N-Phenyl-1,2,3,4-tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17ß-Hydroxysteroid Dehydrogenase 1 Inhibitors.

ABSTRACT

17ß-Hydroxysteroid dehydrogenases catalyse interconversion at the C17 position between oxidized and reduced forms of steroidal nuclear receptor ligands. The type 1 enzyme, expressed in malignant cells, catalyses reduction of the less-active estrone to estradiol, and inhibitors have therapeutic potential in estrogen-dependent diseases such as breast and ovarian cancers and in endometriosis. Synthetic decoration of the nonsteroidal N-phenyl-1,2,3,4-tetrahydroisoquinoline (THIQ) template was pursued by using Pomeranz-Fritsch-Bobbitt, Pictet-Spengler and Bischler-Napieralski approaches to explore the viability of this scaffold as a steroid mimic. Derivatives were evaluated biologically in vitro as type 1 enzyme inhibitors in a bacterial cell homogenate as source of recombinant protein. Structure-activity relationships are discussed. THIQs possessing a 6-hydroxy group, lipophilic substitutions at the 1- or 4-positions in combination with N-4'-chlorophenyl substitution were most favourable for activity. Of these, one compound had an IC50 of ca. 350 nM as a racemate, testifying to the applicability of this novel approach.