Identification of ortho-naphthoquinones as anti-AML agents by highly efficient oxidation of phenols

Article abstract of DOI:10.1016/j.bioorg.2019.01.025

A straightforward method for synthesizing ortho-naphthoquinones was identified using an easily available cobalt–Schiff base complex. Efficient oxidation of phenols to ortho-naphthoquinones was useful in obtaining compounds with potent biological activity

Full text of DOI:10.1016/j.bioorg.2019.01.025

BioorganicChemistry86(2019)97–102
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Identification of ortho-naphthoquinones as anti-AML agents by highly
efficient oxidation of phenols
Huidan Huanga, Ming Yana, Jianqiu Chena, Biao Yuanc, Guitang Chenc, Shujie Chengc,
⁎
⁎
Dechun Huanga, Zhen Gaob, , Chongjiang Caoa,
a Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 210009, China
b College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China
c Department of Food Quality and Safety, School of Engineering, China Pharmaceutical University, Nanjing 211816, China
A B S T R A C T
A straightforward method for synthesizing ortho-naphthoquinones was identified using an easily available cobalt–Schiff base complex. Efficient oxidation of phenols
to ortho-naphthoquinones was useful in obtaining compounds with potent biological activity for the treatment of acute myeloid leukemia (AML). Among these
compounds, the compound 4h effectively inhibited the proliferation of different AML cell lines in vitro. Further in vivo antitumor studies indicated that 4h at 40 mg/
kg/d led to tumor regression in led to tumor regression in an MV4-11 xenograft model without evident toxicity. The cobalt-Schiff base complex was found to be an
efficient catalyst in the transformation of phenols to ortho-quinones, and the compound 4h represents a potential scaffold to optimize the production of a treatment
for AML.
1. Introduction
are most widely investigated anticancer agents for solid tumors (Fig. 1)
[13]. Our cooperated group has synthesized several ortho-naphthoqui-
nones with potent antitumor activity against non-small cell lung cancer
[12–15]. Several quinones have recently been found to efficiently treat
AML [8,16,17]. We committed to develop ortho-naphthoquinones as
novel effective antitumor agents with a superior safety profile. An in-
depth study of these ortho-naphthoquinones as treatment for AML has
not been conducted; thus, we intended to evaluate their activity in
order to obtain a potential treatment for AML.
Acute myeloid leukemia (AML) is one of the most common type of
leukemia [1,2]. Cytotoxic or targeted drugs and hematopoietic stem cell
transplant therapy is typically used to treat patients with AML. How-
ever, these therapies remain unsatisfactory with 3–8% survival at
5 years in patients aged more than 60 years and up to 50% in patients
younger than 60 years [3,4]. Thus, an efficient and well-tolerated drug
for the treatment of AML needs to be developed. The challenge to AML
treatment is attributed to the heterogeneity of various leukemogenic
mutations and cytogenetic abnormalities with a poorly understood in-
terplay among them in each patient [5,6]. A therapy focused on tar-
geting the broader characteristic of all AML cells would be an efficient
method. Growing evidence shows that compared with normal cells,
AMLs are characterized by high levels of oxidative stress relative to
normal cells [7,8]. Oxidative stress is develop by reactive oxygen spe-
cies (ROS) that accumulate as a result of an imbalance between ROS
generation and elimination [9]. Numerous genetic changes that confer
an elevated ROS phenotype occur within AML. An elevated basal ROS
level increases the susceptibility of AML cells to exogenously induced
ROS-mediated cell death [7,10]. Potentiating ROS in cancers by using
small molecules has been regarded as a rational approach to drug de-
sign in order to strengthen the relationship between ROS and AML
[11,12].
In the present study, we focused on developing a novel method to
construct ortho-naphthoquinones before evaluating the biological ac-
tivity of these compounds. Substantial research has focused on the
synthesis of ortho-naphthoquinones. In the process of constructing the
naphthoquinone scaffold, oxidation of phenolics or amines to form the
quinone scaffold plays a key role. Accordingly, a large number of oxi-
dation agents have been identified. Classical methods use Fremy’s salt
K2(SO3)2NO or HNO3, as well as hypervalent iodine derivatives such as
IBX [18–20]. Although several of these oxidants are efficient, however,
these methods have disadvantages, such as low yield, and induces un-
desirable side effects.
