Synthesis and characterization of the new cytostatic complex cis-diammineplatinum(II)-chlorocholylglycinate.
Owing to the high efficiency of hepatocytes to take up bile acids, these endogenous compounds or their analogues can be considered as potential shuttles for delivering drugs to the liver. With the aim of using this strategy to target platinum(II)-related cytostatic drugs toward the hepatobiliary system, a cholylglycinate (CG) derivative of cis-diammineplatinum(II) has been synthesized by treatment of cis-diammineplatinum(II) dichloride with sodium cholylglycinate. The complex, named Bamet-R2, was characterized by spectroscopy and elemental analysis. Results obtained in these studies together with conductivity measurements, which pointed to nonelectrolyte behavior, allowed the structure of the complex to be identified as C26H48N3O6ClPt. The compound was found to be soluble (up to 3 mM) in water and was highly soluble (more than 10 mM) in ethanol, methanol, and dimethyl sulfoxide. Its stability in solution was monitored by HPLC analysis. In deionized water, the compound remains > 90% pure in solution for up to 7 days and > 80% for up to 28 days. However, in 150 mM NaCl it remains as > 90% pure compound in solution for only 1 day. By contrast with the parent compound CG, Bamet-R2 was found to significantly inhibit the growth of rat hepatocytes in primary culture and L1210 murine leukemia cells, although in a less marked way than that observed for cisplatin. The cytostatic effect of Bamet-R2 was particularly strong against human colon adenocarcinoma LS174T cells. The results point to the potential usefulness of Bamet-R2 in the antitumoral therapy of enterohepatic-derived neoplasias.
Criado
J J
JJ
Department of Inorganic Chemistry, University of Salamanca, Spain.
Macias
R I
RI
Medarde
M
M
Monte
M J
MJ
Serrano
M A
MA
Marin
J J
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D006000:Glycocholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007939:Leukemia L1210 / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009944:Organoplatinum Compounds; D051381:Rats; D013057:Spectrum Analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C108271:diaminneplatinum(II)-chlorocholylglycinate; D006000:Glycocholic Acid; D002945:Cisplatin