Design and synthesis of new 7,8-dimethoxy-α-naphthoflavones as CYP1A1 inhibitors

Article abstract of DOI:10.1016/j.cclet.2013.01.006

The flavonoids as inhibitors of CYP1A1 exhibit chemopreventive effects against certain procarcinogens and have been considered as the promising cancer preventive agents. A series of novel 7,8-dimethoxy-α-naphthoflavones as the substrate analogs were designed and prepared. The enzyme assay suggested that all of these new flavones were stronger inhibitors of CYP1A1 than the lead compound α-naphthoflavone. Among the tested ones, 3h showed the most potent inhibitory effects.

Full text of DOI:10.1016/j.cclet.2013.01.006

Chinese Chemical Letters 24 (2013) 215–218
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Design and synthesis of new 7,8-dimethoxy-
inhibitors
a-naphthoflavones as CYP1A1
*
Jia-Hua Cui, Dagula Hu, Xu Zhang, Zheng Jing, Jing Ding, Ru-Bing Wang, Shao-Shun Li
School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The flavonoids as inhibitors of CYP1A1 exhibit chemopreventive effects against certain procarcinogens
and have been considered as the promising cancer preventive agents. A series of novel 7,8-dimethoxy-
naphthoflavones as the substrate analogs were designed and prepared. The enzyme assay suggested that
Received 19 November 2012
Received in revised form 18 December 2012
Accepted 27 December 2012
Available online 29 January 2013
a
-
all of these new flavones were stronger inhibitors of CYP1A1 than the lead compound a-naphthoflavone.
Among the tested ones, 3h showed the most potent inhibitory effects.
ß 2013 Shao-Shun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
Keywords:
reserved.
a-Naphthoflavone
CYP1A1 inhibitors
7,8-Dimethoxy-a-naphthoflavone
Flavonoids
1. Introduction
whose chemical structure was similar to that of 7,12-DMBA-3,4-
diol (2, Fig. 1), a substrate of CYP1A1 [8]. The derivatives of 3a were
Flavonoids, a class of 2-phenyl-1,4-benzopyrone derivatives as
the secondary metabolites of plants, are known to exhibit various
medicinal properties [1,2]. One of these properties is the inhibition
of carcinogen-induced tumor formation in several human organs
[3–5]. The mechanism by which the flavonoids display the
chemopreventive effects has been considered as the interaction
of these compounds with human P450 enzymes [6,7].
CYP1A1 is one member in the P450 family, which would
catalyze the bioactivition of certain procarcinogens such as
benzo[a]pyrene (B[a]P) and 7,12-dimethyl benzanthracene
(7,12-DMBA) [8], and it plays a pivotal role in carcinogen-induced
tumor initiation [9]. The dietary flavones apigenin and luteolin,
inhibitors of the CYP1A1 enzyme, could inhibit the formation of
carcinogenic products and have been considered as promising
also prepared to examine the SARs in the B-ring modification.
The most common method of synthesizing substituted flavones
is the cyclodehydration of 1-(o-hydroxyaryl)-3-phenyl-1,3-dike-
tones (12a) [13]. The diketones, in turn, were prepared by the
benzylation of o-hydroxyacetophenones (10) with benzoic acid
derivatives and subsequent Baker–Venkataraman (B–V) rear-
rangement [14–16]. The o-hydroxyacetophenones could be
obtained from the C-acylation of phenols [17]. According to the
retrosynthetic analysis (Scheme 1), we employed 5,6-dimethoxy-
1-naphthol (8) as the key intermediate for the preparation of 3a
and its derivatives.