Cobalt–Schiff base complexes, which are known to reversibly bind
oxygen, have been commonly used to catalyze oxygen activation in the
oxidation of phenols to para-quinones [21]. However, studies on the use
of these complexes to oxidize ortho-naphthoquinones as catalytic con-
version models of naphthol have rarely been reported. Using easily
Ortho-naphthoquinones, such as Tanshinone IIA and β-lapachone
⁎ Corresponding authors.
E-mail addresses: gaozhen@njtech.edu.cn (Z. Gao), ccj33@163.com (C. Cao).
https://doi.org/10.1016/j.bioorg.2019.01.025
Received 11 September 2018; Received in revised form 12 January 2019; Accepted 12 January 2019
Availableonline18January2019
0045-2068/©2019PublishedbyElsevierInc.

H. Huang et al.
BioorganicChemistry86(2019)97–102
Table 1
Condition screening for oxidation of phenol 3a into quinone 4a.a
.
Fig. 1. Structures of representative ortho-naphthoquinone compounds.
Entry
Catalyst
Additive
Solvent
Time (h)
T
Conv.(%)
available Co(salen) (1, 2), we demonstrated the oxidation of phenols
leading to a straightforward method for synthesizing ortho-naphtho-
quinones (Fig. 2). The obtained ortho-naphthoquinones were also
screened for cytotoxicity against AML cells. In vivo antitumor studies
were performed to evaluate the efficacy of the most potent compound.
1
1
2
1
2
2
2
2
2
2
2
2
2
2
2
2
–
MeOH
2
2
5
5
2
2
2
2
2
2
2
2
2
2
3
r.t.
r.t.
r.t.
r.t.
35
50
52
31
48
60
63
58
62
58
70
85
63
92
70
78
2
–
MeOH
3b
4b
5
–
MeOH
–
MeOH
–
MeOH
6
–
MeOH
45
7
–
MeOH
60
8
DIPEA
Pyr
TEA
TEA
TEA
TEA
TEA
Pyr
MeOH
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
2. Synthetic methodology
9
MeOH
10
11
12
13
14
15
MeOH
We initially investigated the reaction conditions for 3-methyl-5-
hydroxynaphthol[1,2-b]furan (3a) as a model substrate. By using O2
with 10% of catalysts 1 or 2 to treat 3a, ortho-naphthoquinone (4a) was
obtained at 50% and 52% yields, respectively. Further reducing the
amount of catalyst 1 to 5% prompts a significant decrease in 4a yield;
meanwhile, reducing catalyst 2 to 5% and shortening the reaction time
to 5 h result in nearly the same 4a yield (entries 3–4). Thus, catalyst 2
exhibits higher reactivity, compared with 1. The moderate reactivity of
catalyst 1 may be attributed to its poor oxygen-binding capacity. Thus,
catalyst 2 was selected for further study. No considerably increase in
yield was observed when the temperature was set higher than the room
temperature (entries 5–7). The presence of additional aromatic or ali-
phatic nitrogen bases reportedly enhanced the reactivity of the cata-
lytically active complex [21]. The effect of adding an axial ligand was
then evaluated. The yield of ortho-naphthoquinone (4a) from naphthol
was significantly improved by adding a base N,N-diisopropylethyla-
mine, pyridine, or triethylamine (TEA) to oxidations catalyzed by 2
(entries 8–10). Oxidation of 3a by using catalytic amounts of Co(salen)
and equimolar amounts of TEA obtains the highest yield (70%) of 4a.
We then evaluated the effect of solvents and determined that CH3CN/
H2O was the best solvent for this reaction among those tested (entries
11–15). Therefore, the optimized reaction conditions consist of 2
(10 mol %), TEA (100 mol %), and CH3CN/H2O (solvent) at room
temperature for 2 h under O2 (50 psi) (Table 1).
