Synthesis, reactive oxygen species generation and copper-mediated nuclease activity profiles of 2-aryl-3-amino-1,4-naphthoquinones

Article abstract of DOI:10.1016/j.bmcl.2012.04.009

Here we report a series of 2-aryl-3-amino-1,4-naphthoquinones that generated reactive oxygen species (ROS) such as superoxide and hydrogen peroxide upon incubation in pH 7.4 under ambient aerobic conditions. ROS generation from these compounds was sensitive to structural modifications at the 3-amino position and a 2-aryl substituent promoted ROS generation. A number of these compounds were found to induce DNA damage in the presence of Cu(II) without any added reducing agent. Our data suggests that 2-aryl-3-amino-1,4-naphthoquinones' propensity to produce ROS correlated well with its DNA damage inducing ability. 2-Phenyl-3-pyrrolid-1-yl-1,4-naphthoquinone (22) was found to damage DNA at 1 μM suggesting that these compounds may have therapeutic relevance in targeting cancers which over-express Cu(II).

Full text of DOI:10.1016/j.bmcl.2012.04.009

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3766–3769
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, reactive oxygen species generation and copper-mediated
nuclease activity profiles of 2-aryl-3-amino-1,4-naphthoquinones
⇑
Vinayak S. Khodade, Allimuthu T. Dharmaraja, Harinath Chakrapani
Department of Chemistry, Indian Institute of Science Education and Research Pune, Pune 411 008, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Here we report a series of 2-aryl-3-amino-1,4-naphthoquinones that generated reactive oxygen species
(ROS) such as superoxide and hydrogen peroxide upon incubation in pH 7.4 under ambient aerobic con-
ditions. ROS generation from these compounds was sensitive to structural modifications at the 3-amino
position and a 2-aryl substituent promoted ROS generation. A number of these compounds were found to
induce DNA damage in the presence of Cu(II) without any added reducing agent. Our data suggests that
2-aryl-3-amino-1,4-naphthoquinones’ propensity to produce ROS correlated well with its DNA damage
inducing ability. 2-Phenyl-3-pyrrolid-1-yl-1,4-naphthoquinone (22) was found to damage DNA at 1 lM
suggesting that these compounds may have therapeutic relevance in targeting cancers which over-
express Cu(II)
Received 28 December 2011
Revised 16 March 2012
Accepted 3 April 2012
Available online 9 April 2012
Keywords:
Jadomycin
DNA damage
Reactive oxygen species
Superoxide
Ó 2012 Elsevier Ltd. All rights reserved.
Hydrogen peroxide
Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2),
superoxide (OÀ2 ) and hydroxyl radical (ÅOH) are generated during
immune response to combat pathogens.1–5 Together, these reactive
species cause extensive damage to biomacromolecules such as
lipids, DNA and proteins.1–5 Certain cancers have been shown to
be sensitive to the toxic effects of ROS suggesting that compounds
that generate ROS may have therapeutic potential.2,6–8 For example,
1,4-naphthoquinones such as menadione (1), juglone (2) and
plumbagin (3) are known to generate ROS through redox cycling;
menadione has shown potent anti-proliferative activity against
various cancers including breast and bladder cancers.9–14
Piperlongumine (4), a small molecule ROS generator was found
to selectively kill cancer cells and not normal cells.15 Recently, we
reported that 2,3-epoxy-1,4-naphthoquinones such as 5 were glu-
tathione-activated sources of ROS;16 compounds which were better
generators of ROS were superior inhibitors of human leukaemia
THP1 cell proliferation. Thus, development of new ROS generators
is of therapeutic interest. The jadomycins are a family of 2-aryl-3-
amino-1,4-naphthoquinone-based natural products produced by
the soil microbe Streptomyces venezuelae ISP5230 which have
anti-bacterial, anti-cancer, and anti-viral activities.17–39 Recently,
several members of the jadomycin family were reported to induce
DNA damage, a biomarker for ROS, under diverse conditions.39 For
example, 6 cleaved supercoiled plasmid DNA in the presence of
Cu(OAc)2 without the requirement of an added reducing agent27,40
and nuclease activity 6 was significantly inhibited in the presence of
scavengers of ROS suggesting the intermediacy of ROS. We pro-
posed 2-aryl-3-amino-1,4-naphthoquinones as candidates for ROS
generation; systematic modification of both the amine and the aryl
substituent could help tune ROS generating properties (Fig. 1).
O
HO
Me
O
O
O
R
O
O2N
N
X
O
O
O
1
O
O
=
; R = Me, X = H
5
R1
OH
2; R = H, X = OH
3; R = Me, X = OH
H
HO
O
O
6, Jadomycin B; R1
7, Jadomycin L; R1
CH3
CH3
N
Ar
O
X
CH3
CH3
Ar = 3,4,5-(trimethoxy)Ph
=
4, Piperlongumine
R'
N
O
R
⇑
Figure 1. Proposed 2-aryl-3-amino-1,4-naphthoquinone scaffold for ROS genera-
tors and Cu(II)-mediated DNA cleaving agents.
Corresponding author. Tel.: +91 20 2590 8090; fax: +91 20 2589 9790.
E-mail address: harinath@iiserpune.ac.in (H. Chakrapani).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.009

