals. The bound ruthenium(III) species may be detached from these adducts by addition of excess citrate at low pH. The behavior of the investigated ruthenium(III) complexes with apoTf is compared with that of the recently described and strictly related ru-im and ru-ind antitumour complexes, and discussed in the frame of general strategies of drug targeting.
Highlights
After the discovery of the excellent antitumor properties of cisplatin, in the late seventies, large interest has concentrated on the design and the synthesis of other platinum and nonplatinum metal complexes to be used for anticancer chemotherapyI The main goal of the intense research activity conducted in this field is to prepare new inorganic compounds that are active versus tumor cell lines ..not sensitive to cisplatin; several attempts are being done to increase the selectivity of these compounds for the target tissue and reduce their systemic toxicity
Under physiological conditions hydrolysis appears to be at least a two-step process, the first step corresponding to the loss of a first chloride group and the second step to further hydrolytic events
Metal-Based Drugs nm in the case of complex and around 540 nm in the case of complex II. These results indicate that both complexes or, more precisely, their hydrolysis products do interact with apotransferrin and that the interaction occurs in concomitance with the second hydrolytic process
Summary
After the discovery of the excellent antitumor properties of cisplatin, in the late seventies, large interest has concentrated on the design and the synthesis of other platinum and nonplatinum metal complexes to be used for anticancer chemotherapyI The main goal of the intense research activity conducted in this field is to prepare new inorganic compounds that are active versus tumor cell lines ..not sensitive to cisplatin; several attempts are being done to increase the selectivity of these compounds for the target tissue and reduce their systemic toxicity. A large number of platinum derivatives as well as several compounds with other metals like ruthenium, titanium, tin, and gold, have been synthesized and tested for anticancer properties[1]. In some cases these compounds demonstrated, in comparison to cisplatin, a different pattern of in vitro antitumor activities and a lower systemic toxicity. Complexes that are about entedng the first phase of clinical trials are the ruthenium(Ill) complexes imidazolium trans(bisimidazole) tetrachlomruthenate(lll) (ru-im or ICR) and indazolium trans(bisindazole) tetrachlomruthenate(lll) (ru-ind), developed by Keppler, for which a good antitumor activity versus several human colon carcinoma cell lines has been reported1"3. The corresponding ruthenium(Ill) compounds developed by the group of Mestroni in which one of the two axial heterocycles-imidazole (Im) or indazole (Ind)o is replaced
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