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 synthesis of the diastereomeric [1,2‐bis(4‐fluorophenyl)‐ethylenediamine][dicarboxylato]platinum(II) complexes, rac‐ and meso‐4F‐Pt(X) [X: oxalato (Ox), malonato (Mal), hydroxymalonato (OHMal), phenylmalonato (PhMal), tetrahydro‐4H‐pyran‐4,4‐dicarboxylato (Thpdc)], the evaluation of their structure, water solubility, resistance against attack by nucleophiles, and growth inhibiting properties on the human MCF‐7 breast cancer cell line are described [parent compounds: rac‐4F‐Pt(CBDC) and meso‐4F‐Pt(CBDC); reference complexes: carboplatin, cisplatin, rac‐ and meso‐4F‐PtCl2]. The most active 4F‐Pt(X) complexes, rac‐4F‐Pt(Mal), rac‐4F‐Pt(OHMal) and rac‐4F‐Pt(Thpdc), equal the parent compound rac‐4F‐Pt(CBDC) as well as cisplatin and surpass carboplatin in their effect on the MCF‐7 breast cancer cell line. Their water solubility, which is of importance for an application in the cancer chemotherapy, is higher than that of rac‐4F‐Pt(CBDC), especially in the case of rac‐4F‐Pt(OHMal) and rac‐4F‐Pt(Thpdc). In comparison to the dichloroplatinum(II) analogue (4F‐PtCl2) the stability of the three compounds in the presence of the strong nucleophile iodide is markedly enhanced, which means a reduction of the protein bound drug fraction in the blood and tissue compartments accompanied by an increase of the active, free drug level. The found physio‐chemical properties of these compounds meet the requirements for the transferability of their promising breast cancer inhibiting effects detected in cell culture experiments to in vitro conditions.
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