[Aqua-1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine] sulfatoplatinum(II) complexes with variable substituents in the 2-phenyl ring

Abstract

In the search for new anti-breast cancer compounds a series of diastereomeric aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine]sulfato platinum(II) complexes was tested on the hormone-sensitive MXT-M-3.2 breast cancer of the mouse. By simultaneous determination of tumor and uterine weights at the end of the experiment we obtained an insight into the mode of action. Changes in the uterine weights indicate whether the anti-breast cancer effect of the test substance is caused either by its capability to reduce the endogenous estrogen level via inhibition of estrogen biosynthesis (mechanism B), or by its estrogenic side effects which enhance the immune defense in the host animals (mechanism C). Studies on the [3H]thymidine incorporation into DNA of MDAMB-231 breast cancer cells showed that all test compounds inhibit deoxyribonucleic acid synthesis, like cisplatin (mechanism A). However, in comparison to the standard cisplatin, their activities were low. The three most effective test compounds threo-2-PtSO4 (2-phenyl-residue), threo-5-PtSO4 (2-(4-hydroxyphenyl)-residue), and threo-8-PtSO4 (2-(2-fluoro-4-hydroxyphenyl)-residue) seem to exert their anti-breast cancer effect by mechanism B. Moreover, threo-5-PtSO4 was moderately active on the hormone- insensitive MXT-M-3.2 (Ovex) breast cancer of the mouse. Aqua[erythro-1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-chloro-4-hydroxypheny l) ethylenediamine]sulfato-platinum(II) (erythro-9-PtSO4) was the only breast cancer inhibiting compound of the series acting mainly according to mechanism C. A minor contribution of mechanism A, impairment of the DNA function in the tumor cell, to the anti-breast cancer activity of these aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine]sulfato platinum(II) complexes cannot be excluded, since such effects are apparent in the MDA-MB-231 as well as in the MCF-7 breast cancer cell line at higher drug concentrations. In this test series which was performed with the crystal violet chemosensitivity assay, the MCF-7 cells proved to be somewhat more sensitive.

(4R,5S)/(4S,5R)-4,5-Bis(4-hydroxyphenyl)-2-imidazolines: Ligands for the Estrogen Receptor with a Novel Binding Mode

“…Although the Karplus relationship can be strictly applied only to open-chain compounds and six-membered rings, 22 it nevertheless provides insight into the conformational behavior of fivemembered rings. 23 The (4S,5R)/(4R,5S)-configurated 4,5-diaryl-2-imidazolines can adapt conformations with an arrangement of the benzylic protons at a dihedral angle between 0°a nd 60°. The coupling constant of about 12 Hz correlates with an angle of 0-15°, which confirms the proposed planar structure of the 2-imidazoline ring.…”

“…The compounds described in this paper were derived from antitumor active [1,2-diarylethylenediamine]platinum(II) complexes. 23,28 We have already shown in an earlier SAR study that the substitution pattern in the aromatic rings and the configuration at the benzylic C atoms determine the mode of action. The…”

Tumour-inhibiting platinum complexes—state of the art and future perspectives

“…Several of these complexes strongly inhibit growth of hormone-dependent rat mammary tumours. (Anti)oestrogenic effects seem to prevail over a DNA damaging mode of action in those compounds which exhibit selectivity for hormone-sensitive tumours (Karl et al 1988;Schlemmer et al 1999;Gust et al 2000), whereas a lack of endocrine effects is mostly associated with either a loss of selectivity or even a total loss of activity (Gust and Schönenberger 1993;Gust et al 1995). Complexes containing 2-phenylindole ligands show a higher affinity for the oestrogen receptor and a marked selectivity for hormone-dependent tumours.…”

Searching for the Magic Bullet: Anticancer Platinum Drugs Which Can Be Accumulated or Activated in the Tumor Tissue

“…Among a series of diastereomeric aqua[1-(2,6-dichloro-4hydroxyphenyl)-2-phenyl]sulfatoplatinum(II) complexes compounds with threo-configurated ligands were more effective cell growth inhibitors than those with erythroligands [42]. They were more effective against MCF-7 cells than MDA-MB 231 cells.…”