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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).

The stability of the carboplatin market drug products Ribocarbo 1 and Ribocarbo-L 1 in 0.9% sodium chloride or 5% glucose infusion solution was investigated by HPLC analysis using a Nucleosil-120-5-C18 column, an eluent consisting of methanol and an aqueous solution of H 2 SO 4 (0.001 N with Na 2 SO 4 (0.02 M); 10:90 or 5:95 (v/v)), and UV detection.At room temperature, carboplatin is stable in 0.9% NaCl solution for 1 h only. During the following 168 h, a 10% degradation to cisplatin and the intermediate diamminechloro[O 1 -1-carboxylato-1-carboxycyclobutane]platinum(II) takes place. This reaction is independent of the carboplatin concentration used.Under identical conditions in 5% glucose solution the carboplatin concentrations decrease during 72 h by about 2±3% and by 5±6% after 168 h of storage. At 4 C, a 10 mg/ml solution is stable during the experiment, whereas from a 1 mg/ml carboplatin infusion, 2% of the drug are lost after day 7 and about 3% after day 28. Degradation products were unequivocally identi®ed. The presence of highly toxic carboplatin hydrolysis products, however, could be excluded.

Enantiomerically pure 1, 2‐diamino‐1‐(4‐fluorophenyl)propanes were synthesized by stereospecific and stereoselective procedures by use of the (1R, 2S)‐ and (1S, 2R)‐2‐amino‐1‐(4‐fluorophenyl)propanols (12a) as intermediates. The enantiomeric purity was determined by 1H NMR spectroscopy after conversion of the propanolamines and the diamines with (1R)‐myrtenal into mono‐ and diimines. For the coordination to platinum the diamines were reacted with K2PtCl4. The resulting dichloroplatinum(II) complexes 4F‐Ph/Me‐PtCl2 were tested for antiproliferative activity on the MCF‐7 breast cancer cell line. (SS)‐ and (RR)‐4F‐Ph/Me‐PtCl2 produced the strongest inhibitory effect. Both complexes showed cytocidal effects, (SS)‐4F‐Ph/Me‐PtCl2 even in a concentration of 1 μM. The (1S, 2R)‐ and (1R, 2S)‐configurated complexes were far less active (SS > RR > RS = SR) and comparable in this respect with the standard cisplatin.

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