A new class of CYP1B1 inhibitors derived from bentranil

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Cytochrome P450 1B1 (CYP1B1) is frequently overexpressed in various tumors, contributing to drug resistance.
• CYP1B1 is emerging as a promising molecular target for cancer prevention and therapeutic strategies.
• Existing CYP1B1 inhibitors often feature rigid polycyclic structures like flavonoids, trans-stilbenes, and quinazolines.

Purpose of the Study:

• To design and synthesize a novel class of CYP1B1 inhibitors based on bentranil analogues.
• To evaluate the inhibitory potential and selectivity of the synthesized compounds against CYP1B1.
• To investigate the binding interactions of the most potent inhibitors within the CYP1B1 active site.

Main Methods:

• Synthesis of a series of bentranil analogues.
• In vitro determination of IC50 values for CYP1B1 inhibition.
• Assessment of selectivity index (SI) against CYP1A1 and CYP1A2 compared to a known inhibitor (α-naphthoflavone).
• Molecular docking simulations to predict binding affinity and orientation within the CYP1B1 active site.

Main Results:

• Five synthesized bentranil analogues were tested for CYP1B1 inhibition.
• Compounds 6o and 6q exhibited potent CYP1B1 inhibition with IC50 values in the nanomolar (nM) range.
• The selectivity index (SI) for CYP1B1 over CYP1A1 and CYP1A2 for the novel compounds was significantly higher (30-fold) than that of α-naphthoflavone.
• Molecular docking studies indicated that compound 6q possessed superior binding within the CYP1B1 active site, aligning with experimental findings.

Conclusions:

• Bentranil analogues represent a promising new class of CYP1B1 inhibitors.
• Compounds 6o and 6q are identified as lead inhibitors with high potency and selectivity.
• Further development based on these lead compounds could yield novel cancer therapeutics with improved affinity, selectivity, and solubility.