2. Experimental
cancer preventive agents [6,7,10].
a-Naphthoflavone (a-NF, Fig. 1,
With the synthetic method, 1,5-dihydroxynaphthalene (4) was
used as the starting material (Scheme 2) which was oxidized to 5-
hydroxy-1,2-naphthoquinone (5) by Fremy’s radical in a sodium
acetate-acetic acid buffer (pH 4.3). Then the phenolic hydroxyl
group was easily protected by the methoxymethyl (MOM) ether to
afford 6. The reduction–methylation of 6 in a one-pot two-step
strategy and subsequent acidic hydrolysis of the MOM ether were
carried out to give 5,6-dimethoxy-1-naphthol (8) as the key
intermediate under mild conditions. Compared with the reported
methods [18,19], which were confined to Diels–Alder reactions
under stringent conditions, our synthetic strategies using the
oxidation of 4 and the reduction–methylation of 6 gave 8 under
milder conditions with a higher yield (16%, four steps).
1), potent inhibitor of CYP1A1, inhibits CYP1A1 on the
a
metabolism of B[a]P via a classical competitive mechanism
and blocks the transformation of the procarcinogen to its active
form [11].
Preparing the substrate analogs is an effective approach in the
rational design of enzyme inhibitors [12]. Thus, in search for new
potent inhibitors of CYP1A1, we took
and synthesized 7,8-dimethoxy-
a-NF as the lead compound
a-naphthoflavone (3a, Fig. 1)
* Corresponding author.
E-mail address: ssli@sjtu.edu.cn (S.-S. Li).
1001-8417/$ – see front matter ß 2013 Shao-Shun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.01.006

216
J.-H. Cui et al. / Chinese Chemical Letters 24 (2013) 215–218
HO
HO
8
H3CO
H3CO
4'
10
2'
CH3
1
D
B
O
O
6'
A
C
3
6
CH3
2
O
1
O
3a
Fig. 1. The chemical structures of two CYP1A1 inhibitors and a substrate.
H3CO
H3CO
Cyclization
O
O
B-V rearrangement
O
OH
O
12a
O
O
3a
O
O
O
O
O
O
Ph
O
O
OH
O
OH
O
10
8
Scheme 1. The retrosynthetic analysis of 7,8-dimethoxy-a-naphthoflavone.
O
O
O
O
OH
O
O
b)
a)
c)
OMOM
OH
OMOM
OH
7
6
5
4
O
O
O
5
4
O
4a
O
e)
O
d)
f)
8a
8
O1H
O
OH
OAc
8
9
10
O
8
H3CO
O
10
O
1
g)
O
h)
i)
O
R
H3CO
R
6
3
R
O
O
OH
O
O
O
O
3a-3j
11a-11j
12a-12j
R
R
R
R
3a: phenyl;
3d: 3,4-dimethoxyphenyl;
3e: p-chlorophenyl;
3g: m-chlorophenyl; 3j: m-fluorophenyl
3h: p-fluorophenyl;
3b: p-methoxyphenyl;
3c: o-methoxyphenyl;
3f: o-chlorophenyl;
3i: o-fluorophenyl;
Scheme 2. Reagents and conditions: (a) Fremy’s radical, pH 4.3 buffer, 10 8C for 2 h; (b) MOMCl, DIEA, CH2Cl2, 0 8C for 2 h; (c) Me2SO4, NaOH, Na2S2O4, Bu4N+Brꢀ, THF-H2O,
0 8C for 3 h; (d) HCl, MeOH, r.t. for 12 h; (e) AcCl, NEt3, 0 8C for 0.5 h, r.t. for 2.5 h; (f) BF3–Et2O, 120 8C for 5 min; (g) RCOOH, DCC, DMAP, CH2Cl2, r.t. for 12 h; (h) KOH, Py, reflux,
1 h; (i) H2SO4, EtOH, reflux, 1 h.
Then the O-acylation of the phenol 8 was produced in the
presence of acetyl chloride and triethylamine. The Fries rearrange-
ment of the acetate 9 was conducted using boron trifluoride-
diethyl ether to give 10 in high yield. The spectroscopic data [20]
was in agreement with the structural change from the acetate 9 to
the ketone 10. On the 1H NMR spectrum of 10 [20], an
which indicated the presence of the intra-molecular hydrogen
bond. Meanwhile, the strong absorption band of the carbonyl
group shifted from 1761 cmꢀ1 to 1622 cmꢀ1 in IR spectra and the
partially positive carbon in this group was deshielded to an extent
of d
34 in 13C NMR spectra. These characteristics were attributed to
a decrease of the electron density in the C55O bond from the acetate
9 to the ketone 10.
exchangeable sharp signal at the downfield (d 14.15) was observed,

J.-H. Cui et al. / Chinese Chemical Letters 24 (2013) 215–218
217
Table 1
4. Conclusion
Inhibitory effects of new 7,8-dimethoxy-a-naphthoflavones on human CYP1A1-
mediated EROD activity (IC50 values in nmol/L).