V. S. Khodade et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3766–3769
3767
Development of new Cu(II)-mediated DNA damaging agents is of
potential therapeutic interest as clinical studies show that several
cancers including breast cancers are associated with elevated levels
of copper in comparison with their normal counterparts.41–49 Jado-
mycin B (6) was found to inhibit proliferation of two breast ductal
carcinoma;21,37 other examples of compounds that display Cu(II)-
mediated DNA cleavage activities are prodigiosin and tambjamine
E both natural products with potent anti-tumour activity.50–53
Here, we synthesized and evaluated ROS generation and copper-
mediated nuclease activity of a series of 2-aryl-3-amino-1,4-
naphthoquinones.
2-Aryl-3-amino-1,4-naphthoquinones can be obtained in two
steps from 2-bromo-1,4-naphtoquinone (9), which in turn was
prepared from 1-naphthol (8) and N-bromosuccinimide in acetic
acid in 74% yield (Scheme 1). Pd(II)-catalyzed Suzuki coupling with
phenylboronic acid produced 10a in 90% yield (Scheme 1).54–56
Addition of ammonia to 10a produced compound 11 in 50%
yield.57 The npropylamine, nbutylamine, and N,N-dimethylamino-
ethylamine derivatives 12–14 were prepared in yields ranging
from 64% to 78% (Table 1, entries 2–4).
prepared in 25–58% yields (Table 1, entries 9–11).58 Addition of
secondary amines pyrrolidine and piperidine gave 22 and 23 in
77 and 86% yields, respectively (Table 1, entries 12 and 13).
Next, we evaluated 11–23 for their ability to generate hydrogen
peroxide using a reported xylenol orange-based colorimetric meth-
od for the estimation of hydrogen peroxide.59–62 All compounds
were found to generate H2O2 after incubation for 1 h but to varying
extents (Fig. 2). Compounds 11–21 produced <2 lM H2O2 during
1 h with no clear relationship between peroxide yield and electron
donating versus electron withdrawing substituents (Fig. 2). How-
ever, amongst the compounds tested, the pyrrolidine derivative
22 produced the highest amount of peroxide (7.6% yield) in this
time period; while the yield of H2O2 from piperidine 23 was dimin-
ished (ꢀ2%). An independent fluorescence assay using Amplex Red/
horseradish peroxidase was conducted and we found a comparable
amount of H2O2 was generated in the case of 22 (1.45 lM, 6%
yield). The formation of hydrogen peroxide was also inferred by
the use of catalase, an enzyme that catalyzes the decomposition
of hydrogen peroxide. Incubation of 22 in pH 7.4 after 1 h followed
by treatment of this reaction mixture with catalase showed com-
plete disappearance of color attributable to H2O2 in the xylenol or-
ange assay.
Having identified that a 3-pyrollidin-1-yl substituent resulted
in the most efficient H2O2 generation, we proposed to study the ef-
fect of changing the electronics around the 2-aryl ring on hydrogen
peroxide generation, compounds 10b–10d were prepared using a
reported methodology (Scheme 1). Compounds 24–26 were pre-
pared by addition of pyrrolidine to 10b–10d (Table 1, entries 14–
16). The analogue 27 was prepared by the reaction of 1,4-naphtho-
quinone and pyrrolidine in 68% yield (Table 1, entry 17). Hydrogen
peroxide yields from 24 to 26 during 1 h were comparable with
that of 22 (Fig. 2). However, yield of H2O2 was diminished in the
case of 27 suggesting that an aryl substituent was necessary for
generation of ROS (Fig. 2).
1,5-Dihydroflavins are examples of compounds that can sponta-
neously react with oxygen to generate hydrogen peroxide (Scheme
2).63–65 Molecular orbital calculations suggest that the lone pair on
the nitrogen bearing the ethyl group is of higher energy and hence
susceptible for electron transfer to oxygen to generate superoxide,
which can then further react to form hydrogen peroxide.
When 22 was incubated in pH 7.4 buffer, we found evidence for
superoxide generation using a luminol-based chemiluminescence
assay (Fig. 3);66 luminescence due to superoxide was completely
quenched in the presence of superoxide dismutase, an enzyme that
catalyzes the decomposition of superoxide. A similar assay was
conducted for selected analogues of 22; analogues that generated
higher amounts of H2O2 also produced higher amounts of superox-
ide (Fig. 3).
The allylamine and benzylamine derivatives 15 and 16 were
isolated in 60% and 80% yield, respectively (Table 1, entries 5 and
6). In order to test the effect of modulating electronics of the aryl
ring of benzylamine, compounds 17 and 18 were synthesized
(Table 1, entries 7 and 8). Next, aniline derivatives 19–21 were
O
OH
O
Ar
Br Pd(OAc)2
ArB(OH)2
NBS
HOAc
O
O
9; 74%
10a; Ar = Ph, 90%
8
10b
10c
; Ar = 2-OMePh, 82%
; Ar = 4-OMePh, 81%
10d; Ar = 4-FPh, 52%
Scheme 1. Synthesis of 9 and 10a–d.
Table 1
Synthesis of 11–27
O
O
O
Ph
R1
Ph
HN
R
+
R1
N
R
O
11-23
10a
Pyrrolidine and N-methylpyrrolidine were incubated under
similar conditions and no evidence for the generation of superox-
ide and/or hydrogen peroxide was found suggesting that the adja-
cent quinone was necessary for ROS generation. Based on these
results, we proposed the following mechanism (Scheme 3). Trans-
fer of an electron from 22 to oxygen produces the radical cation
22a with resonance forms 22b and 22c. We inferred that the
Entry
Ar
R
R1
Ha
Product
Yield
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
50
64
78
72
60
80
81
63
53
58
25
77
86
33
57
67
68
nPra
nBua
a
CH2CH2NMe2
Allyla
Bna
a
(4-OMePh)CH2
a
(4-Cl)PhCH2
9
Phb
10
11
12
13
14
15
16
17
4-OMePhb
4-NO2Phb
R1RNH = Pyrrolidinea
R1RNH = Piperidinea
R1RNH = Pyrrolidinea
R1RNH = Pyrrolidinea
R1RNH = Pyrrolidinea
R1RNH = Pyrrolidinea
Ph
2-OMePh
4-OMePh
4-FPh
H
a
Reaction was conducted in dioxane at rt.
Reaction was conducted in acetic acid and water at 90 °C.
Figure 2. Hydrogen peroxide yields of 11–27 during incubation in pH 7.4 buffer as
determined by a xylenol-orange based colorimetric assay.
b

