Details

Autor(en) / Beteiligte

• Sahin, Zafer
• Ertas, Merve
• Berk, Barkın
• Biltekin, Sevde Nur
• Yurttas, Leyla
• Demirayak, Seref

Titel

Studies on non-steroidal inhibitors of aromatase enzyme; 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives

Ist Teil von

• Bioorganic & medicinal chemistry, 2018-05, Vol.26 (8), p.1986-1995

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• [Display omitted] •Synthesis of pyrimidine 2-carbothioamide were carried out by a new original method.•New resveratrol analogues as aromatase inhibitors defined.•Compound 1 was 2000 times and Compound 8 was 9 times more active than ketoconazole. Compounds 15 and 21 were equivalent to ketoconazole.•Compounds 13, 15, and 21 showed significant biological effect in both tests aromatase inhibitory activity and cytotoxicity. Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects. Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition. In this study, 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC50 values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC50:0.42 nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site.