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17β-Hydroxysteroid dehydrogenases act at the pre-receptor level, catalysing 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 in all three ring systems was pursued 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-hydroxyl group, lipophilic substitutions at the 1- or 4- positions in combination with  N -4'-chlorophenyl substitution were most favourable for activity. Of these, racemic  41c  had an IC 50  of ca. 350 nM, testifying to the applicability of this novel approach.

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17β-hydroxysteroid dehydrogenase 1, Inhibition, SAR, breast cancer, tetrahydroisoquinoline