3768
V. S. Khodade et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3766–3769
LC/MS analysis showed complete disappearance of 22 with addi-
N
N
O
O
O2
tional products with m/z of 358.05 (consistent with 22g) and
343.11 (consistent with 22h). Again, these intermediates are com-
parable with reported compounds 28b and 28a, respectively gen-
erated during decomposition of 28 (Scheme 3).63–65 Our data
suggests that ROS generation by 2-aryl-3-amino-1,4-naphthoqui-
nones was sensitive to structural modifications to the amine: a sec-
ondary amine generated higher amounts of ROS in comparison
with a primary amine. However, this observation is consistent with
reported structure-activity relationship studies of jadomycins,
which show that the identity of the substituent adjacent to the ter-
tiary amine played an important role in determining biological
activity.37
Next, we evaluated the DNA damage inducing ability of selected
compounds 12, 16, 19, 22–26 using a reported pBR322 supercoiled
plasmid DNA-based assay (see Supplementary data).27,67 None of
the compounds tested showed detectable levels of DNA damage
in the absence of Cu(II). However, in the presence of Cu(II), we
O2 + 2H+
H2O2
N
O2
N
Et
Me
N
N
O
O
N
N
O
O
N
N
N
Et
Me
N
Et
Me
28
N
N
O
N
N
O
O
O
O
N
N
N
Me
N
Et
Me
O
H
Et
O
28b
28a
found significant levels of supercoiled DNA cleavage at 25 lM
Scheme 2. Reported mechanism of superoxide and hydrogen peroxide generation
from 1,5-dihydroflavins.
(Fig. 4). The pyrrolidine-based compounds 22, 24–26 were superior
DNA cleaving agents in comparison with other compounds tested.
A concentration course of copper-mediated nuclease activity of
22 was conducted and significant DNA damage was seen at con-
centrations as low as 1
lM (lane 2, Fig. 5) and nearly all DNA
was cleaved at 10 M of 22 (lane 6, Fig. 5). Such concentrations
l
of DNA cleavage may have physiological relevance as packing of
DNA in the form of nucleosomes enhances DNA damage induced
by hydrogen peroxide and Cu(II).68,69 Nuclease activity data analy-
sis revealed that compounds generating higher amounts of ROS
were better DNA cleaving agents in the presence of copper. For
example, compounds 22, 24–26 produced higher amounts of
hydrogen peroxide (Fig. 2) in comparison with other analogues
tested and were better DNA cleaving agents (Fig. 4). Hydrogen per-
oxide in the presence of Cu(II) has been reported to induce nicks in
Figure 3. Superoxide yields during incubation of selected compounds in pH 7.4
buffer as determined by a luminol-based chemiluminescence assay.
carbon radical 22b was an important contributor as removal of a
stabilizing aryl ring (as in 27) resulted in diminution of ROS gener-
ation (Fig. 2). Modifications to the aryl ring did not significantly af-
fect ROS generation (22, 24–26, Fig. 2); this observation can be
rationalized as no significant change in the electronic absorption
amongst these pyrrolidine analogues suggesting similar conjuga-
tion of the aryl ring with the pyrrolidin-1-yl group (kmax = 490–
493 nm). LC/MS (ESI) analysis of 22 incubated in pH 7.4 for 1 h
showed the formation of a new product with an m/z of 322.14,
which corresponds to the addition of an ‘OH’ group, perhaps 22e,
which could be generated from 22d (Scheme 3). The alcohol 22e
is similar to 28a, which was previously reported as a product of
decomposition of 28 (Scheme 2).63–65 Upon incubation for 6 h,
Figure 4. Determination of nuclease activity of selected jadomycin analogues at
25
l
M in the presence of equimolar amounts of Cu(OAc)2 using pBR322 supercoiled
L total volume) contained 1:1 compound:
plasmid DNA. Reaction mixtures (20
l
Cu(II) 100 ng Form I DNA in 10 mM MOPS buffer, pH 7.4, and were incubated at
37 °C for 24 h. Lane 1, DNA only; Lane 2, 12:Cu(II); Lane 3, 16:Cu(II); Lane 4,
19:Cu(II); Lane 5, 22:Cu(II); Lane 6, 23:Cu(II); Lane 7, 24:Cu(II); Lane 8, 25:Cu(II);
Lane 9, 26:Cu(II). Nicked DNA is represented by II.
O
H
Ph
OH
Ph
O
O
O
O
Ph
O
O
O
H2O
22f
N
N
Cu-oxo
Cu(I)
N
H2O2
O
O
O2
22h
22g
22f
DNA Damage
Cu(II)
O
O
O
OH
OH
Ph
N
Ph
N
Ph
N
Ph
N
Ph
H2O
22
N
O
H
O
O
O2
+ H+
O
O2
O
O
O2 O2
22a
22c
22b
22d
22e
Scheme 3. Proposed mechanism of superoxide and hydrogen peroxide generation from 22. MS (ESI) for 22e: [M+H]+: calcd, 322.14; found, 322.22; 22g: [M+Na]+: calcd,
358.11; found, 358.05; 22h: [M+Na]+: calcd, 343.12; found, 343.10.

