Author/Editor		Mottinelli, Marco; Sinreih, Maša; Lanišnik-Rižner, Tea; Leese, Mathew P.; Potter, Barry V. L.
Title		N-Phenyl-1,2,3,4-tetrahydroisoquinoline:an alternative scaffold for design of 17[beta]-hydroxysteroid dehydrogenase 1 inhibitors
Type		članek
Publication year		2020
Volume		str. str.,
ISSN		1860-7179 - ChemMedChem : Chemistry Enabling Drug Discovery
Language		eng
Abstract		17[beta]-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.
Keywords		17[beta]-hydroxysteroid dehydrogenase 1 tetrahydroisoquinoline breast cancer 17[beta]-hidroksisteroidna dehidrogenaza 1 tetrahidroizokinolin rak na dojki