Stability and cellular studies of [rac-1,2-bis(4-f luorophenyl)-ethylenediamine][cyclobutane-1,1-dicarboxylato]platinum(II), a novel, highly active carboplatin derivative

The synthesis of the diastereomeric [1, 2-bis(4-fluorophenyl)ethylenediamin e][cyclobutane-1, 1-dicarboxylato]platinum(II) complexes, rac- and meso-4F- Pt(CBDC), the evaluation of their structures, their tumor-inhibiting proper ties and their stability in physiological environment are described (refere nce 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 c ell lines (MCF-7 and MDA-MB-231). Rac-4F-Pt(CBDC) is largely insensitive ag ainst attack of nucleophiles e.g. Cl-, a prerequisite for sufficient stabil ity in vivo and for fewer side effects. In accordance with this, in vitro s tudies on the binding of rac-4F-Pt(CBDC) to albumin, the main plasma protei n, show that the free, non-protein-bound fraction is relatively high, comin g close to that of carboplatin. These properties are of importance for the transferability of the promising effects found in the cell culture experime nts to in vivo conditions. The distinctly better anti-breast cancer activit y 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-O VCAR-3 is also strongly inhibited by rac-4F-Pt(CBDC).