CH3CN
EtOH
CH3CN/H2O
CH2Cl2
CH3OH/CH2Cl2
a
Reaction conditions: 3a (0.50 mmol), catalyst 2 (10 mol %) under O2 (50
psi).
corresponding product in similar amounts although a longer reaction
time and higher catalyst loadings were required. To demonstrate the
practicability of the method, the model procedure was successfully
scaled up with comparable yield. The product 4a (1.85 g, 79%) was
prepared when the reaction was run in a 10 mmol scale (Scheme 3).
A possible catalytic cycle for these reactions, employing the model
substrate 3a for illustrative purposes, is shown in Scheme 4. The first
starting cobalt–Schiff base/ligand complex A is converted to the su-
peroxo complex B upon reaction with O2 [23,24]. Reacting B with the
model substrate 3a then generates the phenoxy radical C and D, which
is transformed into the intermediate E, followed by elimination of water
and the product 4a. The mediate F was further oxidized to regenerate
the catalyst B.
3. Biological activity
With the optimized reaction conditions in hand, other ortho-naph-
thoquinones were systematically screened. In Scheme 1, naphthol de-
rivatives are successfully transformed into the desired products in
moderate to high yields. Most naphthols were synthesized as described
in previous studies, with moderate to high yields [12–15]. The naphthol
3h was synthesized as shown in Scheme 2 [13,22].
3.1. In vitro cytotoxic activity screening
When these compounds were obtained with good yields, we in-
vestigated the antiproliferative activity of these ortho-naphthoquinones
against AML cells by MTT assay. We observed that most ortho-naph-
thoquinones exhibited moderate to high activities toward these AML
cell lines (MV4-11, MOLM-14, and THP-1) (Table 2). Except for com-
pound 4e and 4f, which showed poor activity toward all of the three
Notably, the effectiveness of 2 as a catalyst was also demonstrated
by the oxidation of nitrogen-containing heteroaromatic naphthol sub-
strate 3h to the quinone 4h in high yield. The model 3h yielded
Fig. 2. Structures of cobalt–Schiff base complexes used in this study.
98

H. Huang et al.
BioorganicChemistry86(2019)97–102
Scheme 1. Substrate scope of ortho-naphthoquinones. Reaction conditions: catalyst 2 (0.05 mmol), 3 (0.5 mmol), TEA (0.5 mmol) in CH3CN/H2O for 2 h at room
temperature for 2 h under O2 (50 psi). Isolated yield.
cell lines. Most of the methyl-substituted naphtho[1,2-b]furan-4,5-
diones 4b-4d showed more potent activity than compound 4a toward
MV4-11 cells. When introducing the nitrogen atom into the benzene
ring (compound 4h), the cytotoxicity toward MV4-11 is significantly
improved (IC50 = 0.11
0.07 μM). In addition, the 2-ethyl naphtho
[2,1-d]oxazole-4,5-diones (4g) also showed good activity with
IC50 = 0.41 μM toward MV4-11 cells. As for the MOLM-14 cell lines,
only three compounds (4c, 4g and 4h) showed inhibitory activity. This
result indicated that the ortho-quinone maybe the key pharmacophore
for their antitumor activity due to the A ring or C ring are different with
each other of these three compounds. Compounds 4a-4c showed more
inhibitory activity against THP-1 compared with single methyl-sub-
stitution at the benzene ring (4d and 4e). Among these compounds, 4g
and 4h showed potent inhibitory activity toward all these three cell
lines, probably due to the improved physicochemical properties. Spe-
cifically, the compound 4h showed a concentration-dependent decrease
Scheme 3. Scale-up experiment.
