Abstract:
The overexpression of CYP1 family of enzymes is reported to be associated with
development of human carcinomas. It has been well reported that CYP1A1 specific
inhibitors prevents carcinogenesis. Herein, thirteen pyridine-4-yl series of chalcones
were synthesized and screened for inhibition of CYP1 isoforms 1A1, 1B1 and 1A2 in
SacchrosomesTM and live human HEK293 cells. The structure-activity relationship
analysis indicated that chalcones bearing tri-alkoxy groups (8a and 8k) on nonheterocyclic
ring displayed selective inhibition of CYP1A1 enzyme, with IC50 values of
58 and 65 nM, respectively. The 3,4,5-trimethoxy substituted derivative 8a have shown
>10 fold selectivity towards CYP1A1 with respect to other enzymes of the CYP1 subfamily
and >100-fold selectivity with respect to CYP2 and CYP3 family of enzymes.
The potent and selective CYP1A1 inhibitor 8a displayed antagonism of B[a]P mediated
activation of aromatic hydrocarbon receptor (AhR) in yeast cells, and also protected
human cells from CYP1A1-mediated B[a]P toxicity in human cells. This potent and
selective inhibitor of CYP1A1 enzyme have a potential for development as cancer
chemopreventive agent.
