Lead optimization of 4-imidazolylflavans: New promising aromatase inhibitors

• Published in: European journal of medicinal chemistry 2011-06, Vol.46 (6), p.2541-2545
• Main Authors: Yahiaoui, Samir, Pouget, Christelle, Buxeraud, Jacques, Chulia, Albert José, Fagnère, Catherine
• Format: Article
• Language: English
• Subjects: 7,8-Benzo-4-imidazolylflavans; Antineoplastic agents; Aromatase - metabolism; Aromatase inhibitors; Aromatase Inhibitors - chemical synthesis; Aromatase Inhibitors - chemistry; Aromatase Inhibitors - pharmacology; Biological and medical sciences; Dose-Response Relationship, Drug; Enantiomers; Flavonoids; Flavonoids - chemical synthesis; Flavonoids - chemistry; Flavonoids - pharmacology; General aspects; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.03.043

Our previous studies have shown that several 7-substituted-4-imidazolylflavans are potent inhibitors of aromatase. These compounds were designed considering the anti-aromatase effect of some natural flavonoids and the importance of an azole ring for synthetic inhibitors such as letrozole or anastrozole towards binding to the heme iron of aromatase. In this study, we report the optimization of these lead compounds by the modulation of flavan A ring. The resulting 7,8-benzo-4-imidazolylflavans were tested in order to assess their ability to inhibit aromatase. Biological data concerning enantiomers obtained from the chiral separation of the racemate compound 4-imidazolyl-7-methoxyflavan are also presented. Previously we demonstrated that 4-imidazolylflavans are potent inhibitors of aromatase. The present article reports the synthesis of new highly active 7,8-benzo-4-imidazolylflavans and demonstrates the stereochemistry impact on the activity. [Display omitted] ► 4-Imidazolylflavans are potent inhibitors of aromatase. ► New synthesized 7,8-benzo-4-imidazolylflavans are highly active. ► Great influence of stereochemistry on biological effect was demonstrated. ► Modulation of flavonoids could provide new promising aromatase inhibitors.