for further in vivo evaluation. The oral efficacy of 4h was evaluated in a
xenograft model in athymic nude mice with a subcutaneous implant of
an MV4-11 cell pellet (Fig. 4). When the tumors grew to ∼150 mm3,
the animals were randomly injected with a vehicle, 4h (20 and 40 mg/
kg), and the control sunitinib (40 mg/kg) once a day for three weeks. At
both doses of 4h, the tumor growth of implanted AML tumor was in-
hibited (p < 0.01 vs. the vehicle-treated control, Fig. 4). The com-
pound 4h (40 mg/kg) demonstrated potent in vivo antitumor activity
with tumor growth inhibition (63.4%) comparable to that of sunitinib
(40 mg/kg, 66.8%). In addition, no body weight loss was observed in
animals treated with 4h compared with the vehicle (Fig. 4B). These
after exposure for 48 h with IC50 values of 0.11
0.07 μM for MV4-11,
0.65 0.12 μM for MOLM-14, and 0.60 0.14 μM for THP-1 (Fig. 3).
3.2. In vivo antitumor activity study.
The compound 4h exhibited superior potency; thus, it was selected
Scheme 2. Reactions and conditions. (i) HNO3 (62%), 0 °C to r.t., 3 h, 90% yield. (ii) H2, Pd/C, r.t., 6 h, 92% yield. (iii) freshly distilled 2,3-butanedione, reflux,
30 min, 85% yield. (iv) ceric ammonium nitrate, r.t., 1 h. 95% yield. (v) CH2Cl2, 0 °C to r.t., 12 h, 55% yield. (vi) dil. HCl, 75 °C, 3 h, 80% yield.
99

H. Huang et al.
BioorganicChemistry86(2019)97–102
Scheme 4. Proposed mechanism for ortho-naphthoquinone formation from naphthol catalyzed by the catalyst Co.
results clearly demonstrated the efficacy and tolerability of the novel
Table 2
ortho-quinone scaffold 4h in MV4-11 nude mice xenograft models.
In vitro antitumor activity of compounds 4a-4ha.
Entry
Compound
MV4-11 (μM)
MOLM-14 (μM)
THP-1 (μM)
4. Conclusion
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
> 10
> 10
> 10
5.81
6.12
4.19
> 10
> 10
> 10
1.50
0.60
0.82
1.03
0.89
In conclusion, we described a simple, efficient and scalable method
for the oxidation of phenols to quinones. The efficient oxidation of
phenols to ortho-quinones in this study helped obtain a series of com-
pounds with efficient biological activity for the treatment of AML. In
addition, the compound 4h exhibited efficacy both in vitro and in vivo.
These findings encourage further investigations around the ortho-
naphthoquinones. We aim to identify the optimal ortho-naphthoqui-
nones for the treatment of AML in clinicals.
7.98
7.10
9.21
> 10
> 10
0.41
0.11
1.82
0.98
1.68
6.20
> 10
> 10
> 10
4.98
0.65
1.12
4 g
4h
0.10
0.07
0.31
0.12
0.64
0.14
a
For the detailed structures of compounds 4a-4h, see Scheme 1.
5. Experimental section
5.1. Chemistry
5.1.1. General experimental methods
Reactions were monitored by thin-layer chromatography on silica
gel plates (60F-254) visualized under UV light. Melting points were
determined on a Mel-TEMP II melting point apparatus without correc-
tion. 1H NMR and 13C NMR spectra were recorded in CDCl3 on a Bruker
Avance 300 MHz spectrometer at 300 MHz and 75 MHz, respectively.
Chemical shifts (δ) are reported in parts per million (ppm) from tetra-
methylsilane (TMS) using the residual solvent resonance (CDCl3:
7.26 ppm for 1H NMR, 77.16 ppm for 13C NMR. Multiplicities are ab-
breviated as follows: s = singlet, d = doublet, t = traplet, q = quartet,
m = multiplet). IR spectra were recorded on a Nicolet iS10 Avatar FT-
IR spectrometer using KBr film. MS spectra were recorded on a LC/MSD
TOF HR- MS Spectrometer. Flash column chromatography was per-
formed with 100–200 mesh silica gel and yields refer to
Fig. 3. Cell proliferation of different AML cells (MV4-11, MOLM-14 and THP-1)
treated with compound 4h.
