Investigation of the Configurational and Conformational Influences on the Hormonal Activity of 1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines and of their Platinum(II) Complexes. 1. Synthesis, Estradiol Receptor Affinity, and Estrogenic Activity of Diastereomeric [N-Alkyl- and N,N'-Dialkyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) Complexes

Gust, Ronald; Niebler, Karlheinz; Schönenberger, Helmut

doi:10.1021/jm00012a006

Cited by 20 publications

(14 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The latter effect was already confirmed for the classes of 1,2-diamino-1,2-diarylethanes, 4,5-diarylimidazolines, and 4,5-diarylimidazoles by using a 2-halo-4-hydroxyphenyl or a 2,6-dihalo-4-hydroxyphenyl substitution pattern. [2,13,20,21] Type B pyrroles are hydrophobic molecules that can interact with hydrophobic amino acids but also form hydrogen bonds via their phenol groups in the ligand binding domain (LBD) of the ER. The role of the pyrrole core for ER interaction is difficult to qualify.…”

Section: Discussionmentioning

confidence: 99%

Development of 2,3,5‐Triaryl‐1H‐pyrroles as Estrogen Receptor α Selective Ligands

Schäfer¹,

Wellner²,

Strauss³

et al. 2011

ChemMedChem

Self Cite

View full text Add to dashboard Cite

1-Alkyl-2,3,5-triaryl-1H-pyrroles (for which alkyl=methyl, ethyl, n-propyl, or 2-methylpropyl) were tested for stability, estrogen receptor (ER) binding, and inhibition of tumor cell growth. These pyrroles (type B) showed higher stability in aqueous solution than their 1,2,4-triaryl-1H-pyrrole congeners (type A pyrroles), exclusive ERα binding (no ERβ interaction), and a hormonal profile of partial agonists at ERα. The most potent compound, 1-(2-methylpropyl)-2,3,5-tris(4-hydroxyphenyl)-1H-pyrrole (5 d), was less active than the lead structure 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) in MCF-7 cells stably transfected with the plasmid EREwtcluc (MCF-7/2a), but more potent in U2-OS/α cells. Furthermore, 5 d showed weak anti-estrogenic properties (IC50=310 nM). An additional propyl chain at C4 decreased the stability and pharmacological effects.

show abstract

Section: Discussionmentioning

confidence: 99%

Development of 2,3,5‐Triaryl‐1H‐pyrroles as Estrogen Receptor α Selective Ligands

Schäfer¹,

Wellner²,

Strauss³

et al. 2011

ChemMedChem

Self Cite

View full text Add to dashboard Cite

show abstract

“…For instance platinum complexes, displaying a diphenylethanediamine ligand have shown activity in breast cancer cells. Diphenylethanediamine has a three-dimensional structure relatively close to that of diethylstilboestrol and derivatives, which has an oestrogenic activity and, therefore, a supplementary antiproliferative effect on a hormone dependant cancer cell line could be demonstrated [80].…”

Section: Conflicting Resultsmentioning

confidence: 99%

The Relation Between Stereochemistry and Biological Activity of Platinum(II) Complexes Chelated with Chiral Diamine Ligands: An Intricate Problem

Dufrasne¹,

Galanski

2007

CPD

View full text Add to dashboard Cite

Abstract:The origin of activity differences between stereoisomers of anticancer platinum(II) complexes chelated with chiral diamine ligands has been almost exclusively explained by diastereoselective interactions with DNA. Although this model has been widely accepted in vitro and in vivo experiments showed some conflicting results, leading to the conclusion that other biomolecules might be responsible for this stereoselectivity as well. These compounds, called bionucleophiles, are in most instances amino acids or proteins present in biological fluids. As these chiral molecules are very reactive towards the platinum complexes, they may contribute to stereoselectivity, but also to resistance and toxicity. This review gives a general survey of chiral platinum(II) complexes and their interactions with DNA. The bionucleophiles which have been identified and the consequences of their reaction with platinum(II) complexes are discussed. Analytical techniques used to investigate interactions between established and potential chiral platinum drugs and bionucleophiles are presented.

show abstract

“…Dinoprost tromethamine (PGF 2␣ ) was obtained as gift from Upjohn (Kalamazoo, MI). N, ethylenediamines (compounds 1-10) were synthesized according to previously published studies (von Angerer, 1982;Karl et al, 1988;Gust et al, 1995). The following drugs were purchased: 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride, 17␤-estradiol, indomethacin, raloxifene hydrochloride, TEA, ODQ, SQ 22536, KT 5720, KT 5823, and SB 203580 from Sigma-Aldrich (Taufkirchen, Germany).…”

Section: Methodsmentioning

confidence: 99%

Characterization of the Relaxant Response to N,N′-Dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine in Porcine Coronary Arteries

Moritz

Gust²,

Pertz³

2007

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

N, ethylenediamines show structural analogy with estrogens and selective estrogen receptor modulators. Because the vasodilator properties of these compounds are unknown, we investigated their potential to relax porcine coronary arteries and determined the mechanism(s) of relaxation. Isolated porcine coronary arterial rings were suspended in organ chambers, precontracted with KCl (30 mM), and the relaxant response was determined by measurement of changes in isometric force. Dependent on the chemical structure, the drugs induced concentration-dependent relaxation in rings with and without endothelium. N,NЈ-Dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (8) was most potent and showed a 12-to 15-fold higher vasodilatory effect than 17␤-estradiol (E2). The vasorelaxation was independent of endothelium. Calcium concentrationdependent contractions in high-potassium depolarizing me- . Western blot analysis demonstrated that 8, unlike E2, raloxifene, and tamoxifen, failed to stimulate p38 MAPK. It is concluded that N,NЈ-dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine induces endothelium-independent relaxation of coronary arteries; the mechanism apparently involves inhibition of L-type Ca 2ϩ channels. The drug may be protective against cardiovascular diseases.N, ethylenediamines (Table 1) represent a class of compounds that are structurally similar to synthetic estrogens such as diethylstilbestrol (DES) and hexestrol (HEX) and to selective estrogen receptor modulators (SERMs) such as tamoxifen and the red wine polyphenol resveratrol (Fig. 1) (Metzler and Pfeiffer, 2001). For some of these ethylenediamines, a highestrogen receptor affinity of both diastereomeric forms with a preference for the meso isomer over the d,l-isomer has been reported previously. In addition, a strong inhibitory effect on the 7,12-dimethylbenz[a]anthracene-induced hormone-dependent mammary carcinoma in rats and a high potency in Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.120337.ABBREVIATIONS: DES, diethylstilbestrol; HEX, hexestrol; SERM, selective estrogen receptor modulator; E2, 17␤-estradiol; MAPK, mitogenactivated protein kinase; KHS, Krebs-Henseleit solution; PGF 2␣ , prostaglandin F 2␣ ; ICI 182,780,[7][8][9]4,5,5,

show abstract

Cited by 20 publications

References 7 publications

Development of 2,3,5‐Triaryl‐1H‐pyrroles as Estrogen Receptor α Selective Ligands

Development of 2,3,5‐Triaryl‐1H‐pyrroles as Estrogen Receptor α Selective Ligands

The Relation Between Stereochemistry and Biological Activity of Platinum(II) Complexes Chelated with Chiral Diamine Ligands: An Intricate Problem

Characterization of the Relaxant Response to N,N′-Dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine in Porcine Coronary Arteries

Contact Info

Product

Resources

About