Cytochrome
P450 family 1 (CYP1) enzymes catalyze the metabolic
activation of environmental procarcinogens such as benzo[
a
]pyrene, B[
a
]P, into carcinogens, which initiates
the process of carcinogenesis. Thus, stopping the metabolic activation
of procarcinogens can possibly prevent the onset of cancer. Several
natural products have been reported to show unique ability in inhibiting
CYP1 enzymes. We found that khellin, a naturally occurring furanochromone
from
Ammi visnaga
, inhibits CYP1A1
enzyme with an IC
50
value of 4.02 μM in CYP1A1-overexpressing
human HEK293 suspension cells. To further explore this natural product
for discovery of more potent and selective CYP1A1 inhibitors, two
sets of semisynthetic derivatives were prepared. Treatment of khellin
with alkali results in opening of a pyrone ring, yielding khellinone
(
2
). Claisen–Schmidt condensation of khellinone
(
2
) with various aldehydes in presence of potassium hydroxide,
at room temperature, provides a series of furanochalcones
3a–v
(khellinochalcones). Treatment of khellinone (
2
) with
aryl aldehydes in the presence of piperidine, under reflux, affords
the flavanone series of compounds
4a–p
(khellinoflavanones).
The khellinoflavanone
4l
potently inhibited CYP1A1 with
an IC
50
value of 140 nM in live cells, with 170-fold selectivity
over CYP1B1 (IC
50
for CYP1B1 = 23.8 μM). Compound
4l
at 3× IC
50
concentration for inhibition
of CYP1A1 completely protected HEK293 cells from CYP1A1-mediated B[
a
]P toxicity. Lung cancer cells, A549 (p53
+
)
and Calu-1 (p53-null), blocked in growth at the S-phase by B[
a
]P were restored into the cell cycle by compound
4l
. The results presented herein strongly indicate the potential
of these khellin derivatives for further development as cancer chemopreventive
agents.
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