Synthesis of benzonaphthofuroquinones and benzoylnaphthindolizinediones by reactions of flavonoids with dichlone under basylous, oxygenous and aqueous conditions: Their cytotoxic and apoptotic activities

Article abstract of DOI:10.1039/d0ra06043g

Using flavonoids and dichlone as substrates, benzonaphthofuroquinones (1, 2, 3, 5, 6, novel; 4 new) and benzoylnaphthindolizinediones (7, 8, known; 9, new) were synthesized through common base-catalyzed method and a new method of combining base-catalyzed with O2/H2O exposing. The possible reaction mechanisms may involve the process like isomerization, hydration, oxidation, decomposition and intermolecular condensation. Benzonaphthofuroquinones (2, 3, 4, 5) were found to exhibit potent cytotoxicity against carcinoma cell lines and low toxicity to normal cell lines. The compounds 4 and 5 not only expressed a significant late-stage-apoptosis against human leukemia and melanoma, but also promoted the cleavage of caspase-3 and PARP in human leukemia, which suggested that the late-stage-apoptosis and caspase-3 pathway may be responsible for the cytotoxicities of these benzonaphthofuroquinones. The replacement of the furan ring with pyrrole system in benzoylnaphthindolizinediones (7, 8, 9) resulted in the loss of anticancer activity.

Full text of DOI:10.1039/d0ra06043g

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PAPER
Synthesis of benzonaphthofuroquinones and
benzoylnaphthindolizinediones by reactions of
flavonoids with dichlone under basylous,
oxygenous and aqueous conditions: their cytotoxic
and apoptotic activities†
Cite this: RSC Adv., 2020, 10, 28644
Peng Luo,ac Wanxing Wei,a Saqlain Haider,b Shabana I. Khan,b Mei Wang,b
ac
b
*
*
Weigao Pan
and Amar G. Chittiboyina
Using flavonoids and dichlone as substrates, benzonaphthofuroquinones (1, 2, 3, 5, 6, novel; 4 new) and
benzoylnaphthindolizinediones (7, 8, known; 9, new) were synthesized through common base-catalyzed
method and a new method of combining base-catalyzed with O2/H2O exposing. The possible reaction
mechanisms may involve the process like isomerization, hydration, oxidation, decomposition and
intermolecular condensation. Benzonaphthofuroquinones (2, 3, 4, 5) were found to exhibit potent
cytotoxicity against carcinoma cell lines and low toxicity to normal cell lines. The compounds 4 and 5
not only expressed a significant late-stage-apoptosis against human leukemia and melanoma, but also
promoted the cleavage of caspase-3 and PARP in human leukemia, which suggested that the late-stage-
apoptosis and caspase-3 pathway may be responsible for the cytotoxicities of these
benzonaphthofuroquinones. The replacement of the furan ring with pyrrole system in
benzoylnaphthindolizinediones (7, 8, 9) resulted in the loss of anticancer activity.
Received 10th July 2020
Accepted 29th July 2020
DOI: 10.1039/d0ra06043g
rsc.li/rsc-advances
mechanism give poor selectivity for cytotoxicities between
carcinoma and normal cells, and its furan ring attached to the
1. Introduction
naphthoquinone scaffold along with the lipophilic character of
the alkyl substituents is a key feature required for the
enhancement of anticancer activity.4 While, dinaphtho[1,2-
b:20,30-d]furan-7,12-dione derivatives (Scheme 1, A5), with
additional naphtha-moiety on a-dunnione, had anticancer
mechanisms of topoisomerase-I mediated DNA cleavage,
epidermal and vascular endothelial growth factor receptors
inhibitory actions, which mechanisms owned high selectivity
for cytotoxicities.5
So modifying dunniones with aromatic ring-group may be
a good way to achieve anticancer mechanisms correlated with
cancer-related-biomacromolecules, which may result in high
selectivity for cytotoxicity. Flavonoids were potential phenol
source for modifying uses, in which the two phenol moieties
and a variable central-three-carbons-chain may provide various
substituent groups. Meanwhile, constructing other phenol-
modied a-dunnione-like derivatives (such as using pyrrol
system instead of furan system) may be useful to investigate the
changes of cytotoxicities or anticancer mechanisms.
Quinones, an important class of compounds, are found in many
biochemical systems. Anticancer drugs like daunorubicin and
mitomycin C are known to contain the quinone scaffold in their
structures. Their cytotoxic activity is attributed to different
mechanisms including redox cycling, intercalation of DNA
strands, free radical generation and alkylation via quinone
methide formation.1,2
Dunnione analogs, members of naphthoquinones family,
were found to exhibit potent cytotoxicity against breast and
pancreatic cancer cell lines (Scheme 1, A1–A3).3 Presence of
a phenolic hydroxy group at C-5 position in 2,3-dihydro-5-
hydroxy-2-(prop-1-en-2-yl)naphtho[2,3-b]furan-4,9-dione
(Scheme 1, A4) results in an increase in the antiproliferative
effects.1 a-Dunnione (CS-3, Scheme 1, A3) inhibited the respi-
ration of the tumor cells by interfering with the electron
transport at some point between NADH and ubiquinone which
aCollege of Chemistry and Chemical Engineering, Guangxi University, Nanning
530004, China. E-mail: agao81706672@163.com
bNational Center for Natural Products Research, School of Pharmacy, University of
Mississippi, University Park, Mississippi 38677, USA. E-mail: amar@olemiss.edu
cGuangxi University of Chinese Medicine, Nanning 530001, China
In reported methods, benzo- or naphthanaphthofur-
oquinones (a-dunniones analogs) was synthesized mainly
through base-catalyzed condensation reaction. Condensation of
dichlone with methyl 1,4-dihydroxy-2-naphthoate or 2-acetyl-
1,4-dihydronaphthalene with presence of K2CO3 under reux
† Electronic supplementary information (ESI) available: NMR spectra, gures of
apoptosis analysis and western blotting analysis. See DOI: 10.1039/d0ra06043g
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Scheme 1 The reported dunnione analogs with cytotoxicity.