100

H. Huang et al.
BioorganicChemistry86(2019)97–102
Fig. 4. Compound 4h retards the tumor growth in vivo in MV4-11 xenografts nude (p < 0.05). (A) The tumor volume measurement. (B) Body weight measurement.
chromatographically and spectroscopically pure compounds.
All chemicals purchased from commercial suppliers were used as
received unless otherwise stated. Reactions and chromatography frac-
tions were monitored by Merck silica gel 60 F-254 glass TLC plates. All
solvents were reagent grade and, when necessary, were purified and
dried by standard methods.
227.0703, found: 227.0708.
2-Methylnaphtho[2,1-d]oxazole-4,5-dione (4f). m.p. 180–181 °C. 1H
NMR (300 MHz, CDCl3) δ: 8.17 (d, J = 7.5 Hz, 1H), 7.72–7.70 (m, 2H),
7.60–7.54 (m, 1H), 2.67 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 179.8,
175.1, 161.6, 139.3, 137.5, 127.3, 124.2, 123.6, 122.7, 119.8, 119.3,
11.7. IR (ν, cm−1): 3415, 2361, 1683, 1638, 1592, 1561, 1228, 1065,
1002, 839, 581. ESI-HRMS m/z [M + Na]+ calculated for C12H7NO3Na:
236.0318, found: 236.0312.
5.2. Experimental procedures
2-Ethylnaphtho[2,1-d]oxazole-4,5-dione (4g). m.p. 190–192 °C. δ:
8.09 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 3.8 Hz, 2H), 7.50–7.45 (m, 1H),
2.90 (q, J = 7.6 Hz, 2H), 1.39 (t, J = 7.6 Hz, 3H). IR (ν, cm−1): 3415,
1685, 1562, 1229, 1067, 838, 573. ESI-HRMS m/z [M + Na]+ calcu-
lated for C13H9NO3Na: 250.0475, found: 250.0470.
5.2.1. Procedure for the preparation of 4a-4h
To a solution of o-phenol substrates (3, 0.5 mmol) and Co catalyst
(0.05 mmol) were combined in 5 mL CH3CN/H2O in a Fisher-Porter
bottle. The TEA (0.05 mmol) was added to the mixture and stirred for
15 min. The bottle was flushed with oxygen three times and then
pressurized with oxygen to 50 psi and stirred at room temperature.
After the reaction finished, the mixture was poured into cooled water
(50 mL), extracted with ethyl acetate (3 × 100 mL), and washed with
brine (100 mL). The organic layer was combined, dried over sodium
sulfate, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel to provide the desired
products.
2,3,7-Trimethylfuro[2,3-f]quinoxaline-5,6-dione
(4h).
m.p.
178–179 °C. δ: 7.42 (s, 1H), 2.68 (s, 1H), 2.63 (s, 1H), 2.01 (s, 1H) IR (ν,
cm−1): 3425, 1678, 1089, 857, 773. ESI-HRMS m/z [M + H]+ calcu-
lated for C13H11N2O3: 243.0764, found: 243.0768.
5.3. Biological experiments
5.3.1. Cytotoxicity studies
Growth inhibition was determined by the MTT colorimetric assay.
Cells were plated in 96-well plates at a density of 10,000 cells /mL and
allowed to attach overnight (16 h). The plates were incubated at 37 °C
under a humidified atmosphere containing 5% CO2 for 72 h. MTT
(50 μg) was added and the cells were incubated for another 4 h.
Medium/MTT solutions were removed carefully by aspiration, the MTT
formazan crystals were dissolved in 100 μL of DMSO, and absorbance
was determined on a plate reader at 560 nm. IC50 values (concentration
at which cell survival equals 50% of control) were determined from
semilog plots of percent of control versus concentration.
