Synthesis and Investigations on the Oxidative Degradation of C3/C5‐Alkyl‐1,2,4‐triarylpyrroles as Ligands for the Estrogen Receptor

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‐1 H ‐pyrrole ( 6 d ) (MCF‐7/2a: EC 50 =70 n M ; U2‐OS/α: EC 50 =1.6 n M ). 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.