in pyridine at 90 C resulted in dinaphtho[1,2-b:20,30-d]furan- with 2,3-dichloro-1,4-naphthoquinone (Scheme 3, (1)),11 or by
7,12-dione (Scheme 2, B1)6 or 6-acetyl-5-hydroxydinaphtho[2,3- copper(II)-catalyzed three-component reactions of 2-bromoace-
b:20,10-d]furan-7,12-dione (Scheme 2, B2),7 respectively. [1,3] tophenone, 1,4-naphthoquinone, and pyridine via sp2-C–H
Dioxolo[4,5-f]naphtho[2,3-b]benzofuran-6,11-dione (Scheme 2, difunctionalization of naphthoquinone followed by intra-
B3) or 1,3-dihydroxybenzo[b]naphtho[2,3-d]furan-6,11-dione molecular cyclization and oxidative aromatization (Scheme 3,
(Scheme 2, B4) was synthesized from the reaction of dichlone (2)),12 or by iodine oxidation of 2-alkyl-1,4-naphthoquinones in
with sesamol (or phloroglucinol) in presence of KOH under the presence of substituted pyridines (Scheme 3, (3)).13
ꢀ
reux in pyridine at 90 C (or 30 C).8
In our initial plan, in order to get naphthanaphthofur-
ꢀ
ꢀ
Intermolecular C–C-bond formation and intermolecular O- oquinones, dihydroavone and chalcone were respectively used
alkylation were the two condensation processes for the to react with dichlone in pyridine under anoxic and anhydrous
synthesis of naphthofuroquinones scaffold. Other methods of conditions, however, no targeted products were obtained.
preparation included light irradiation and oxidation were re- Unintentionally, the anoxic and anhydrous conditions being
ported. 2-Hydroxynaphtho-1,4-dione was converted to negative removed and reaction system being exposed to the moist air,
ion by pyrex-ltered light, and reacted with 2-naphthol exciplex unexpected benzoylnaphthindolizinediones were found. So this
to produce a C–C bond rstly, and then to form a C–O bond by O2/H2O exposing combining with base-catalyzed method were
dehydration.9 Quinone-arenols were prepared from hydroqui- developed.
none monomethylethers by oxidants to form C–C bond in the
With regard to recent works about the utilization of water to
rst step, and by oxidative cyclization of quinone-arenols to give promote reaction, ecofriendly and efficient synthesis of sulfo-
C–O
bond
in
the
second
step
to
produce nylated N-heteroaromatics14 and 2-sulfonyl quinolines/pyri-
dibenzofuranquinones.10
dines15 were conducted in water, and in the iodine-catalyzed
In reported methods, benzoylnaphthindolizinediones (a- odorless synthesis of S-thiocarbamates, water played a dual
dunnione-like compounds) were synthesized by potassium role, viz. co-solvent and H/O source.16
carbonate-catalyzed one-pot tandem reactions of the N-ylides
Scheme 2 The reported synthetic methods for benzo- or naphthanaphthofuroquinones.
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Scheme 3 The reported synthetic methods for benzoylnaphthindolizinediones.
7.56 while dC-15 almost unchanged at 117.8, which meaned that
the second dichlone moiety, through intermolecular O-alkyl-
ation condensation, was located at 14-O (ortho effect) in 2, and
at 13-O in 3 (Scheme 4).
2. Results and discussion
2.1 Chemistry
2.1.1 Structure elucidation and characterization. Ten
derivatives were synthesized here, viz. 3,4-dihydroxy-1-(3,5,7-
trihydroxy-4-oxo-4H-chromen-2-yl)naphtho[2,3-b]benzofuran-
In case of 5, eight aromatic methines signals were found. As
for resonances changes occurring on the B-ring of avonoid
moiety, two methine-protons signals at dH 7.22–7.24 (1H, d, J ¼
8.3 Hz)] and dH 7.61–7.63 (1H, d, J ¼ 8.3 Hz) with their coupling
in 1H–1H COSY were observed while the third one vanished,
which meant that C–C condensation reaction occurred in
position 11 (Scheme 4). Furthermore, a new aromatic oxygen-
ated carbon signal at dC 154.7 (C-2) was found, so an additional
C–O covalent bond was formed to produce the furan ring
(Scheme 4). 6 manifested obvious proton/carbon resonances
changes on the B-ring comparing to those of 5, so the second
naphthoquinone moiety was located at 13-O (Scheme 4). 4 was
produced from 5 (Scheme 4), so the hydroxyl group was located
at position 13, which had been conrmed by its NMR data and
single crystal structure in our previous work.17
6,11-dione
(1),
4-hydroxy-3-((3-hydroxy-1,4-dioxo-1,4-dihy-
dronaphthalen-2-yl)oxy)-1-(3,5,7-trihydroxy-4-oxo-4H-chromen-
2-yl)naphtho[2,3-b]benzofuran-6,11-dione (2), 3-hydroxy-4-((3-
hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)oxy)-1-(3,5,7-
trihydroxy-4-oxo-4H-chromen-2-yl)naphtho[2,3-b]benzofuran-
6,11-dione (3), 4-hydroxynaphtho[2,3-b]benzofuran-6,11-dione
(4), 4-hydroxy-1-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)naph-
tho[2,3-b]benzofuran-6,11-dione (5), 4-((3-hydroxy-1,4-dioxo-1,4-
dihydronaphthalen-2-yl)oxy)-1-(3,5,7-trihydroxy-4-oxo-4H-chro-
men-2-yl)naphtho[2,3-b]benzofuran-6,11-dione
hydroxybenzoyl)benzo[f]pyrido[1,2-a]indole-6,11-dione (7), 12-
benzoylbenzo[f]pyrido[1,2-a]indole-6,11-dione (8), 12-(4-
hydroxybenzoyl)benzo[f]pyrido[1,2-a]indole-6,11-dione (9), 1,4-
dioxo-3-(pyridin-1-ium-1-yl)-1,4-dihydronaphthalen-2-olate (10,
side product).
