Abstract
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 ...
Abstract
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.
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