Synthesis and in vitro pharmacological behavior of platinum(II) complexes containing 1,2-diamino-1-(4-fluorophenyl)-2-alkanol ligands.
In continuation of our effort to optimize the pharmacological profile of [1,2-diamino-1,2-bis(4-fluorophenyl)ethane]dichloridoplatinum(II) complexes, we synthesized [1,2-diamino-1-(4-fluorophenyl)alkanol]dichloridoplatinum(II) analogs. The aim of this study was to evaluate the influence of hydroxyl groups at the C2 moiety on aqueous solubility, lipophilicity, cellular platinum accumulation, and cytotoxicity against MDA-MB-231, U-937, RAJI, and SC-1 cells as well as against cisplatin-sensitive and cisplatin-resistant A2780 and A2780cisR ovarian carcinoma cells. As expected, the OH groups improved the water solubility and decreased the lipophilicity of the neutral ligands, resulting in complexes with favorable pharmacokinetic properties. The cellular uptake of the compounds in MDA-MB-231 and U-937 cells proved to depend on the configuration and showed only a slight correlation with lipophilicity. The most active complexes were R,R/S,S configured, which points to a carrier-mediated mode of action. [threo-1,2-Diamino-1-(4-fluorophenyl)propan]dichloridoplatinum(II) and [threo-2,3-diamino-3-(4-fluorophenyl)propan-1-ol]dichloridoplatinum(II) possessed only low cross-resistance to cisplatin and were up to 10-fold more active in lymphoma cell lines.
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine , Innrain 80/82, 6020 Innsbruck, Austria.
Irene
I
Würtenberger
Bernhard
B
Angermaier
Brigitte
B
Kircher
Ronald
R
Gust
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry* / Q000494:pharmacology; D020298:U937 Cells
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D010984:Platinum; D002945:Cisplatin