(6),
12-(2-
7 had been conrmed by its NMR data and single crystal
structure in our previous work.18
By the coupling relationships in 1H–1H COSY of 8, proton
signals of dH 7.91–7.93 (2H, d, J ¼ 7.5 Hz), 7.46–7.49 (2H, t, J ¼
7.5 Hz), 7.60–7.63 (1H, t, J ¼ 7.5 Hz) were assigned to a ve-
consecutive-methines-chain of phenyl group. Considering the
facts that the HR ESI-MS spectra gave a molecular formula of
Structures of 1–10 were elucidated and characterized by
NMR (1H, 13C, DEPT, 1H–1H COSY, HSQC, HMBC), MS (ESI-MS,
APCI-MS and HR ESI-MS) and IR spectra (see the ESI† le).
In NMR spectra of 1, total of seven aromatic methines
signals were observed. As concerns resonances changes occur-
ring on the B-ring of avonoid moiety, one methane signal at
dH/dC 7.36(s)/118.6 (position 15) was remained while the other
one disappeared, which suggested that intermolecular C–C
condensation reaction occurred in position 11. Furthermore,
a new aromatic oxygenated carbon signal at dC 154.1 (C-2) was
found, so an additional C–O covalent bond was formed, which
contributed to produce the furan ring (Scheme 4). As compared
with H-15/C-15 resonances of 1 at dH-15/dC-15 7.36/118.6, the
C
23H13NO3 and pyridine was used as solvent in the reaction,
proton signals of dH 9.83–9.85 (1H, d, J ¼ 7.0 Hz), 7.21–7.24 (1H,
t, J ¼ 7.3 Hz), 7.41–7.44 (1H, m), 7.97–7.99 (1H, d, J ¼ 9.0 Hz)
were assigned to a four-consecutive-methines-chain of pyridine
moiety by the 1H–1H COSY coupling relationships, which meant
that pyridine was involved in the intermolecular condensation
reaction (Scheme 5).
Instead of ve consecutive coupling protons in 8, four
protons with coupling relationships between signals of dH 6.80–
6.82 (2H, d, J ¼ 8.5 Hz) and those of dH 7.73–7.77 (2H, m) were
corresponding resonances of 2 moved to up-eld shi at dH-15
/
dC-15 7.29/113.3, and as to 3, dH-15 move to down-eld shi at
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Scheme 4 Synthesis of benzonaphthofuroquinones and the possible reaction mechanism of 4. Reagents and conditions: (1) pyridine, 85 ꢀC,
24 h; (2) pyridine, moist air (O2/H2O) injection, 85 ꢀC, 24 h.
observed in 9. Furthermore, one more aromatic oxygenated which were generated from trans-chalcone via retro-aldol
carbon at dC 162.8 was found in 9 than in 8 (Scheme 5).
decomposition aer hydration and isomerization, reacted
benzoylnaph-
2.1.2 Synthesis and discussion for reaction mechanisms. with above intermediate to build
a
The preparations of 1, 2, 3, 5, 6 were conducted by common thindolizinedione skeleton (7, 8, 9, Scheme 5). The fact that 7
methods6,7 using avonols (myricetin or quercetin) as and 8 were derived from the different part of chalcone provided
substrates under pyridine-catalyzed conditions (Scheme 4). evidence for the isomerization reaction of chalcone hydrate.
Besides mono condensation products (1, 5), additional dichlone
Two phases of the hydration and dealdolization reactions of
molecule was introduced to form bis-naphthoquinones chalcone (1,3-diphenyl-2-propen-1-one) and their reaction rate
compounds (2, 3, 6) merely by intermolecular C–O condensa- constants were reported by J. Peter Guthrie et al. Hydration of
tion (Scheme 4).
chalcone was catalyzed by aqueous sodium hydroxide to give the
The structure of 4 was conrmed by both single crystal X-ray hydrate (1,3-diphenyl-3-hydroxy-1-propanone) rstly, and then
diffraction and NMR-spectrum in our previous work.17 In the retro-aldol reaction of this hydrate was also catalyzed by aqueous
condensation reaction of quercetin with dichlone under basy- sodium hydroxide to produce benzaldehyde and acetophenone.20
lous, anoxic and anhydrous conditions, 4 was not found, while
providing additional condition of O2/H2O exposing, 4 was ob-
tained (Scheme 4). It may indicate that C-ring of avonol moiety
in 5 was cleaved by hydration, and then a “2,3-dioxo-3-(2,4,6-
trihydroxyphenyl)propanal” group was eliminated to give
a benzonaphthofuroquinone core (4, Scheme 4). However, this
“2,3-dioxo-3-propanal” elimination mechanism was not found
in the literature, so further work should be done to conrm it.
In Scheme 5, occurrence of side product (10) provided
evidence for the existence of intermediate of dichlone reacted
with pyridine, and the structure of 10 and its synthetic method
(under similar conditions and using the same substrates) were
reported by Andreas Schmidt et al.19 Dihydroavone (nar-
ingenin) isomerized into trans-chalcone. Acetophenone blocks,
2.2 Biology
2.2.1 Cytotoxicity. Some of the benzonaphthofuroquinones
(1, 2, 3, 4, 5) exhibited anticancer effects, while the benzoyl-
naphthindolizinediones (7, 8, 9) showed no activities (Table 1).
The formed furan-ring in benzonaphthofuroquinones being
replaced by pyrrol-ring in benzoylnaphthindolizinediones
resulted in the loss of anticancer activity (Table 1).
Doxorubicin manifested strong cytotoxicities against both
carcinoma and normal cell lines, while 1, 2, 3, 4, 5 possessed
good anticancer activities and low toxicity to normal cells. 3
owed high antagonistic effect against almost all test solid
carcinoma cell lines, while 2, 5 just showed good inhibition
against SK-MEL (solid carcinoma), and 4, 5 had good inhibition
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Scheme 5 Synthesis of benzoylnaphthindolizinediones and the possible reaction mechanisms. Reagents and conditions: pyridine, moist air (O2/
H2O) injection, 85 ꢀC, 24 h.
against HL-60 (non-solid carcinoma) (Table 1). The potent 53.7% and 27.9%, respectively) at low concentration (5 mM), and
cytotoxic derivatives (2, 3, 4, 5) were selected for further the apoptotic proportions mainly distributed in the upper right
apoptotic test and western blotting analysis.
