BREAST-CANCER INHIBITING DIASTEREOMERIC ,2-BIS(4-FLUOROPHENYL)ETHYLENEDIAMINE]PLATINUM(II) DERIVATIVES - SYNTHESIS AND STUDIES ON THE RELATIONSHIP BETWEEN REACTIVITY AND ANTITUMOR-ACTIVITY

Antitumor active [1,2-bis(4-fluorophenyl)ethylenediamine] platinum(II) diastereoisomers containing acetic acid derivatives as 'leaving group s' (acetate: meso/rac-4F-Pt(Ac)(2); monochloroacetate: meso/rac-4F-Pt( ClAc)(2); dichloroacetate: meso/rac-4F-Pt(Cl2Ac)(2); trichloroacetate: meso/rac-4F-Pt(Cl3Ac)(2); glycolate: meso/rac-4F-Pt(OHAc)(2); phenyla cetate: meso/rac-4F-Pt(PhAc)(2)) were synthesized and characterized by IR and H-1 NMR spectroscopy. In all complexes except meso/rac-4F-Pt(P hAc)(2), which exist as [meso/rac-4F-PtPhAc](+)PhAc(-), both carboxyli c acid residues are coordinated to platinum. Kinetic studies on the re action behavior of the title compounds with nucleophiles were performe d by using iodide as nucleophile. The studies show that the new comple xes react with nucleophiles predominantly via the 'solvent path' (i.e. via the reactive intermediates=Pt(X) (OH2)(+) and =Pt(OH2)(2)(2+)). T herefore the rates of the reactions in which the reactive species are formed affect the antitumor activity of the complexes as well as their inactivation by bionucleophiles during the transport to the tumor. Th e extent of accumulation in the tumor cell, too, influences the antitu mor activity of a complex. The rate constants are discussed in view of the activities of the respective complexes on the human MCF-7 breast cancer cell line. From the title compounds the Cl2Ac and Cl3Ac derivat ives do not come close to the standard cisplatin, neither in chemical reactivity nor in biological activity. Meso/rac-4F-Pt(Ac)(2) and meso/ rac-4F-Pt(ClAc)(2), respectively, show similar hydrolysis rates but lo wer antitumor activities than cisplatin, presumably due to a reduced d rug uptake by the tumor cell. Meso/rac-4F-Pt(PhAc)(2) compare well wit h their standard carboplatin in respect to both properties. Other than the remaining, poorly water soluble title compounds, meso/rac-4F-Pt(O HAc)(2) equal their standard cisplatin in terms of water solubility an d antitumor activity (rac-4F-Pt( OHAc)(2)>meso-4F-Pt(OHAc)(2)). Howeve r, they rue markedly faster hydrolyzed than cisplatin. By use of rac-4 F-Pt(Ac)(2) as an example it was confirmed that, in contrast to the pa rent compound rac-4F-PtCl2, the new complex type is also active under in vivo conditions owing to its markedly lower reactivity (mainly due to the lack of a direct substitution by strong nucleophiles), which en tails a reduced inactivation of the drug on its way to the tumor. The in vitro testing on tumor cell lines combined with the evaluation of t he water solubility and with kinetic studies on the reaction with nucl eophiles is a useful method for the preselection of potent platinum co mplexes deserving further thorough in vitro and in vivo investigations .