Design, synthesis and evaluation of fluorinated CYP1B1 inhibitors based on a trans-stilbene scaffold

Cytochrome P450 1B1 (CYP1B1) is selectively overexpressed in various tumor cells and plays a critical role in the metabolic inactivation of chemotherapeutic agents, leading to drug resistance. Therefore, the development of selective CYP1B1 inhibitors represents a promising strategy to overcome chemoresistance. In this study, we designed and synthesized 19 novel trans-stilbene derivatives by introducing fluorine atoms or fluorinated side chains, aiming to potentially enhance drug metabolic stability and binding affinity. Among them, compounds 4h and 4i exhibited the most potent inhibitory activity against CYP1B1, with IC₅₀values of 6.5 ± 0.9 nM and 5.4 ± 0.5 nM, respectively, and demonstrated high selectivity within the CYP1 family over CYP1A1 and CYP1A2. In A549 cell models, both compounds significantly reversed DMBA-induced PTX resistance in a concentration-dependent manner. Furthermore, fluorescence staining revealed that compound 4i preferentially bound to CYP1B1-overexpressing tumor cells, including A549, HeLa, MCF-7, and HCT-15 cells, but not to non-cancerous 293T cells. These findings highlight the potential of fluorinated trans-stilbene derivatives as promising CYP1B1-targeted therapeutics for combating drug-resistant cancers.