Breast cancer inhibiting diastereomeric diacetato[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) derivatives: synthesis and studies on the relationship between reactivity and antitumor activity

Abstract

Antitumor active [1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) diastereoisomers contg. HOAc derivs. 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 Pt. Kinetic studies on the reaction behavior of the compds. with nucleophiles were performed by using iodide as nucleophile. The new complexes react with nucleophiles predominantly via the 'solvent path' (i.e. via the reactive intermediates [(chelate)Pt(X)(OH2)]+ and [(chelate)Pt(OH2)2]2+). Therefore 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. The extent of accumulation in the tumor cell, too, influences the antitumor activity of a complex. The rate consts. are discussed in view of the activities of the resp. complexes on the human MCF-7 breast cancer cell line. The Cl2Ac and Cl3Ac derivs. do not come close to the std. cisplatin, neither in chem. reactivity nor in biol. activity. Meso/rac-4F-Pt(Ac)2 and meso/rac-4F-Pt(ClAc)2, resp., 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 std. carboplatin in respect to both properties. Other than the remaining, poorly water sol. title compds., meso/rac-4F-Pt(OHAc)2 equal their std. cisplatin in terms of water soly. and antitumor activity (rac-4F-Pt(OHAc)2>meso-4F-Pt(OHAc)2). However, they are markedly faster hydrolyzed than cisplatin. Using rac-4F-Pt(Ac)2 as an example in contrast to the parent compd. 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 soly. and with kinetic studies on the reaction with nucleophiles is a useful method for the preselection of potent Pt complexes deserving further thorough in vitro and in vivo studies.