2.2.2 Apoptosis. In the case of apoptosis against human proportions of 36.8% and 20.1%, respectively.
quadrant (Annexin V+/7-AAD+, late-apoptotic-stage) with
leukemia (Fig. S1,† see the ESI†), 2 (20 mM) showed no apoptotic
With regard to apoptosis against melanoma (Fig. S2,† see the
activity; and 3 (20 mM) manifested some slight late-stage- ESI†), 2 (30 mM) and 3 (30 mM) had no apoptotic activities; while
apoptosis (Q2, Annexin V+/7-AAD+) and early-stage-apoptosis 4 (30 mM) and 5 (30 mM) induced obvious Annexin V-positive
(Q3, Annexin V+/7-AADꢁ); while 4, 5 signicantly induced apoptosis (45.8% and 17.0%, respectively), in which, the
Annexin V-positive apoptosis (with apoptotic proportions of major apoptotic proportions (41.7% and 15.1%, respectively)
Table 1 Cytotoxicities against carcinoma and normal cell lines
Non-cancer cell linesd
(IC50, mM)
Cancer cell linesc (IC50, mM)
Treatments
SK-MEL
KB
BT-549
SK-OV-3
HL-60
LLC-PK1
Vero
1
2
3
4
5
6
7
8
14.83
3.88
2.02
12.88
5.26
39.8
NAa
29.66
10.87
5.90
37.88
10.96
NAa
23.31
10.87
3.57
37.88
28.51
NAa
NAa
NAa
NCa
NCa
27.95
6.21
22.73
21.93
NAa
18.17
17.32
2.57
4.29
NAa
24.84
27.95
18.18
21.93
39.8
NCa
38.82
15.53
15.91
NCa
NCa
NAa
NAa
NAa
NAa
NCa
NAa
NAa
NAa
NAa
NAa
NCa
NCa
9
NAa
NAa
NAa
NAa
NAa
NCa
NCa
b
Doxorubicin
Cisplatin
1.29
0.92
1.84
4.05
—
0.92
9.21
b
b
b
b
b
b
—
—
—
—
1.46
—
—
a
b
c
NA or NC mean not active up to 40 mM. Not tested. SK-MEL: malignant melanoma, KB: oral epidermal carcinoma, BT-549: ductal breast
carcinoma, SK-OV-3: ovary carcinoma, HL-60: human leukemia. d LLC-PK1: kidney epithelial, VERO: African green monkey kidney broblast.
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were observed in the upper right quadrant (Annexin V+/7-AAD+, 1383, 1363, 1322, 1286, 1246, 1186, 1161, 1112, 1051, 975, 897,
late-apoptotic-stage).
841, 794, 711, 655. 1H NMR (400 MHz, DMSO-d6) d: 8.10–
2.2.3 Western blotting analysis. As to HL-60 (Fig. S3-A,† see 8.12(1H, m, H-9), 7.99–8.01 (2H, m, H-31, 34), 7.94–7.96 (2H, m,
the ESI†), 3 (20 mM), 4 (3 mM) and 5 (5 mM) signicantly induced H-32, 33), 7.92–7.94 (1H, m, H-6), 7.84–7.86 (2H, m, H-7, 8), 7.29
the cleavage of caspase-3 and PARP, while 2 (20 mM) induced (1H, s, H-15), 6.40 (1H, s, H-24), 6.20 (1H, s, H-22). 13C NMR and
obvious PARP-cleavage and slight caspase-3 cleavage, which DEPT (101 MHz, DMSO-d6) d: 182.3 (C-4), 177.4 (C-29), 176.9 (C-
suggested that 4 and 5 own relatively higher signicant 19), 176.6 (C-26), 174.9 (C-1), 165.0 (C-23), 162.0 (C-21), 160.1 (C-
apoptosis inducing effect. With regard to melanoma (Fig. S3-B,† 27), 156.9 (C-25), 153.5 (C-14), 148.3 (C-17), 140.6 (C-2), 140.2 (C-
see the ESI†), 4, 5 manifested slight apoptosis inducing effect at 12), 139.5 (C-28), 138.5 (C-18), 134.9 (C-7, 32, 33), 134.7 (C-8),
concentration of 30 mM.
132.7 (C-10), 132.2 (C-13), 131.1 (C-5), 130.6 (C-16), 130.2 (C-
35), 130.0 (C-30), 127.0 (C-3), 126.9 (C-31), 126.5 (C-9), 126.3
(C-34), 126.2 (C-6), 113.3 (C-15), 110.7 (C-11), 105.1 (C-20), 99.5
(C-22), 94.4 (C-24). 1H was assigned to 13C by HSQC correlations.
In the 1H–1H COSY spectrum, the couplings of H-6 with H-7, H-
3. Experimental
3.1 General information and characterization data
Flash column chromatographic separations were accomplished 7 with H-8, H-8 with H-9, H-31 with H-32, H-32 with H-33, H-33
on Biotage Isolera Four system (Biotage, Uppsala, Sweden). with H-34 were determined. In the HMBC spectrum, the
NMR was recorded on DRX-400 and DRX-500 NMR spectrome- correlations of H-6 with C-7, 8; H-9 with C-7, 8; H-15 with C-11,
ters (Bruker, Rheinstetten, Germany). ESI-, APCI- and HR ESI- 13, 14, 17; H-22 with C-20, 24; H-31 with C-33; H-34 with C-32
MS were recorded on Agilent 1290 LC-MS or Agilent G6530 were observed.