A series of novel 7,8-dimethoxy-
a
-naphthoflavones as the
Compd. IC50 (nmol/L) Compd. IC50 (nmol/L) Compd. IC50 (nmol/L)
substrate analogs were designed and prepared. The enzyme assay
suggested that all of these new flavones were stronger inhibitors of
3a
3b
3c
3d
2.3
2.8
4.1
3.1
3e
3f
1.3
7.2
2.7
1.0
3i
3j
1.6
1.6
11.9
–
CYP1A1 than the lead compound
a-naphthoflavone. Among the
3g
3h
a
-NF
tested ones, 3h showed the most potent inhibitory effects.
–
Acknowledgments
The research is supported by the State Key Laboratory
Cultivation Base for the Chemistry and Molecular Engineering of
Medicinal Resources, Ministry of Science and Technology of China
(No. CHEMR2012-B08). We are grateful to the Instrumental
Analysis Center of Shanghai Jiaotong University for recording
the IR and 13C NMR spectra.
The benzoylation of the hydroxyl group of 10 and subsequent
B–V rearrangement of the benzoate with KOH as the catalyst
afforded 1,3-diketone 12a–12j, which was boiled in absolute
alcohol in the presence of sulfuric acid (20 eq.) to afford the new
7,8-dimethoxy-a-naphthoflavones 3a–3j. The purification of the
products 3a–3j included the usual column chromatography and
further crystallization from anhydrous ethanol. The alcoholic
solution of each compound 3a–3j gave a color from light orange to
violet when treated with Mg–HCl.
The inhibitory effects of these compounds against CYP1A1 were
determined using the 7-ethoxyresorufin-O-deethylation (EROD)
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essay reported by Yamaori et al. [21]. The lead compound a-NF was
prepared according to Mahal’s method [15] and used as the
positive control and the recombined human CYP1A1 (10 fmol) was
employed as the enzyme source.
An incubation system consisted of an enzyme source, 7-
ethoxyresorufin (150 nmol/L), the compounds tested at various
concentrations, 1.3 mmol/L NADP+, 3.3 mmol/L glucose 6-phos-
ephate,
3.3 mmol/L MgCl2 and 50 mmol/L Tris–HCl buffer (pH 7.4)
containing 1% BSA in a final volume of 200 L with the DMSO
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15 min and the reaction was terminated by the addition of the ice-
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cold acetonitrile (100
mL). The fluorescence derived from resor-
ufin generated during the incubation was measured on a Thermo
Scientific Varioskan Flash apparatus with the excitation and
emission filters at 545 nm and 590 nm respectively. All of the IC50
values obtained by the nonlinear least-squares regression
analysis with Origin 7.5 software for all the compounds tested
were listed in Table 1.
[11] A.P. Koley, J.T.M. Buters, R.C. Robinson, et al., Differential mechanisms of cyto-
chrome P450 inhibition and activation by a-naphthoflavone, J. Biol. Chem. 272
(1997) 3149–3152.
[12] S.S. Li, Medicinal Chemistry, 1st ed., Science Publication, Beijing, 2009.
[13] R. Livingstone, Rodd’s Chemistry of Carbon Compounds, vol. IV, Elsevier Publish-
ing Co., Amsterdam, 1977.
3. Results and discussion
[14] W. Baker, Molecular rearrangement of some o-acyloxyaceto phenones and the
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[15] H.S. Mahal, K. Venkataraman, Synthetical experiments in the chromone group.
