Quinazoline derivatives as selective CYP1B1 inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Cytochrome P450 1B1 (CYP1B1) is implicated in the development of multiple carcinomas, including breast, ovarian, renal, skin, and lung cancers.
• Developing potent and specific CYP1B1 inhibitors is a promising strategy for novel cancer therapeutics.

Purpose of the Study:

• To design and synthesize novel quinazoline analogs as potential CYP1B1 inhibitors.
• To evaluate the inhibitory activity and selectivity of synthesized compounds against CYP1B1 and related enzymes.

Main Methods:

• Synthesis of 20 quinazoline analogs.
• Screening for CYP1B1 and CYP1A1 inhibition using Sacchrosomes™.
• Determination of IC50 values and selectivity profiling against CYP1, CYP2, and CYP3 families.
• Molecular modeling studies.
• In cellulo evaluation in yeast and human cells.

Main Results:

• Quinazoline analogs 5c and 5h demonstrated potent CYP1B1 inhibition with IC50 values in the nanomolar range.
• Selectivity studies indicated a low potential for drug-drug interactions with homologous CYPs.
• Molecular modeling rationalized the observed inhibition patterns.
• Cellular permeability and potent CYP1B1 inhibition within live cells were confirmed for the lead compounds.

Conclusions:

• Quinazoline scaffold is a viable basis for designing potent CYP1B1 inhibitors.
• Compounds 5c and 5h are promising candidates for further development as anti-cancer agents targeting CYP1B1.
• The synthesized inhibitors exhibit favorable selectivity profiles and cellular activity.