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

Abstract

Abstract17β‐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.

Visible Light Induced Copper‐Catalyzed Enantioselective Deaminative Arylation of Amino Acid Derivatives Assisted by Phenol

“…[37] In addition, a chiral tetrahydroisoquinoline scaffold, which has been shown to inhibit 17β-hydroxysteroid dehydrogenase 1 enzyme for the treatment of breast cancer, was also synthesized by three-step routine operations. [38] We then performed mechanistic studies to better understand this phenol-assisted process. First, when 2,2,6,6tetramethylpiperidin-1-oxyl (TEMPO) was used as a radical scavenger, the deaminative arylation reaction was significantly inhibited, accompanying the isolable radical-trapping product 5 (Figure 5a).…”

“…To demonstrate the practicality of this strategy, phenylacetamide products were hydrolyzed to synthesize chiral drug molecules such as ( S )‐ibuprofen and ( S )‐naproxen without losing their enantiopurity (Figure 4). [37] In addition, a chiral tetrahydroisoquinoline scaffold, which has been shown to inhibit 17 β ‐hydroxysteroid dehydrogenase 1 enzyme for the treatment of breast cancer, was also synthesized by three‐step routine operations [38] …”

Targeting the formation of estrogens for treatment of hormone dependent diseases–current status

“…In the last decades, several compounds were developed and explored for their ability to block the HSD17B1 enzyme (Brozic et al, 2008;Niinivehmas et al, 2018;Abdelsamie et al, 2019;Herman et al, 2019;Kulmany et al, 2021;Mottinelli et al, 2021), and several molecules were patented (Poirier, 2010;2015).…”

Medicinal chemistry perspectives of 1,2,3,4-tetrahydroisoquinoline analogs – biological activities and SAR studies

“…Mottinelli and co-workers synthesized N -substituted THIQs via Bischler–Nepieralski cyclization approach. 18 Initially, 3-methoxy-phenyl acetic acid 58 was converted to its amide 60, which was then reduced to amine 61 using LiAlH 4 . The amine 61 was then converted to N -acyl derivative 62 using acyl chloride.…”