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acyloxyacetophenous, J. Chem. Soc. (1935) 868–870.
The structures of the compounds prepared were characterized
by 1H NMR and ESI-HRMS [22]. In the 1H NMR spectra of
compounds 3a–3j, the signals of methoxy groups on the
naphthalene part of the skeleton were observed at
The values of the protons on the C-ring of the new flavones 3a–3j
were in the range of 7.04–6.79. Two pairs of doublets assigned to
d 4.07–4.02.
d
two groups of coupled protons (H5–H6 and H9–H10) on the
naphthalene part were also observed in the 1H NMR spectrum of
each compound. In ESI-HRMS (positive-ion mode), each compound
showed the [M+H]+ peak.
[17] F.A. Carey, Organic Chemistry, 7th ed., McGraw-Hill Inc., New York, 2008.
[18] R.G.F. Giles, A.B. Hughes, M.V. Sargent, Regioselectivity in the reactions of
methoxydehydrobenzenes with furans. Part 2. 2-methoxyfuran and methoxyde-
hydrobenzenes, J. Chem. Soc. Perkin Trans. I (1991) 1581–1587.
[19] K.S. Huang, E.C. Wang, H.M. Chen, Syntheses of substituted naphthalenes and
naphthols, J. Chin. Chem. Soc. 51 (2004) 585–605.
The results of the EROD essay showed that the introduction of
[20] The spectroscopic data of compound 9 and 10. 9: White crystals; mp 89–91 8C; IR
(KBr, cmꢀ1): v 2965, 2933, 1761vs (C5O), 1369, 1274, 1212, 1079, 1007; 1H NMR
(300 MHz, CDCl3): d 8.02 (d, 1H, J = 9.0 Hz, H-C(4)), 7.61 (d, 1H, J = 9.0 Hz, H-C(8)),
7.45 (dd, 1H, J = 7.2, 9.0 Hz, H-C(3)), 7.31 (d, 1H, J = 9.0 Hz, H-C(7)), 7.11 (d, 1H,
J = 7.2 Hz, H-C(2)), 3.99 (s, 6H, CH3O), 2.45 (s, 3H, CH3CO); 13C NMR (100 MHz,
CDCl3): d 169.4 (quat., C5O), 148.8, 146.7, 143.1, 130.6, 122.9 (quat., 5 CAr,), 125.7,
119.5, 117.5, 116.2, 115.6 (5 CArH), 61.1 (OCH3), 56.8 (OCH3), 20.9 (CH3); ESI-
HRMS: Calcd. for C14H15O4 247.0970; found 247.0958 [M+H]+. 10: Light yellow
plates; mp 136–138 8C; IR (KBr, cmꢀ1): v 2980, 2950, 1622vs (C5O), 1497, 1488,
1394, 1281, 1085; 1H NMR (CDCl3, 300 MHz): d 14.15 (s, 1H, OH), 8.23 (d, 1H,
J = 9.3 Hz, H-C(4)), 7.61 (d, 1H, J = 9.0 Hz, H-C(8)), 7.51 (d, 1H, J = 9.0 Hz, H-C(7)),
7.28 (d, 1H, J = 9.3 Hz, H-C(3)), 4.02 (s, 3H, CH3O), 3.96 (s, 3H, CH3O), 2.67 (s, 3H,
CH3CO). 13C NMR (100 MHz, CDCl3): d 203.8 (quat., C5O), 162.9, 152.3, 142.4,
methoxy groups at the 7- and 8-position of a-NF greatly increased
the inhibitory effect since all the new flavones 3a–3j designed as
the substrate analogs were more potent inhibitors than the lead
(IC50 of 11.9 nmol/L). These ones 3h–3j that possessed a fluoro
atom on their B-rings exhibited lower IC50 values than their
counterparts containing a chloro atom or methoxy substitutions
on their B-rings. Among the tested compounds, 3h exhibited the
strongest inhibitory effect, a 12-fold more potent inhibitor (IC50 of
1.0 nmol/L) on CYP1A1 mediated-EROD activity compared to the
lead.

