Synthesis and characterization of sodium cis-dichlorochenodeoxycholylglycinato(O,N) platinum(II) - Cytostatic activity

With a view to using bile acids as shuttles for delivering platinum-related cytostatic drugs to liver tumors, a chenodeoxycholylglycinato(CDCG)-deriva tive of platinum(II) has been synthesized. The complex - named Bamet-M2- wa s chemically characterized by elemental analysis, FT-IR, NMR, FAB-MS, and U V spectroscopy. The results indicate the following composition: C26H42N2O5C l2NaPt(II), the metal Pt(II) being bound to two Cl- and one bidentate CDCG moiety, i.e., Na[Pt CDCG(N,O) Cl-2]. The compound is highly soluble (up to 20 mM) in water and (up to 35 mM) in ethanol, methanol and DMSO. Hydrolysis was investigated because this is assumed to be an important step in intrac ellular activation and interaction with DNA of this type of compounds. The reaction kinetics of this complex in aqueous solution show unusual behaviou r; the substitution process with the displacement of two Cl- was almost ins tantaneous, and the resulting species were found to be very stable. Kinetic studies carried out in the presence of different NaCl concentrations (up t o 500 mM) revealed similar fast and nonreversible aquations of Bamet-M2. Th is contrasts with the slow aquation of cisplatin in extracellular-line solu tions (i.e., at high NaCl concentrations) as compared with fast hydrolysis in cells. This difference may partly account for the low cytostatic activit y observed here for Bamet-M2 against several tumor cell-lines.