5.2.2. Synthesis
3-Methylnaphtho[1,2-b]furan-4,5-dione (4a). m.p. 170–172 °C. 1H
NMR (300 MHz, CDCl3) δ: 8.09 (d, J = 7.8 Hz, 1H), 7.69–7.62 (m, 2H),
7.47 (t, J = 9.0 Hz, 1H), 2.31 (s, 3H). IR (ν, cm−1): 3134, 1672, 1590,
1539, 1020. ESI-HRMS m/z [M + Na]+ calculated for C13H8O3Na:
235.0371, found: 235.0374. HPLC purity (80% methanol in water):
tR = 8.01 min, 99.62%.
3-Ethylnaphtho[1,2-b]furan-4,5-dione (4b). m.p. 220–222 °C. 1H
NMR (300 MHz, CDCl3) δ: 8.06 (d, J = 7.5 Hz, 1H), 7.72–7.62 (m, 2H),
7.48–7.43 (m, 1H), 7.28 (s, 1H), 2.73 (q, J = 7.4 Hz, 2H), 1.26 (t,
J = 7.4 Hz, 3H). IR (ν, cm−1): 3415, 2971, 1677, 1215, 1088. ESI-
HRMS m/z [M + H]+ calculated for C14H11O3: 227.0703, found:
227.0707.
5.3.2. In vivo antitumor activity
Log-phase MV4-11 cells were harvested, washed 3 times with PBS,
followed by resuspension at a concentration of 5 × 106 per mL. A total
of 100 μL of cell suspension was injected into the flanks of athymic nude
mice (7–8 weeks). Tumor sizes were regularly measured using calipers,
and volumes were calculated using the following formula: volume
(mm3) = length × width × width/2. After the tumors had grown to
100–150 mm3, all the mice were randomized into four groups (five
mice for each group) in two independent experiments and dosed with
4h (20 mg/kg and 40 mg/kg), Sunitinib (40 mg/kg), or control. All
agents were administered daily for three weeks through tail vein in-
jection, and tumor growth was monitored and measured every day.
After three weeks, mice were euthanized and the average tumor vo-
lumes were calculated.
3,6,9-Trimethylnaphtho[1,2-b]furan-4,5-dione (4c). m.p. 203–204 °C.
1H NMR (300 MHz, CDCl3) δ: 8.09 (d, 1H, J = 7.8 Hz), 7.69–7.62 (m,
2H), 7.47 (t, 1H, J = 9.0 Hz), 2.31 (s, 3H). IR (ν, cm−1): 3416, 2360,
2342, 1670, 1507, 1242. ESI-HRMS m/z [M + H]+ calculated for
C
15H13O3: 241.0859, found: 241.0854.
3,7-Dimethylnaphtho[1,2-b]furan-4,5-dione (4d). m.p. 216–217 °C.
1H NMR (300 MHz, CDCl3) δ: 7.90 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H),
7.46 (d, J = 7.1 Hz, 1H), 7.26 (d, J = 1.3 Hz, 1H), 2.44 (s, 3H), 2.31 (d,
J = 1.2 Hz, 3H). IR (ν, cm−1): 3416, 2963, 2926, 1675, 1091, 804. ESI-
HRMS m/z [M + H]+ calculated for C14H11O3: 227.0703, found:
227.0701.
3,8-Dimethylnaphtho[1,2-b]furan-4,5-dione (4e). m.p. 192–193 °C.
1H NMR (300 MHz, CDCl3) δ: 7.96 (d, J = 8.1 Hz, 1H), 7.50 (s, 1H),
7.23 (s, 2H), 2.46 (s, 3H), 2.29 (s, 3H). IR (ν, cm−1): 3447, 2360, 2342,
1673, 1223. ESI-HRMS m/z [M + H]+ calculated for C14H11O3:
Acknowledgments
This work was supported by National Natural Science Foundation of
101

H. Huang et al.
BioorganicChemistry86(2019)97–102
China (31571901) and grants from the National Key Research and
Development Program of China (2017YFD0401301). The authors have
no other relevant affiliations or financial involvement with any orga-
nization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript apart from
those disclosed. No writing assistance was utilized in the production of
this manuscript.
susceptibility of deubiquitinases for inhibition with small molecules, Angew. Chem.