TOF MS spectrometer (Agilent Technologies Inc., California,
3: black powder; 112 mg, yield 16% (nal product/myricetin
USA). Western blot results were visualized on Mini-HD9-Auto ꢂ 100%); mp 425–426 ꢀC. ESI-MS: 659.0 [M + CH3OH–H2O +
Biomolecular imager (Leader Oriental Technology. LTD, Bei- H]+, 656.8 [M + CH3OH–H2O–H]ꢁ; ACPI-MS: 657.0 [M + CH3OH–
jing, China). Dichlone and avonoids were purchased from H2O–H]ꢁ. HRESI-MS found [M ꢁ H]+ 643.0463; C35H16O13 [M ꢁ
Fisher Scientic (Fair Lawn, NJ, USA) and Ark Pharm, Inc. H]+ requires 643.0518. IR (solid, cmꢁ1): 3647, 3317, 3071, 1673,
(Arlington Heights, IL, USA). Cell lines were gotten from the 1645, 1630, 1603, 1591, 1571, 1508, 1474, 1434, 1369, 1320,
American Type Culture Collection (Manassas, VA). Caspase-3 1277, 1246, 1226, 1211, 1178, 1156, 1104, 1060, 1010, 974, 948,
(3G2) mouse mAb, caspase-3 antibody, cleaved caspase-3 916, 900, 887, 833, 789, 750, 710, 695. 1H NMR (400 MHz,
(Asp175) (5A1E) rabbit mAb, PARP (46D11) rabbit mAb and DMSO-d6) d: 8.09–8.11 (1H, m, H-9), 8.04–8.05 (1H, m, H-34),
horseradish peroxidase (HRP) were purchased from Cell 7.99–8.01 (1H, m, H-31), 7.89–7.90 (1H, m, H-6), 7.87–7.88
Signaling Technology, Inc (Danvers, MA, USA).
(2H, m, H-32, 33), 7.82–7.86 (2H, m, H-7, 8), 7.56 (1H, s, H-15),
3.1.1 Characterization data. 1: orange powder; 315 mg, 6.22 (2H, s, H-22, 24). 13C NMR and DEPT (101 MHz, DMSO-d6)
yield 45% (nal product/myricetin ꢂ 100%); dp (decomposition d: 179.4 (C-4), 177.0 (C-29), 177.0 (C-19), 176.8 (C-26), 174.9 (C-
point) 385 ꢀC. ESI-MS: 473.0 [M + H]+, 471.0 [M ꢁ H]ꢁ; ACPI-MS: 1), 164.5 (C-23), 161.5 (C-21), 157.3 (C-25), 156.2 (C-27), 146.2
473.0 [M + H]+, 471.0 [M ꢁ H]ꢁ. HRESI-MS found [M ꢁ H]ꢁ (C-17), 143.3 (C-2), 140.6 (C-14), 139.6 (C-28), 138.9 (C-12), 137.7
471.0353; C25H11O10 [M
ꢁ
H]ꢁ requires 471.0352. IR (C-18), 135.1–135.2 (C-7, 32, 33), 134.6 (C-8), 133.5 (C-10), 131.8
(solid, cmꢁ1): 3548, 3318, 3058, 1720, 1707, 1655, 1595, 1508, (C-5), 130.0 (C-35), 129.9 (C-30), 128.5 (C-13), 127.2 (C-6), 126.6
1459, 1366, 1310, 1164, 1074, 1063, 1049, 983, 964, 793, 711, (C-9), 126.4 (C-31, 34), 124.0 (C-3), 123.0 (C-16), 121.1 (C-11),
1
672. H NMR (400 MHz, DMSO-d6) d: 8.13 (1H, m, H-9), 7.90– 117.8 (C-15), 104.6 (C-20), 98.8 (C-22), 94.0 (C-24). 1H was
7.91 (1H, m, H-6), 7.84–7.86 (2H, m, H-7, 8), 7.36 (1H, s, H-15), assigned to 13C by HSQC correlations. In the 1H–1H COSY
6.29 (1H, s, H-22), 6.24 (1H, s, H-24). 13C NMR and DEPT (101 spectrum, the couplings of H-6 with H-7, H-7 with H-8, H-8 with
MHz, DMSO-d6) d: 180.2 (C-4), 177.0 (C-19), 175.0 (C-1), 164.3 (C- H-9, H-31 with H-32, H-32 with H-33, H-33 with H-34 were
23), 161.5 (C-21), 157.3 (C-25), 154.1 (C-2), 148.8 (C-14), 147.0 (C- determined. In the HMBC spectrum, the correlations of H-6
17), 146.8 (C-12), 136.9 (C-18), 134.8 (C-7), 134.4 (C-8), 133.6 (C- with C-5; H-7 with C-9; H-8 with C-10; H-9 with C-7; H-15 with
10), 133.2 (C-13), 132.1 (C-5), 127.0 (C-6), 126.4 (C-9), 125.1 (C-3), C-11, 13, 14, 17; H-22 with C-20, 21, 23, 24; H-24 with C-20, 22,
118.6 (C-15), 116.4 (C-16), 115.1 (C-11), 104.4 (C-20), 98.6 (C-22), 23, 25; H-31 with C-33; H-32 with C-33, 34; H-33 with C-31, 32; H-
93.9 (C-24). 1H was assigned to 13C by HSQC correlations. In the 34 with C-32 were observed.
1H–1H COSY spectrum, the couplings of H-6 with H-7, H-7 with
H-8, H-8 with H-9 were determined. In the HMBC spectrum, the quercetin ꢂ 100%); mp 263 C. ESI-MS: 263.0 [M ꢁ H] ; ACPI-
correlations of H-6 with C-10; H-7 with C-9; H-8 with C-6; H-9 MS: 265.0 [M + H]+, 263.0 [M ꢁ 1]ꢁ. HRESI-MS found [M + H]+
with C-1; H-15 with C-11, 13, 14; H-22 with C-20; H-24 with C- 265.0492; C16H9O4 [M + H]+ requires 265.0495. Crystal structure,
4: red columnar crystals. 133 mg, yield 20% (nal product/
ꢁ
ꢀ
20, 23, 25 were observed.
IR and NMR data were reported in our previous work.17
2: red powder; 126 mg, yield 18% (nal product/myricetin ꢂ
5: orange powder; 319 mg, yield 48% (nal product/
100%); mp 319–320 ꢀC. ESI-MS: 659.0 [M + CH3OH–H2O + H]+, quercetin ꢂ 100%); mp 387–388 ꢀC. ESI-MS: 457.0 [M + H]+,
657.0 [M + CH3OH–H2O–H]ꢁ; ACPI-MS: 659.0 [M + CH3OH–H2O 455.0 [M ꢁ H]ꢁ; ACPI-MS: 457.0 [M + H]+, 455.0 [M ꢁ H]ꢁ.