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J.-H. Cui et al. / Chinese Chemical Letters 24 (2013) 215–218
133.0, 120.4, 111.8 (quat., 6 CAr), 125.2, 121.4, 113.4, 111.6 (4 CArH), 61.1 (OCH3),
56.3 (OCH3), 26.6 (CH3); ESI-HRMS: Calcd. for C14H15O4 247.0970; found
247.0964 [M+H]+.
CDCl3): d 8.32 (d, 1H, J = 9.3 Hz), 8.13 (d, 1H, J = 9.0 Hz), 8.07 (d, 1H, J = 9.0 Hz),
7.94 (d, 2H, J = 8.4 Hz), 7.55 (d, 2H, J = 8.4 Hz), 7.46 (d, 1H, J = 9.3 Hz), 6.91 (s, 1H,
H-C(3)), 4.07 (s, 3H, CH3O), 4.03 (s, 3H, CH3O); ESI-HRMS: Calcd. for C21H16ClO4
[21] S. Yamaori, M. Kushihara, I. Yamamoto, et al., Characterization of major phyto-
cannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhi-
bitors of human CYP1 enzymes, Biochem. Pharmacol. 79 (2010) 1691–1698.
[22] The spectroscopic data of compounds 3a–3j. 3a: Pale yellow crystals; mp 175–
176 8C; 1H NMR (300 MHz, CDCl3): d 8.38 (d, 1H, J = 9.0 Hz), 8.15 (d, 1H,
J = 9.0 Hz), 8.07 (d, 1H, J = 9.0 Hz), 8.02 (m, 2H, H-C(20), H-C(60)), 7.58 (m, 3H,
H-C(30), H-C(40), H-C(50)), 7.46 (d, 1H, J = 9.0 Hz), 6.96 (s, 1H, H-C(3)), 4.07 (s, 3H,
CH3O), 4.03 (s, 3H, CH3O); ESI-HRMS: Calcd. for C21H17O4 333.1127; found
333.1119 [M+H]+. 3b: Pale-yellow needles; mp 207–209 8C; 1H NMR
(300 MHz, CDCl3): d 8.33 (d, 1H, J = 9.0 Hz), 8.13 (d, 1H, J = 9.0 Hz), 8.04 (d, 1H,
J = 9.0 Hz), 7.95 (d, 2H, J = 9.0 Hz, H-C(20), H-C(60)), 7.44 (d, 1H, J = 9.0 Hz), 7.07 (d,
2H, J = 9.0 Hz, H-C(30), H-C(50)), 6.85 (s, 1H, H-C(3)), 4.06 (s, 3H, CH3O), 4.03 (s, 3H,
CH3O), 3.91 (s, 3H, CH3O); ESI-HRMS: Calcd. for C22H19O5 363.1233; found
363.1217 [M+H]+. 3c: While needles; mp 190–191 8C; 1H NMR (300 MHz, CDCl3):
d 8.31 (d, 1H, J = 9.0 Hz), 8.14 (d, 1H, J = 9.0 Hz), 8.02 (m, 2H), 7.51 (m, 1H), 7.42 (d,
1H, J = 9.0 Hz), 7.25 (s, 1H), 7.17 (m, 1H), 7.08 (d, 1H, J = 8.4 Hz, H-C(30)), 4.05 (s,
3H, CH3O), 4.02 (s, 3H, CH3O), 3.96 (s, 3H, CH3O); ESI-HRMS: Calcd. for C22H19O5
367.0737; found 367.0728 [M+H]+. 3f: Light yellow needles; mp 193–195 8C; 1
H
NMR (300 MHz, CDCl3): d 8.31 (d, 1H, J = 9.0 Hz), 8.16 (d, 1H, J = 9.0 Hz), 8.08 (d,
1H, J = 9.0 Hz), 7.70 (m, 1H, H-C(60)), 7.59 (d, 1H, J = 7.2 Hz, H-C(30)), 7.48 (m, 2H,