Int. Ed. 54 (2015) 599–603.
[12] X. Zhang, J. Bian, X. Li, X. Wu, Y. Dong, Q. You, 2-Substituted 3,7,8-tri-
methylnaphtho[1,2-b]furan-4,5-diones as specific L-shaped NQO1-mediated redox
modulators for the treatment of non-small cell lung cancer, Eur. J. Med. Chem. 138
(2017) 616–629.
[13] J. Bian, B. Deng, L. Xu, X. Xu, N. Wang, T. Hu, Z. Yao, J. Du, L. Yang, Y. Lei, X. Li,
H. Sun, X. Zhang, Q. You, 2-Substituted 3-methylnaphtho[1,2-b]furan-4,5-diones as
novel L-shaped ortho-quinone substrates for NAD(P)H:quinone oxidoreductase
(NQO1), Eur. J. Med. Chem. 82 (2014) 56–67.
[14] J. Bian, L. Xu, B. Deng, X. Qian, J. Fan, X. Yang, F. Liu, X. Xu, X. Guo, X. Li, H. Sun,
Q. You, X. Zhang, Synthesis and evaluation of ( )-dunnione and its orthoquinone
analogues as substrates for NAD(P)H:quinone oxidoreductase 1 (NQO1), Bioorg.
Med. Chem. Lett. 25 (2015) 1244–1248.
References
[1] A. Emadi, J.E. Karp, The state of the union on treatment of acute myeloid leukemia,
Leukemia Lymphoma 55 (2014) 2423–2425.
[15] J.L. Bian, X. Li, N. Wang, X.S. Wu, Q.D. You, X.J. Zhang, Discovery of quinone-
directed antitumor agents selectively bioactivated by NQO1 over CPR with im-
proved safety profile, Eur. J. Med. Chem. 129 (2017) 27–40.
[2] B. Oran, D.J. Weisdorf, Survival for older patients with acute myeloid leukemia: a
population-based study, Haematologica 97 (2012) 1916–1924.
[16] M. Manickam, P.R. Boggu, J. Cho, Y.J. Nam, S.J. Lee, S. Jung, Investigation of
chemical reactivity of 2-alkoxy-1,4-naphthoquinones and their anticancer activity,
Bioorg. Med. Chem. Lett. 28 (2018) 2023–2028.
[3] D.A. Arber, A. Orazi, R. Hasserjian, J. Thiele, M.J. Borowitz, M.M. Le Beau,
C.D. Bloomfield, M. Cazzola, J.W. Vardiman, The 2016 revision to the World Health
Organization classification of myeloid neoplasms and acute leukemia, Blood 127
(2016) 2391–2405.
[17] M.F. Cardoso, P.C. Rodrigues, M.E. Oliveira, I.L. Gama, I.M. da Silva, I.O. Santos,
D.R. Rocha, R.T. Pinho, V.F. Ferreira, M.C. de Souza, Fde C da Silva, F.P. Silva Jr.,
Synthesis and evaluation of the cytotoxic activity of 1,2-furanonaphthoquinones
tethered to 1,2,3–1H-triazoles in myeloid and lymphoid leukemia cell lines, Eur. J.
Med. Chem. 84 (2014) 708–717.
[4] H. Dohner, E.H. Estey, S. Amadori, F.R. Appelbaum, T. Büchner, A.K. Burnett,
H. Dombret, P. Fenaux, D. Grimwade, R.A. Larson, F. Lo-Coco, T. Naoe,
D. Niederwieser, G.J. Ossenkoppele, M.A. Sanz, J. Sierra, M.S. Tallman,
B. Lowenberg, C.D. Bloom, Diagnosis and management of acute myeloid leukemia
in adults: recommendations from an international expert panel, on behalf of the
European LeukemiaNet, Blood 115 (2010) 53–474.
[18] W. Liu, J. Zhou, G. Geng, Q. Shi, F. Sauriol, J.H. Wu, Antiandrogenic, maspin in-
duction, and antiprostate cancer activities of tanshinone IIA and its novel deriva-
tives with modification in ring A, J. Med. Chem. 55 (2012) 971–975.
