title: Synthesis and investigations on the oxidative degradation of C3/C5-alkyl-1,2,4-triarylpyrroles as ligands for the estrogen receptor.
abstract: In this study, we synthesized 1,2,4-triarylpyrroles as ligands for the estrogen receptor (ER). Two pyrrole series were prepared with either C3-alkyl or C3/C5-dialkyl residues. Compounds from both series were susceptible to oxidative degradation-dialkylated compounds (t(1/2) =33-66 h) to a higher extent than their monoalkylated congeners (t(1/2) =140-211 h). Nevertheless, stability was sufficient for determination of in vitro ER binding affinity. The most active agonist in hormone-dependent, ERα-positive MCF-7/2a and U2-OS/α cells was 1,2,4-tris(4-hydroxyphenyl)-3-propyl-1H-pyrrole (6 d) (MCF-7/2a: EC(50) =70 nM; U2-OS/α: EC(50) =1.6 nM). A corresponding inactivity in U2-OS/β cells demonstrated the high ERα selectivity. This trend was confirmed in a competition experiment using estradiol (E2) and purified hERα and hERβ proteins (relative binding affinity (RBA) calculated for 6 d: RBA(ERα)=1.85 %; RBA(ERβ) <0.01 %). Generally, C3/C5-dialkyl substitution led to reduction of activity, possibly due to lower stability.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schäfer
authors.forename: Anja
authors.initials: A
authors.lastname: Wellner
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D010084:Oxidation-Reduction; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D008024:Ligands; D011758:Pyrroles