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Abstract
With a view to using bile acids as shuttles for delivering platinum-related cytostatic drugs to the liver, a cholylglycine(CG)-derivative of platinum(II) has been synthesized. The complex, named Bamet-H2, was characterized by elemental analysis, FT-IR, NMR, FAB-MS, and UV spectroscopy. The results indicate the following composition: C52H84N2O12ClNa Pt(II). Conductivity data suggest that the complex behaves as a sodium salt (1:1) of a complex of Pt(II) bound to one cl-, one bidentate CG moiety, and another monodentate CG moiety, i.e., Na[Pt(CG-O,N)(CG-O)Cl]. The compound is highly soluble (up to 10 mM) in water, ethanol, methanol, DMF, and DMSO. Bamet-H2 was stable in solution (either water or 150 mM NaCl solution), as measured by HPLC, up to 24 h. At this time, more than 90% of the platinum present in water or saline solutions was found to be Bamet-H2. Cytostatic activity against L1210 murine leukemia cells was found. This characteristic was stronger against rat hepatocytes in primary culture. Isolated in situ rat livers were perfused for 40 min with a recirculating medium containing 1 microM Bamet-H2, CG, or cisplatin. Uptake and excretion into bile were much greater for Bamet-H2 than for cisplatin, but less than for CG. Liver content was higher for Bamet-H2 than for cisplatin or CG. The results point to the potential usefulness of Bamet-H2 in the antitumoral therapy of neoplasias derived from liver parenchymal cells.
Highlights
With a view to using bile acids as shuttles for delivering platinum-related cytostatic drugs to the liver, a cholylglycine(CG)derivative of platinum(I1) has been synthesized
Steroids [8],previous works have aimed at synthesizing DACH-Pt complexes with bile acids in order to obtain derivatives with both lipophilicity and water miscibility (9,lO). promising results have been obtained as regards the antitumoral activity of the complexes, no further investigation in this direction has been carried out
The rationale of the present work was that platinum(I1)-containing bile acid derivatives with molecular structures more similar to those of natural bile acids than DACH-Pt-bile acid complexes might be recognized by transmembrane bile acid carrier proteins and be efficiently taken up by hepatocytes
Summary
With a view to using bile acids as shuttles for delivering platinum-related cytostatic drugs to the liver, a cholylglycine(CG)derivative of platinum(I1) has been synthesized. Erfused rat liver viability was confirmed by measuring bile flow, oxygen uptake, perfusion pressure, perfusion flow, potassium and lactate dehydrogenase activityreleased into the perfusate during the experiments, as previously reported [18].Values were similar to those previously o b tained in our laboratory for this preparation [18] and were not significantly modified during the experimental period (40min) (data not shown).
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