[19] Y.D. Shen, Y.X. Tian, X.Z. Bu, L.Q. Gu, Natural tanshinone-like heterocyclic-fused
ortho-quinones from regioselective Diels-Alder reaction: synthesis and cytotoxicity
evaluation, Eur. J. Med. Chem. 44 (2009) 3915–3921.
[5] J.P. Patel, M. Gonen, M.E. Figueroa, et al., Prognostic relevance of integrated ge-
netic profiling in acute myeloid leukemia, N. Engl. J. Med. 366 (2012) 1079–1089.
[6] E. Papaemmanuil, M. Gerstung, L. Bullinger, V.I. Gaidzik, P. Paschka, N.D. Roberts,
N.E. Potter, M. Heuser, F. Thol, N. Bolli, G. Gundem, P. Van Loo, I. Martincorena,
P. Ganly, L. Mudie, S. McLaren, S. O'Meara, K. Raine, D.R. Jones, J.W. Teague,
A.P. Butler, M.F. Greaves, A. Ganser, K. Döhner, R.F. Schlenk, H. Döhner,
P.J. Campbell, Genomic classification and prognosis in acute myeloid leukemia, N.
Engl. J. Med. 374 (2016) 2209–2221.
[20] C. Antczak, D. Shum, B. Bassit, M.G. Frattini, Y. Li, E. de Stanchina,
D.A. Scheinberg, H. Djaballah, Identification of benzofuran-4,5-diones as novel and
selective non-hydroxamic acid, non-peptidomimetic based inhibitors of human
peptide deformylase, Bioorg. Med. Chem. Lett. 21 (2011) 4528–4532.
[21] D. Cedeno, J.J. Bozell, Catalytic oxidation of para-substituted phenols with
cobalt–Schiff base complexes/O2—selective conversion of syringyl and guaiacyl
lignin models to benzoquinones, Trtrahedron Lett. 53 (2012) 2380–2383.
[22] C. Morin, T. Besset, J.C. Moutet, M. Fayolle, M. Brückner, D. Limosin, K. Becker,
E. Davioud-Charvet, The aza-analogues of 1,4-naphthoquinones are potent sub-
strates and inhibitors of plasmodial thioredoxin and glutathione reductases and of
human erythrocyte glutathione reductase, Org. Biomol. Chem. 6 (2008)
2731–2742.
[7] P.S. Hole, R.L. Darley, A. Tonks, Do reactive oxygen species play a role in myeloid
leukemias? Blood 117 (2011) 5816–5826.
[8] B. Carter-Cooper, S. Fletcher, D. Ferraris, E. Choi, D. Kronfli, S. Dash, P. Truong,
E. Sausville, R. Lapidus, A. Emadi, Synthesis, characterization and antineoplastic
activity of bis-aziridinyl dimeric naphthoquinone – a novel class of compounds with
potent activity against acute myeloid leukemia cells, Bioorg. Med. Chem. Lett. 27
(2017) 6–10.
[9] C. Gorrini, I.S. Harris, T.W. Mak, Modulation of oxidative stress as an anticancer
strategy, Nat. Rev. Drug Discov. 12 (2013) 931–947.
[23] B. Biannic, J.J. Bozell, Efficient cobalt-catalyzed oxidative conversion of lignin
models to benzoquinones, Org. Lett. 15 (2013) 2730–2733.
[10] M.J. Solivio, D.B. Nemera, L. Sallans, E.J. Merino, Biologically relevant oxidants
cause bound proteins to readily oxidatively cross-link at Guanine, Chem. Res.
Toxicol. 25 (2012) 326.
[24] P.G. Cozzi, Metal-Salen Schiff base complexes in catalysis: practical aspects, Chem.
Soc. Rev. 33 (2004) 410–421.
[11] S. Ohayon, M. Refua, A. Hendler, A. Aharoni, A. Brik, Harnessing the oxidation
102