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

Gust, Ronald, Krauser, Rudolf, Schmid, Beate and Schönenberger, Helmut (1996) 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. Inorganica chimica acta 250 (1-2), pp. 203-218.

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Abstract

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.

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Item type:

Article

Date:

1996

Additional Information (public):

CAN 126:69235 78-7 Inorganic Chemicals and Reactions 105856-26-6 Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), BIOL (Biological study) (cytotoxicity for breast cancer); 184895-34-9; 185069-15-2 Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), RCT (Reactant), BIOL (Biological study), RACT (Reactant or reagent) (cytotoxicity for breast cancer and reaction with acetic acid or its derivs.); 65-85-0 (Benzoic acid); 76-03-9 (Trichloroacetic acid); 79-11-8 (Monochloroacetic acid); 79-14-1; 79-43-6 (Dichloroacetic acid) Role: RCT (Reactant), RACT (Reactant or reagent) (for prepn. of platinum bis(fluorophenyl)ethylenediamine acetate complex); 105990-74-7 Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), PRP (Properties), RCT (Reactant), BIOL (Biological study), RACT (Reactant or reagent) (kinetics of iodide substitution and cytotoxicity for breast cancer); 184895-28-1P; 184895-29-2P; 184895-30-5P; 184895-31-6P; 184895-32-7P; 184895-33-8P; 185069-09-4P; 185069-10-7P; 185069-11-8P; 185069-12-9P; 185069-13-0P; 185069-14-1P Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), PRP (Properties), RCT (Reactant), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation), RACT (Reactant or reagent) (prepn., kinetics of substitution and breast cancer cytotoxicity of platinum bis(fluorophenyl)ethylenediamine acetate deriv. complexes)

Institutions:

Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Prof. Schönenberger
Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer)

Projects:

SFB 234

Identification Number:

Value	Type
1996:700389	Other

Keywords:

Hydrolysis kinetics (of platinum bis(fluorophenyl)ethylenediamine acetate deriv. complexes) Substituent effects (of platinum bis(fluorophenyl)ethylenediamine acetate deriv. complexes vs. breast cancer cytotoxicity) Substitution reaction kinetics (of platinum bis(fluorophenyl)ethylenediamine acetate deriv. complexes with iodide) Antitumor agents (platinum bis(fluorophenyl)ethylenediamine acetate deriv. complexes as) platinum bisfluorophenylethylenediamine acetate deriv prepn cytotoxicity fluorophenylethylenediamine platinum acetate deriv prepn cytotoxicity cytotoxicity platinum bisfluorophenylethylenediamine acetate deriv substituent kinetics substitution platinum bisfluorophenylethylenediamine acetate deriv breast cancer cytotoxicity platinum bisfluorophenylethylenediamine acetate diastereoisomer platinum bisfluorophenylethylenediamine acetate prepn cytotoxicity

Dewey Decimal Classification:

500 Science > 540 Chemistry & allied sciences

Status:

Published

Refereed:

Yes, this version has been refereed

Created at the University of Regensburg:

Yes

Item ID:

17711

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