H-C(40), H-C(50)), 7.41 (d, 1H, J = 9.0 Hz), 6.79 (s, 1H, H-C(3)), 4.05 (s, 3H, CH3O),
4.03 (s, 3H, CH3O); ESI-HRMS: Calcd. for C21H16ClO4 367.0737; found 367.0733
[M+H]+. 3g: Light yellow needles; mp 194–195 8C; 1H NMR (300 MHz, CDCl3): d
8.32 (d, 1H, J = 9.0 Hz), 8.12 (d, 1H, J = 9.0 Hz), 8.06 (d, 1H, J = 9.0 Hz), 7.98 (s, 1H,
H-C(20)), 7.85 (d, 1H, J = 6.6 Hz), 7.53 (m, 2H), 7.47 (d, 1H, J = 9.0 Hz), 6.91 (s, 1H,
H-C(3)), 4.07 (s, 3H, CH3O), 4.03 (s, 3H, CH3O); ESI-HRMS: Calcd. for C21H16ClO4
367.0737; found 367.0726 [M+H]+. 3 h: Pale yellow needles; mp 206-208 8C; 1
H
NMR (300 MHz, CDCl3): d 8.33 (d, 1H, J = 9.0 Hz), 8.13 (d, 1H, J = 9.0 Hz), 8.07 (d,
1H, J = 9.0 Hz), 8.01 (m, 2H), 7.46 (d, 1H, J = 9.0 Hz), 7.27 (m, 2H), 6.88 (s, 1H, H-
C(3)), 4.07 (s, 3H, CH3O), 4.03 (s, 3H, CH3O); ESI-HRMS: Calcd. for C21H16FO4
351.1033; found 351.1024 [M+H]+. 3i: Pale yellow crystals; mp 192–193 8C; 1H
NMR (300 MHz, CDCl3): d 8.33 (d, 1H, J = 9.0 Hz), 8.14 (d, 1H, J = 9.0 Hz), 8.07 (d,
1H, J = 9.0 Hz), 8.00 (m, 1H, H-C(60)), 7.55 (m, 1H), 7.45 (d, 1H, J = 9.0 Hz), 7.38 (m,
1H), 7.28 (m, 1H), 7.04 (s, 1H, H-C(3)), 4.07 (s, 3H, CH3O), 4.03 (s, 3H, CH3O); ESI-
HRMS: Calcd. for C21H16FO4 351.1033; found 351.1045 [M+H]+. 3j: Light yellow
crystals; mp 192–194 8C; 1H NMR (300 MHz, CDCl3): d 8.33 (d, 1H, J = 9.0 Hz),
8.12 (d, 1H, J = 9.0 Hz), 8.06 (d, 1H, J = 9.0 Hz), 7.76 (d, 1H, J = 7.5 Hz, H-C(60)), 7.73
(m, 1H), 7.55 (m, 1H), 7.47 (d, 1H, J = 9.0 Hz), 7.27 (m, 1H), 6.93 (s, 1H, H-C(3)),
4.07 (s, 3H, CH3O), 4.03 (s, 3H, CH3O); ESI-HRMS: Calcd. for C21H16FO4 351.1033;
found 351.1020 [M+H]+.
363.1233; found 363.1221 [M+H]+. 3d: Pale yellow crystals; mp 220–222 8C; 1
H
NMR (300 MHz, CDCl3): d 8.31 (d, 1H, J = 9.0 Hz), 8.13 (d, 1H, J = 9.0 Hz), 8.05 (d,
1H, J = 9.0 Hz), 7.65 (d, 1H, J = 8.4 Hz, H-C(60)), 7.45 (m, 2H, H-C(20), H-C(50)), 7.04
(d, 1H, J = 9.0 Hz), 6.86 (s, 1H, H-C(3)), 4.07 (s, 3H, CH3O), 4.03 (s, 3H, CH3O), 4.02
(s, 3H, CH3O), 3.99 (s, 3H, CH3O); ESI-HRMS: Calcd. for C23H21O6 393.1338; found
393.1345 [M+H]+. 3e: Pale yellow needles; mp 204–206 8C; 1H NMR (300 MHz,