title: Stability and cellular studies of [rac-1,2-bis(4-fluorophenyl)-ethylenediamine][cyclobutane-1,1- dicarboxylato]platinum(II), a novel, highly active carboplatin derivative.
abstract: The synthesis of the diastereomeric [1,2-bis(4-fluorophenyl)ethylenediamine][cyclobutane-1, 1-dicarboxylato]platinum(II) complexes, rac- and meso-4F-Pt(CBDC), the evaluation of their structures, their tumor-inhibiting properties and their stability in physiological environment are described (reference complexes: the dichloro- and sulfatoplatinum(II) analogues, carboplatin and cisplatin). The most interesting diastereomer, rac-4F-Pt(CBDC), equals cisplatin and surpasses carboplatin in its effect on human breast cancer cell lines (MCF-7 and MDA-MB-231). Rac-4F-Pt(CBDC) is largely insensitive against attack of nucleophiles e.g. Cl-, a prerequisite for sufficient stability in vivo and for fewer side effects. In accordance with this, in vitro studies on the binding of rac-4F-Pt(CBDC) to albumin, the main plasma protein, show that the free, non-protein-bound fraction is relatively high, coming close to that of carboplatin. These properties are of importance for the transferability of the promising effects found in the cell culture experiments to in vivo conditions. The distinctly better anti-breast cancer activity of rac-4F-Pt(CBDC) than of carboplatin has been attributed to its ability to accumulate in the tumor cells. The human ovarian cancer cell line NIH-OVCAR-3 is also strongly inhibited by rac-4F-Pt(CBDC).
authors.affiliation: Institut für Pharmazie I der FU Berlin, Germany. rgust@zedat.fu-berlin.de
authors.forename: R
authors.initials: R
authors.lastname: Gust
authors.forename: B
authors.initials: B
authors.lastname: Schnurr
authors.forename: R
authors.initials: R
authors.lastname: Krauser
authors.forename: G
authors.initials: G
authors.lastname: Bernhardt
authors.forename: M
authors.initials: M
authors.lastname: Koch
authors.forename: B
authors.initials: B
authors.lastname: Schmid
authors.forename: E
authors.initials: E
authors.lastname: Hummel
authors.forename: H
authors.initials: H
authors.lastname: Schönenberger
mesh_terms: D001943:Breast Neoplasms; D016190:Carboplatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D048429:Cell Size; D002851:Chromatography, High Pressure Liquid; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010051:Ovarian Neoplasms; D010984:Platinum / Q000032:analysis; D012709:Serum Albumin / Q000378:metabolism; D012995:Solubility; D014407:Tumor Cells, Cultured
chemical_list: C116172:(1,2-bis(fluorophenyl)ethylenediamine)(cyclobutane-1,1-dicaroxylato)platinum(II); D012709:Serum Albumin; D010984:Platinum; D016190:Carboplatin