Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors

Abstract

Fluorination of 13-epimeric estrones and their 17-deoxy counterparts was performed with Selectfluor as the reagent. In acetonitrile or trifluoroacetic acid (TFA), 10β-fluoroestra-1,4-dien-3-ones were formed exclusively. Mechanistic investigations suggest that fluorinations occurred via SET in acetonitrile, but another mechanism was operative in TFA. Simultaneous application of N-chlorosuccinimide (NCS) and Selectfluor in TFA led to a 1.3:1 mixture of 10β-fluoroestra-1,4-dien-3-one and 10β-chloroestra-1,4-dien-3-one as the main products. The potential inhibitory action of the 10-fluoro- or 10-chloroestra-1,4-dien-3-one products on human aromatase was investigated via in vitro radiosubstrate incubation. The classical estrane conformation with trans ring anellations and a 13β-methyl group seems to be crucial for the inhibition of the enzyme, while test compounds bearing the 13β-methyl group exclusively displayed potent inhibitory action with submicromolar or micromolar IC50 values. Concerning molecular level explanation of biological activity or inactivity, computational simulations were performed. Docking studies reinforced that besides the well-known Met374 H-bond connection, the stereocenter in the 13 position has an important role in the binding affinity. The configuration inversion at C-13 results in weaker binding of 13α-estrone derivatives to the aromatase enzyme.

Synthesis of Ester‐Linked Ursolic Acid‐Based Hybrid Compounds: Potential Antibacterial and Anticancer Agents

“…Emodel was developed for pose selection and it uses the Glide score to rank poses against one another, where a low value indicates good protein-ligand binding affinity. [63,64] Therefore, the result from this study indicates that the hybrid compounds established more energetically favourable interactions than ursolic acid in the active site of the protein.…”

“…The glide Emodel scores also showed a similar trend establishing the values −89.61, −68.56, −42.11 and −46.53 kcal/mol for the compounds 29, 34, ursolic acid and the co‐ligand, respectively ( Table 3). Emodel was developed for pose selection and it uses the Glide score to rank poses against one another, where a low value indicates good protein‐ligand binding affinity [63,64] . Therefore, the result from this study indicates that the hybrid compounds established more energetically favourable interactions than ursolic acid in the active site of the protein.…”

Aromatase Inhibitors as a Promising Direction for the Search for New Anticancer Drugs

“…The tested compounds containing the 13β-Me group showed strong inhibitory effects with submicromolar and micromolar IC 50 values of 0.49, 5.0, and 2.4 µM. The reference compound in the study was androst-4-ene-3,17-dione with an IC 50 value of 0.22 µM [ 20 ].…”

Reactivities of electrophilic N–F fluorinating reagents

“…When another radical scavenger, N-hydroxyphthalimide (NHPI) was tested, analysis of the crude product by HR-MS revealed the presence of the radical addition product 198. In 2019, Mernyak et al 167 reported the fluorination of 13β-estrone 199 using Selectfluor™ 25 in MeCN to obtain 10β-fluoroestra-1,3-den-3-one 200 in 95% yield (Scheme 19f). However, in the presence of TEMPO, the reaction was inhibited, with only 3% yield of fluorosteroid 200.…”