+ H]+, 657.0 [M + CH3OH–H2O–H]ꢁ. HRESI-MS found [M ꢁ H]+ HRESI-MS found [M + H]+ 457.0554; C25H13O9 [M + H]+ requires
643.0463; C35H16O13 [M
ꢁ
H]+ requires 643.0518. IR 457.0554. IR (solid, cmꢁ1): 3545, 3531, 3288, 3095, 1672, 1646,
(solid, cmꢁ1): 3530, 3078, 1671, 1655, 1627, 1606, 1588, 1498, 1625, 1600, 1577, 1559, 1497, 1438, 1358, 1305, 1278, 1218,
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1193, 1166, 1090, 1015, 971, 943, 900, 842, 825, 798, 751, 709, 8), 7.60–7.63 (1H, t, J ¼ 7.5 Hz, H-21), 7.46–7.49 (2H, t, J ¼
1
695. H NMR (400 MHz, DMSO-d6) d: 8.12–8.14 (1H, m, H-9), 7.5 Hz, H-20, 22), 7.41–7.44 (1H, m, H-13), 7.21–7.24 (1H, t, J ¼
7.91–7.93 (1H, m, H-6), 7.83–7.87 (1H, m, H-8), 7.76–7.80 (1H, 7.3 Hz, H-12). 13C NMR and DEPT (126 MHz, CDCl3) d: 191.9 (C-
m, H-7), 7.61–7.63 (1H, d, J ¼ 8.3 Hz, H-15), 7.22–7.24 (1H, d, J ¼ 17), 180.9 (C-1), 175.0 (C-4), 139.2(C-15), 138.9(C-18), 134.3(C-5),
8.3 Hz, H-14), 6.25 (1H, d, J ¼ 2.0 Hz, H-22), 6.22 (1H, d, J ¼ 133.8(C-7), 133.6 (C-10), 133.1 (C-8), 133.1 (C-21), 129.3 (C-19,
2.0 Hz, H-24). 13C NMR and DEPT (101 MHz, DMSO-d6) d: 179.9 23), 128.4 (C-20, 22), 128.4 (C-3), 128.3 (C-13), 127.8 (C-11),
(C-4), 177.1 (C-19), 175.5 (C-1), 164.3 (C-23), 161.5 (C-21), 157.3 127.2 (C-9), 126.4 (C-6), 121.4 (C-2), 120.4 (C-14), 117.8 (C-12),
1
(C-25), 154.7 (C-2), 149.1 (C-17), 145.9 (C-13), 145.4 (C-12), 137.0 113.7 (C-16). H was assigned to 13C by HSQC correlations. In
1
(C-18), 135.0 (C-7), 134.4 (C-8), 133.7 (C-10), 132.1 (C-5), 129.8 the H–1H COSY spectrum, the couplings of H-6 with H-7, H-7
(C-15), 127.1 (C-6), 126.5 (C-9), 124.5 (C-3), 123.3 (C-11), 116.9 with H-8, H-8 with H-9, H-11 with H-12, H-12 with H-13, H-13
(C-16), 115.0 (C-14), 104.5 (C-20), 98.6 (C-22), 93.9 (C-24). 1H was with H-14, H-19 with H-20, H-20 with H-21, H-21 with H-22,
assigned to 13C by HSQC correlations. In the 1H–1H COSY H-22 with H-23 were determined. In the HMBC spectrum, the
spectrum, the couplings of H-6 with H-7, H-7 with H-8, H-8 with correlations of H-6 with C-4, 8, 10; H-7 with C-5, 9; H-8 with C-6,
H-9 were determined. In the HMBC spectrum, the correlations 7, 10; H-9 with C-1, 5, 7; H-11 with C-3, 12, 13, 15; H-12 with C-
of H-6 with C-8; H-8 with C-5, 6, 9, 10; H-9 with C-7; H-14 with C- 13, 14; H-13 with C-11, 12, 15; H-14 with C-12, 15; H-19 with C-
12, 16; H-15 with C-11, 13, 17; H-22 with C-20, 21, 24; H-24 with 17, 21, 23; H-20 with C-18, 19, 21, 22; H-21 with C-19, 23; H-22
C-20, 22, 25 were observed.
with C-18, 20, 21, 23; H-23 with C-17, 19, 21 were observed.
6: brownish red powder; 98 mg, yield 15% (nal product/
9: red needle crystals; 389 mg, yield 65% (nal product/
+
+
quercetin ꢂ 100%); mp 390–391 ꢀC. ESI-MS: 629.0 [M + H] , naringenin ꢂ 100%); mp 318–319 C. ESI-MS: 368.0 [M + H] ,
627.0 [M ꢁ H]ꢁ; ACPI-MS: 629.0 [M + H]+. HRESI-MS found [M + 366.0 [M ꢁ H]ꢁ; ACPI-MS: 368.0 [M + H]+, 366.0 [M ꢁ H]ꢁ.
