<i>N</i>‐Phenyl‐1,2,3,4‐tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β‐Hydroxysteroid Dehydrogenase 1 Inhibitors
Marco Mottinelli, Maša Sinreih, Tea Lanišnik Rižner, Mathew P. Leese, Barry V. L. Potter
Abstract
Abstract 17β‐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 IC 50 of ca. 350 nM as a racemate, testifying to the applicability of this novel approach.