V. S. Khodade et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3766–3769
3769
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Figure 5. Representative gel image of supercoiled plasmid pBR322 DNA (form I)
cleavage by 22 in the presence of equimolar amounts of Cu(II): Reaction mixtures
(20
incubated at 37 °C for 24 h: Lane 1, DNA; Lane 2, 1
22:Cu(II); Lane 4, 5 M 22:Cu(II); Lane 5, 7.5 M 22:Cu(II); Lane 6, 10
Nicked DNA is represented by II.
l
L) contained 100 ng of form I DNA in 10 mM MOPS buffer, pH 7.4 and were
M 22:Cu(II); Lane 3, 2.5
M 22:Cu(II);
l
lM
l
l
l
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damage.27 However, under our assay conditions, when H2O2 was
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concentrations less than 20 lM (data not shown). Thus, like jado-
mycin B, the major pathway for DNA damage induced by 22 in-
volves electron transfer to Cu(II) to produce Cu(I), which then
reacts with oxygen to produce a copper-oxo species (Scheme 3).
In addition to this mechanism of nick induction, production of hy-
droxyl radicals by Cu(I) has also been proposed in the case of Jado-
mycin L to mediate DNA damage. From our data, it appears that the
2-aryl-3-amino-1,4-naphthoquinones’ propensity to transfer an
electron to Cu(II) to produce Cu(I), and oxygen to produce superox-
ide are closely correlated.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.04.009.
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