H]+ 629.0711; C35H17O12 [M + H]+ requires 629.0715. IR HRESI-MS found [M + H]+ 368.0916; C23H14NO4 [M + H]+
(solid, cmꢁ1): 3651, 3292, 3125, 2925, 2851, 1654, 1636, 1590, requires 368.0917. IR (solid, cmꢁ1): 3650, 3358, 3071, 1670,
1560, 1508, 1474, 1368, 1306, 1264, 1215, 1192, 1165, 1090, 1629, 1614, 1599, 1566, 1560, 1491, 1474, 1436, 1394, 1368,
1073, 1011, 981, 941, 899, 796, 711, 696. 1H NMR (400 MHz, 1306, 1276, 1226, 1211, 1162, 1137, 1063, 1037, 906, 878, 845,
ꢀ
1
DMSO-d6) d: 8.15–8.18 (1H, m, H-9), 8.09–8.11 (1H, m, H-34), 777, 755, 713, 704, 688. H NMR (400 MHz, DMSO-d6) d: 10.41
7.99–8.02 (1H, m, H-31), 7.95–7.97 (1H, m, H-6), 7.89–7.91 (1H, s, 21-OH), 9.63–9.66 (1H, m, H-11), 8.12–8.15 (1H, m, H-6),
(1H, m, H-8), 7.88–7.89 (2H, m, H-32, 33), 7.85–7.87 (1H, m, H- 7.91–7.93 (1H, m, H-9), 7.80–7.85 (1H, m, H-7), 7.73–7.77 (4H,
7), 7.62–7.64 (1H, d, J ¼ 8.4 Hz, H-15), 7.48–7.50 (1H, d, J ¼ m, H-8,14, 19, 23), 7.47–7.51 (1H, m, H-13), 7.36–7.39 (1H, m, H-
8.4 Hz, H-14), 6.26–6.27 (1H, d, J ¼ 2.0 Hz, H-22), 6.23–6.24 (1H, 12), 6.80–6.82 (2H, d, J ¼ 8.5 Hz, H-20, 22). 13C NMR and DEPT
d, J ¼ 2.0 Hz, H-24). 13C NMR and DEPT (101 MHz, DMSO-d6) d: (101 MHz, DMSO-d6) d: 189.5 (C-17), 181.1 (C-1), 174.1 (C-4),
182.0 (C-29), 181.5 (C-26), 179.8 (C-4), 177.1 (C-19), 175.4 (C-1), 162.8 (C-21), 138.1(C-15), 134.6 (C-7), 134.6 (C-5), 133.7 (C-8),
164.4 (C-23), 161.5 (C-21), 157.4 (C-25), 155.2 (C-2), 148.4 (C- 133.5 (C-10), 132.4 (C-19, 23), 130.1 (C-18), 128.3 (C-13), 128.1
17), 144.8 (C-13), 144.8 (C-12), 137.3 (C-18), 135.8 (C-28), 135.1 (C-11), 127.7 (C-3), 126.9 (C-9), 126.4 (C-6), 120.9 (C-2), 120.1 (C-
(C-7), 135.1 (C-33), 134.7 (C-27), 134.5 (C-8), 134.1 (C-32), 133.7 14), 118.7 (C-12), 115.7 (C-20, 22), 114.3 (C-16). 1H was assigned
(C-10), 132.2 (C-5), 131.3 (C-30), 130.9 (C-35), 129.4 (C-15), 127.2 to 13C by HSQC correlations. In the 1H–1H COSY spectrum, the
(C-6), 126.6 (C-9), 126.5 (C-34), 126.2 (C-31), 124.2 (C-3), 123.7 couplings of H-6 with H-7, H-7 with H-8, H-8 with H-9, H-11 with
(C-11), 120.3 (C-16), 114.3 (C-14), 104.5 (C-20), 98.7(C-22), 94.0 H-12, H-12 with H-13, H-13 with H-14, H-19 with H-20, H-22
(C-24). 1H was assigned to 13C by HSQC correlations. In the with H-23 were determined. In the HMBC spectrum, the
1H–1H COSY spectrum, the couplings of H-6 with H-7, H-7 with correlations of H-6 with C-4, 10; H-7 with C-5, 9; H-8 with C-6,
H-8, H-8 with H-9, H-14 with H-15, H-31 with H-32, H-32 with H- 10; H-9 with C-1, 5, 7; H-11 with C-3, 12, 13, 15; H-12 with C-
33, H-33 with H-34 were determined.
11, 13, 14; H-13 with C-11, 15; H-14 with C-12, 15; H-19 with
7: red needle crystals; 326 mg, yield 66% (nal product/ C-17, 21; H-20 with C-18, 21, 22; H-22 with C-18, 20, 21; H-23
chalcone ꢂ 100%); mp 264–265 ꢀC. Its crystal structure, MS, with C-17, 21; 21-OH with 20, 21, 22 were observed.
IR and NMR data were reported in our previous work.18
10: yellow needle crystals; 300–599 mg, yield 20–40% (nal
8: red needle crystals; 336 mg, yield 68% (nal product/ product/dichlone ꢂ 100%); mp 296–297 ꢀC. ESI-MS: 252.2 [M +
chalcone ꢂ 100%); mp 258–259 ꢀC. ESI-MS: 352.2 [M + H]+; H]+; ACPI-MS: 252.2 [M + H]+. HRESI-MS found [M + H]+
ACPI-MS: 352.2 [M + H]+. HRESI-MS found [M + Na]+ 374.0792, 252.0662; C15H10NO3 [M + H]+ requires 252.0655. 1H NMR (400
[2M + Na]+ 725.1689; C23H13NO3Na [M + Na]+ requires 374.0788, MHz, DMSO-d6) d: 8.89–8.91 (2H, d, J ¼ 5.7 Hz, H-11, 15), 8.57–
C
46H26N2O6Na [2M + Na]+ requires 725.1683. IR (solid, cmꢁ1): 8.61 (1H, t, J ¼ 7.6 Hz, H-13), 8.15–8.19 (2H, t, J ¼ 6.7 Hz, H-12,
3690, 3650, 3110, 3098, 3079, 3056, 2956, 2919, 1851, 1667, 14), 8.05–8.07 (1H, d, J ¼ 7.5 Hz, H-6), 7.96–7.98 (1H, d, J ¼
1640, 1623, 1588, 1570, 1490, 1466, 1447, 1392, 1365, 1307, 7.5 Hz, H-9), 7.81–7.85 (1H, t, J ¼ 7.4 Hz, H-7), 7.70–7.73 (1H, t, J
1276, 1227, 1209, 1159, 1134, 1062, 1037, 1018, 998, 905, 877, ¼ 7.3 Hz, H-8). 13C NMR and DEPT (101 MHz, DMSO-d6) d: 184.4
834, 808, 758, 748, 706, 693, 662. 1H NMR (500 MHz, CDCl3) d: (C-1), 172.4 (C-4), 165.4 (C-3), 148.1 (C-11,15), 145.1 (C-13), 134.9
9.83–9.85 (1H, d, J ¼ 7.0 Hz, H-11), 8.27–8.29 (1H, d, J ¼ 7.5 Hz, (C-7), 134.1 (C-5), 132.1 (C-8), 131.6 (C-10), 127.4 (C-12, 14),
1
H-6), 8.03–8.05 (1H, d, J ¼ 7.5 Hz, H-9), 7.97–7.99 (1H, d, J ¼ 126.5 (C-9), 126.3 (C-6), 125.4 (C-2). H was assigned to 13C by
9.0 Hz, H-14), 7.91–7.93 (2H, d, J ¼ 7.5 Hz, H-19, 23), 7.74–7.77 HSQC correlations. In the 1H–1H COSY spectrum, the couplings
(1H, td, J ¼ 7.5, 1.1 Hz, H-7), 7.65–7.68 (1H, td, J ¼ 7.5, 1.1 Hz, H- of H-6 with H-7; H-7 with H-8; H-8 with H-9; H-13 with H-12, 14;
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H-11 with H-12; H-14 with H-15 were determined. In the HMBC conjugated with HRP, treated with Western Lighting Chem-
spectrum, the correlations of H-6 with C-4, 10; H-7 with C-5, 9; iluminescence Reagent and nally visualized on biomolecular
H-8 with C-6, 10; H-9 with C-1, 5; H-11, 15 with C-13; H-13 with imager to determine the expression levels of apoptosis marker
C-11, 15; H-12 with C-11; H-14 with C-15; H-12 with C-14; H-14 proteins including caspase-3 and PARP cleavage (using b-actin
with C-12 were observed.
