Add time:07/21/2019         Source:sciencedirect.com

Antitumor active [1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) diastereoisomers containing acetic acid derivatives as ‘leaving groups’ (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; phenylacetate: meso/rac-4F-Pt(PhAc)2) were synthesized and characterized by IR and 1H NMR spectroscopy. In all complexes except meso/rac-4F-Pt(PhAc)2, which exist as [meso/rac-4F-PtPhAc]+PhAc−, both carboxylic acid residues are coordinated to platinum. Kinetic studies on the reaction behavior of the title compounds with nucleophiles were performed by using iodide as nucleophile. The studies show that the new complexes react with nucleophiles predominantly via the ‘solvent path’ (i.e. via the reactive intermediates = Pt(X)(OH2)+ and =Pt(OH2)22+. Therefore the rates of 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. The extent of accumulation in the tumor cell, too, influences the antitumor 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 derivatives 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 lower antitumor activities than cisplatin, presumably due to a reduced drug uptake by the tumor cell. Meso/rac-4F-Pt(PhAc)2 compare well with their standard carboplatin in respect to both properties. Other than the remaining, poorly water soluble title compounds, meso/rac-4F-Pt(OHAc)2 equal their standard cisplatin in terms of water solubility and antitumor activity rac-4F-Pt(OHAc)2 > meso-4F--Pt(OHAc)2). However, they are markedly faster hydrolyzed than cisplatin. By use of rac-4F-Pt(Ac)2 as an example it was confirmed that, in contrast to the parent 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 entails 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 the water solubility and with kinetic studies on the reaction with nucleophiles is a useful method for the preselection of potent platinum complexes deserving further thorough in vitro and in vivo investigations.

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