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)-derivative of platinum(II) has been synthesized. The complex--named Bamet-M2--was chemically characterized by elemental analysis, FT-IR, NMR, FAB-MS, and UV spectroscopy. The results indicate the following composition: C26H42N2O5Cl2NaPt(II), the metal Pt(II) being bound to two Cl- and one bidentate CDCG moiety, i.e., Na[Pt CDCG(N,O) Cl2]. 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 intracellular activation and interaction with DNA of this type of compounds. The reaction kinetics of this complex in aqueous solution show unusual behaviour; the substitution process with the displacement of two Cl- was almost instantaneous, and the resulting species were found to be very stable. Kinetic studies carried out in the presence of different NaCl concentrations (up to 500 mM) revealed similar fast and nonreversible aquations of Bamet-M2. This contrasts with the slow aquation of cisplatin in extracellular-line solutions (i.e., at high NaCl concentrations) as compared with fast hydrolysis in cells. This difference may partly account for the low cytostatic activity observed here for Bamet-M2 against several tumor cell-lines.
Criado
J J
JJ
Department of Inorganic Chemistry, University of Salamanca, Spain. jjct@gugu.usal.es
Garcia-Moreno
M C
MC
Macias
R R
RR
Marin
J J
JJ
Medarde
M
M
Rodriguez-Fernandez
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry*; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006000:Glycocholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C108271:diaminneplatinum(II)-chlorocholylglycinate; D006000:Glycocholic Acid; D002945:Cisplatin