Flexibility in the bridge of chalcone derivatives is important for the inhibition of cellular growth

• Published in: Bioorganic & medicinal chemistry letters 2023-10, Vol.95, p.129467-129467, Article 129467
• Main Authors: Stantliff, Trevor M., Hill, Amber, Kuo, Mary Elaine, Neal, Hadley E., Harrod, Tighe C., Goens, Katy, Mashuta, Mark, Christianson, Anna M., Krzysiak, Amanda J.
• Format: Article
• Language: English
• Subjects: Anti-cancer; Anti-proliferative; Biological activity; Chalcone; Conformation; Flexibility
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2023.129467

[Display omitted] Chalcones and their derivatives are a privileged scaffold in medicinal chemistry, demonstrating numerous biological activities. These molecules have shown significant potential toward the development of novel cancer therapies. While much is known about modification to the chalcone aryl rings, little is known about conformations of the bridge between the aryl rings. Here we report the synthesis and biological evaluation of a series of molecules with flexible and rigid bridge conformations. Crystal structures of a select group of molecules were determined. Flexibility in the chalcone bridge containing the enone moiety was determined to be important for activity. Screening in three distinct cancer cell lines showed significant differences in the activity between the flexible and rigid conformations. Crystal structures suggest an increase in bond rotation and weakened π-bonding in the flexible chalcone bridge, which may contribute to the stronger anti-proliferative activity.