Details

Autor(en) / Beteiligte

• Ertas, Merve
• Sahin, Zafer
• Berk, Barkin
• Yurttas, Leyla
• Biltekin, Sevde N.
• Demirayak, Seref

Titel

Pyridine‐substituted thiazolylphenol derivatives: Synthesis, modeling studies, aromatase inhibition, and antiproliferative activity evaluation

Ist Teil von

• Archiv der Pharmazie (Weinheim), 2018-04, Vol.351 (3-4), p.e1700272-n/a

Ort / Verlag

Germany: Wiley Subscription Services, Inc

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non‐steroidal‐type inhibitors. Non‐steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition. In this study, pyridine‐substituted thiazolylphenol derivatives, which are non‐steroidal triazole bioisosteres, were synthesized using the Hantzsch method, and physical analysis and structural determination studies were performed. The IC50 values of the compounds were determined by a fluorescence‐based aromatase inhibition assay. Then, their antiproliferative activities on the MCF7 and HEK 293 cell lines were evaluated with the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Furthermore, the crystal structure of human placental aromatase was subjected to a series of docking experiments to identify the possible interactions between the most active structure and the active site. Lastly, an in silico technique was performed to analyze and predict the drug‐likeness, molecular and ADME properties of the synthesized molecules. From a series of pyridine‐substituted thiazolylphenol derivatives synthesized by the Hantzsch method, 3‐[2‐(pyridin‐4‐yl)thiazol‐4‐yl]phenol (6) was found to be a more active aromatase inhibitor than the standard, ketoconazole. In docking experiments in the aromatase active site, compound 6 fitted well into the pocket, similar to anastrazole where the pyridine ring system was coordinated with the heme moiety.