Development of 2,3,5-triaryl-1H-pyrroles as estrogen receptor α selective ligands

Abstract

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.