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

Abstract

The spatial structures of leaving group derivatives of [meso‐1,2‐bis(2,6‐dichloro‐4‐hydroxyphenyl)ethylenediamine]platinum(II) (meso‐1‐PtL2; L2 = SO4, Cl2, I2, CBDC (cyclobutane‐1,1‐dicarboxylate)) were investigated by NMR methods and correlated with their reactivity against nucleophiles, their estrogenic potency, and their activity on the hormone dependent MCF‐7 mammary carcinoma cell line. It was demonstrated that beside the non‐leaving group meso‐1 the PtL2 moiety of meso‐PtL2 complexes is important for the estrogen receptor binding. Among the tested complexes meso‐1‐PtI2 possesses the highest affinity for the estrogen receptor (RBA = 2.6) and represents a strong estrogen on the MCF‐7‐2a cell line. The use of CBDC as leaving group decreases the effects. Meso‐1‐PtCBDC shows an RBA of 0.06 and has only half of the estrogenic activity. Both complexes are sufficiently stable under physiological conditions, so a transformation into the dichloroplatinum( II) complex prior to the binding to the estrogen receptor can be excluded. Due to their high stability meso‐1‐PtI2 and meso‐1‐ PtCBDC were only marginally active on the human estrogen receptor positive MCF‐7 cell line, while meso‐1‐PtSO4 and meso‐1‐PtCl2 reduced the cell growth to T/Cmax = 45% and 25%, respectively.

Gold complexes with thiosemicarbazones: reactions of bi- and tridentate thiosemicarbazones with dichloro[2-(dimethylaminomethyl)phenyl-C 1,N ]gold(III), [Au(damp-C 1,N )Cl2]

“…The antiproliferative activity of the gold complexes was tested on exponentially dividing human MCF-7 breast cancer cells according to a standardized microtitre assay. 54 The cells were seeded onto 96-well microtitre plates as a suspension with 17 × 10 5 cells ml Ϫ1 . After a 72 h preincubation period, this medium was exchanged for a new one containing the test compound at a concentration of 5 µM.…”

Synthesis, Conformational Studies, and Investigations on the Estrogen Receptor Binding of [R/S-1-(2,6-Dichloro-4-hydroxyphenyl)-ethylenediamine]platinum(II) Complexes

“…Despite the low RBA values 2-PtL 2 complexes interact with the ER and lead to high expression of luciferase. Already in a concentration of 0.1 µM they reached the maximum effect of E2 [6] .…”

“…In our test system we investigated the interaction of the new compounds with the ER in a competition binding assay using calf uterus cytosol and a luciferase assay on MCF-7-2a cells [6] . These estrogen receptor containing mammary carcinoma cells were stable transfected with the plasmid ERE wtc luc.…”

“…Dextran, 17β-estradiol, L-glutamine (L-glutamine solution: 29.2 mg/ml PBS), and Minimum Essential Medium Eagle (EMEM) were purchased from Sigma (Munich, Germany); Dulbeccos Modified Eagle Medium without phenol red (DMEM) from Gibco (Eggenstein, Germany); bovine calf serum (BCS) from Bio Whittaker (Verviers, Belgium); N-hexamethylpararosanil- ine (violet crystals) and gentamicin sulfate from Fluka (Deisenhofen, Germany); glutardialdehyde (25%) from Merck (Darmstadt, Germany); trypsin (0.05%) in ethylenediaminetetraacetic acid (0.02%) (trypsin/EDTA) from Boehringer (Mannheim, Germany); penicillin-streptomycin gold standard (10000 IE penicillin/ml, 10 mg streptomycin/ml) and geneticin disulfate (geneticin solution: 35.71 mg/ml PBS) from ICN Biomedicals GmbH (Eschwege, Germany); Norit A (charcoal) from Serva (Heidelberg, Germany); cell culture lysis reagent (5×) (diluted 1:5 with purified water before use) and the luciferase assay reagent from Promega (Heidelberg, Germany); Optiphase HiSafe3 liquid szintillator from Wallac (Turku, Finland); NET-317-Estradiol [2,4,6, …”

“…In structure-activity studies we could show, that the estrogenic potency of 2-PtCl 2 depends on the configuration of the benzylic C-atoms, the substitution pattern of the aromatic rings, and the leaving group [4,5] . A comparison of the three dimensional structures of 2, 2-PtL 2 and estradiol (E2) [6] indicated, that the carrier ligand 2 changes its spatial structure upon coordination to platinum and is not able to adopt a conformation in which the 1,2-diphenylethane as pharmacophor can superimpose the steroid skeleton. However, the [R/S-1-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) moiety is in a position to mimic the steroid, if the 2,6-dichloro-4-hydroxyphenyl ring is equatorially arranged at the five membered chelate ring.…”