Cyclocurcumin potently inhibits human aromatase as a potential therapeutic agent.

Curcuminoids, including curcumin and its derivatives, show potent inhibition of aromatase (CYP19A1), crucial for estradiol synthesis and breast cancer metastasis. Our study evaluated the efficacy and mechanism of 10 curcuminoids and their metabolites against human and rat CYP19A1 using placental microsomes, revealing species-specific IC values. Cyclocurcumin (IC, 4.43μM) and curcumin (IC, 3.49μM) were the most effective inhibitors for human and rat CYP19A1, respectively. These compounds acted as mixed or competitive inhibitors, reducing estradiol production in human BeWo cells. Docking analysis showed that curcuminoids interact with CYP19A1 active site, forming a hydrogen bond with Met374. 3D-QSAR analysis highlighted the importance of hydrogen bonding in inhibition. A negative correlation was observed between the pKa values and IC values for human CYP19A1. A positive correlation was observed between the lowest binding energy and IC values for human CYP19A1. These findings underscore the potential of curcuminoids as therapeutic agents against breast cancer.