as internal reference).23,24
3.2 Synthesis and isolation
4. Conclusion
One of the selected avonoids (0.002 mol) was mixed with
dichlone (0.006 mol) uniformly, and then 50 mL of pyridine was
added to dissolve the mixed solid in a 100-mL double mouth
round bottom ask. The reacting system was stirred at 85 ꢀC for
24 h (in order to synthesize 4, 7, 8, 9, additional conditions, air
being pumped through a water-lled absorption bottle and then
injected into this mixture solution with ow velocity of 1
bubble/2 s, must be provided), and was nally concentrated to
give a semi-solid mass. The mass was chromatographed on
Biotage Isolera Four ash column chromatography system with
a SNAP Cartridge KP-Sil 10 g column eluted by hexane/ethyl
acetate (100 : 0 to 90 : 10, v/v), and then by chloroform/
methanol (100 : 0 to 90 : 10, v/v) to give fractions. TLC was
used to distinguish the eluted fractions. The fractions were
further isolated by preparative TLC (1000 microns; 20 cm ꢂ 20
cm) using chloroform/methanol or hexane/ethyl acetate as
developing agent to yield derivatives.
By the common base-catalyzed method, not only mono
condensation products (1, 5) but also bis-naphthoquinones
compounds (2, 3, 6) were obtained.
Through a new method of combining base-catalyzed with O2/
H2O exposing, benzonaphthofuroquinone (4) and benzoyl-
naphthindolizinediones (7, 8, 9) were synthesized. To our
knowledge this is the rst report about the reaction of chalcone/
dihydroavone with dichlone under given conditions to
produce benzoylnaphthindolizinediones, as well as the reaction
of avonols with dichlone to achieve benzonaphthofur-
oquinones. Benzoylnaphthindolizinediones were previously
synthesized by methods of potassium carbonate-catalyzing,11 or
copper(II)-catalyzing,12 or iodine oxidation.13
Some of the derivatives (2, 3, 4, 5) showed good anticancer
activities and low toxicity to normal cells, which indicated that
they possess some cytotoxic selectivity. The formed furan-ring
in benzonaphthofuroquinones being replaced by pyrrol-ring
in benzoylnaphthindolizinediones resulted in the loss of anti-
cancer activity. Late-stage-apoptosis and caspase-3 pathway may
contribute to the cytotoxicities of the synthesized
benzonaphthofuroquinones.
3.3 Assay for anticancer activity
Cytotoxicity against non-solid tumor and solid tumor were
tested by Trypan blue dye exclusion method and Neutral red
uptake method, respectively.21 IC50 was calculated from the
dose curves generated by plotting percent growth vs. the test
concentration on a logarithmic scale using Microso Excel. All
assays were performed in triplicate and the mean values are
given in Table 1.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
3.4 Apoptosis analysis
The sensitive cancer cell lines were separately incubated with
derivatives, DMSO and doxorubicin (positive control) at
different concentrations for 24 h, harvested by centrifugation at
300g, washed twice with cold 1ꢂ PBS and resuspended in 100 mL
of binding buffer at a density of 2 ꢂ 106 cells per mL, stained
with 5 mL of PE Annexin-V and 5 mL of 7-AAD for 15 min in the
dark at room temperature and nally subjected to analysis via
Accuri™ C6 ow cytometry.22,23
This work was funded by State Scholarship Fund awarded by
China Scholarship Council, 201706660015; Guangxi Scholar-
ship Fund of Guangxi Education Department, guijiaoshipei-
2016-22; Promotion of Young and Middle-aged Teachers'
Basic Scientic Research Ability in Guangxi Universities by
Guangxi Education Department, 2019KY0329; Opening Project
of First-class Discipline Construction in Guangxi, 2019XK047,
2019XK132 and Guangxi Key Laboratory of Zhuang and Yao
Ethnic
Medicine,
guikejizi-2014-32,
GXZYZZ2019-7,
3.5 Western blotting analysis
GXZYKF2019-6.
The sensitive cancer cell lines were separately treated with
derivatives, doxorubicin (positive control) and DMSO at
different concentrations for 24 h, washed with cold 1ꢂ PBS,
harvested in RIPA lysis solution for 60 min on ice, and then
heated to boiling point for 10 min aer adding loading buffer.
Notes and references
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The cell lysate were centrifuged at 13 000 g for 10 min at 4 C.
Equal amounts of the protein samples were subjected to SDS-
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The membranes were blocked in 5% nonfat milk, incubated
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