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

Abstract

The synthesis of the diastereomeric [1,2-bis(4-fluorophenyl)ethylenediamine][cyclobutane-1, 1-dicarboxylato]platinum(II) complexes, rac- and meso-4F-Pt(CBDC), the evaluation of their structures, their tumor-inhibiting properties and their stability in physiological environment are described (reference 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 cell lines (MCF-7 and MDA-MB-231). Rac-4F-Pt(CBDC) is largely insensitive against attack of nucleophiles e.g. Cl-, a prerequisite for sufficient stability in vivo and for fewer side effects. In accordance with this, in vitro studies on the binding of rac-4F-Pt(CBDC) to albumin, the main plasma protein, show that the free, non-protein-bound fraction is relatively high, coming close to that of carboplatin. These properties are of importance for the transferability of the promising effects found in the cell culture experiments to in vivo conditions. The distinctly better anti-breast cancer activity 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-OVCAR-3 is also strongly inhibited by rac-4F-Pt(CBDC).

Synthesis and Antitumor Activity of [1,2-Bis(4-fluorophenyl)ethylenediamine][dicarboxylato]platinum(II) Complexes

“…In the 4F-Pt(X) complexes with R,R-or S,S-configurated diamine ligands the two 4-fluorophenyl residues are located exclusively in equatorial positions of the five-membered chelate ring, while in those with R,S-configurated diamine ligands the chelate ring exists in a δ↔λ conformer equilibrium, in which each 4-fluorophenyl residue changes its position from axial to equatorial and vice versa [1] .…”

“…This form of drug administration is required to achieve long-lasting cytocidal drug levels which are essential to obtain stable remissions (compare ref. [1] , especially Discussion).…”

“…In a preceding publication [1] we reported on a new derivative of carboplatin in which the two NH 3 residues are replaced by the carrier ligand rac-1,2-bis(4-fluorophenyl)ethylenediamine. This structural variation of carboplatin enhances the drug uptake by breast cancer cells.…”

Small cationic antimicrobial peptides delocalize peripheral membrane proteins

“…To this end, cells were harvested and washed five times with 100 mM Tris/1 mM EDTA before ultrasonication, centrifugation, and ultracentrifugation. Ruthenium contents were quantified using a Vario 6 graphite furnace atomic absorption spectrometer (Analytik Jena) as described previously (82)(83)(84).…”

Structure Activity Studies on Leaving Group Derivatives of [meso-1,2-Bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]-platinum(II)

“…The syntheses of the leaving group derivatives were performed as described earlier [5,9] . Meso-1 was reacted with K 2 PtI 4 to obtain meso-1-PtI 2 which was transformed subsequently into the water soluble aquasulfatoplatinum(II) complex meso-1-PtSO 4 .…”