Novel α-ketoamide based diazeniumdiolates as hydrogen peroxide responsive nitric oxide donors with anti-lung cancer activity

Article abstract of DOI:10.1039/c9cc05266f

A novel type of hydrogen peroxide (H₂O₂)-activated diazeniumdiolate based on an α-ketoamide moietey was developed as a nitric oxide (NO) donor. KA-NO-4 inhibited lung cancer cells with submicromolar activity. The H₂O₂

Full text of DOI:10.1039/c9cc05266f

Showcasing research from Professor Jian Yin’s laboratory,
School of Biotechnology, Jiangnan University, Wuxi, China.
As featured in:
Volume 55 Number 86
7 November 2019 Pages 12883–13018
Novel α-ketoamide based diazeniumdiolates as hydrogen
peroxide responsive nitric oxide donors with anti-lung cancer
activity
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Chemical Communications
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KA-NO, a novel type of hydrogen peroxide (H O )-activated
2
2
diazeniumdiolate based on an α-ketoamide moiety was
developed as nitric oxide (NO) donors. KA-NO-4 inhibited
lung cancer cells with submicromolar activity.
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Novel a-ketoamide based diazeniumdiolates as
hydrogen peroxide responsive nitric oxide donors
with anti-lung cancer activity†
Cite this: Chem. Commun., 2019,
5, 12904
5
Received 9th July 2019,
Accepted 30th September 2019
a
b
a
ac
a
Junjie Fu, ‡ Jing Han, ‡ Tingting Meng, Jing Hu and Jian Yin*
DOI: 10.1039/c9cc05266f
rsc.li/chemcomm
2 2
A novel type of hydrogen peroxide (H O )-activated diazeniumdiolate
based on an a-ketoamide moietey was developed as a nitric oxide (NO)
donor. KA-NO-4 inhibited lung cancer cells with submicromolar
2 2
activity. The H O -responsive behaviour of KA-NO-4 was thoroughly
investigated. The NO-centered mechanism of action of KA-NO-4
was intracellularly studied.
Nitric oxide (NO), once treated simply as an atmospheric pollutant,
was revolutionarily recognized as the endothelium-derived relaxing
factor (EDRF) in 1986 and is now at the forefront of medicinal
chemistry research. The important and multifunctional roles of NO
in biological systems have provoked the rethinking of many old
compounds, such as glyceryl trinitrate and isosorbide dinitrate, as
2
Scheme 1 Reported O -masked diazeniumdiolates activated by different
stimuli (labelled under each structure) and the general mechanism to
release NO.
1
useful medications due to their ability to release NO. Diazenium-
diolates (NONOates), first reported nearly 60 years ago, have been be specifically or highly expressed in cancer cells. As a result, the
developed into promising NO-releasing molecules pioneered by liberation of highly diffusible NO can be spatially controlled. More-
2
Keefer et al. The most intriguing property of diazeniumdiolates is over, several photocaged diazeniumdiolates have been documented
2
12–15
the synthetic accessibility to modify them as O -masked pro- (Scheme 1).
drugs, which are stable but can be triggered by different stimuli the spatiotemporal control of NO release possible.
to decompose into diazeniumdiolate anions and liberate NO Hydrogen peroxide (H )-activated promoieties are hotly
Scheme 1). Numerous masking moieties responsive to different pursued in the fields of medicinal chemistry, analytical chemistry
Light-triggered activation of these prodrugs makes
2 2
O
(
2
16
stimuli can be employed to construct O -masked diazeniumdiolates, and nanomaterials. Compared with the above-mentioned stimuli
the number of which is increasing robustly. The majority of reported such as enzymes and light, there are several unique advantages of
diazeniumdiolate prodrugs are activated by endogenous enzymes utilizing H
2
O
2
as a trigger. Firstly, the levels of H
2
O
2
are signifi-
3
4
17
such as esterase, cytochrome P450 (CYP), lysyloxidase (LOX),
cantly higher in cancer cells (5–1000 mM) than in normal cells
5
6–8
18
b-galactosidase, glutathione transferase (GST), DT-diaphorase (0.001–0.7 mM). Secondly, H O is a hallmark not only in cancer,
2
2
9
10
11
(DTD), nitroreductase (NTR), b-lactamase, (Scheme 1) etc. Of but also in inflammatory diseases and cardiovascular disorders.
particular importance is that many of these enzymes are known to Therefore, H -activated prodrugs can be potentially applicable in
2 2
O
multiple pathological conditions.
The Chakrapani group initiated the synthesis of arylboronate
a
b
Key Laboratory of Carbohydrate Chemistry and Biotechnology,
Ministry of Education, School of Biotechnology, Jiangnan University,
Wuxi 214122, P. R. China. E-mail: jianyin@jiangnan.edu.cn
School of Chemistry & Materials Science, Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Jiangsu Normal University,
Xuzhou 221116, P. R. China
ester based diazeniumdiolates as H
bacteria and in cancer cells.
2
O
2
-inducible NO donors in
Until now, this remains the
only type of H O -responsive diazeniumdiolate, although other
19,20
2
2
2
O -masked diazeniumdiolates keep emerging. This is because aryl-
boronate ester is almost the sole structure, which can be used to
c
Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, P. R. China
Electronic supplementary information (ESI) available. See DOI: 10.1039/
2 2
construct a H O -responsive prodrug. Encouragingly, we recently
†
demonstrated that in addition to arylboronate ester, a-ketoamide
can be another H O -specific switch for prodrug design. Herein,
2 2
c9cc05266f
21
‡
These authors contributed equally.
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diazeniumdiolate with a broad-spectrum antitumor activity was
2
5
selected as the positive control. The four KA-NO prodrugs
exhibited potent cytotoxicity comparable or superior to that of
JS-K against cancer cell lines (Table 1). Meanwhile, com-
promised inhibitory effects were observed for all the tested
compounds in the normal cell line. What particularly
impressed us is the submicromolar IC50 value (0.88 mM) of
KA-NO-4 in lung cancer A549 cells, representing a 40-fold
selectivity when compared with its IC50 in normal cells (35.31 mM).
Three additional lung cancer cell lines were chosen to further
test the anticancer activity of KA-NO-4. Micromolar IC50 values
were observed in NCI-H446 and NCI-H209 cells (5.76 and
8.95 mM, respectively). A decent activity (14.47 mM) was mea-
sured in cisplatin-resistant lung cancer cell line A549/DDP. It is
noteworthy that compound 3, NBA and APM showed negligible
cytotoxicity in A549 cells at a concentration up to 50 mM,
strongly indicating that NO dominantly contributed to the
2 2
Scheme 2 The mechanism of H O -responsive activation of KA-NO to
release NO (top) and the synthetic route of KA-NO (bottom).
we are highly motivated to see if the a-ketoamide structure can be anticancer activity of KA-NO-4. This was further supported by the
employed to develop novel H O -inducible NO donors. This will not fact that the NO scavenger, C-PTIO diminished the cytotoxicity of
2
2
only expand the family of diazeniumdiolates, but also further testify KA-NO-4 in A549 cells (Fig. S1, ESI†).
the universality of a-ketoamide as a prodrug handle. To confirm the H O -induced activation behaviour, KA-NO-4 was
The general structure of a-ketoamide based NO donors (KA-NO) treated with excess amount of H
is shown in Scheme 2. The a-ketoamide moiety is liable to the monitored by NMR and HPLC. KA-NO-4 decomposed quickly upon
attack of H and the intermediate resulting from nucleophilic addition in an equivalent dependent manner (Fig. S2, ESI†).
addition quickly rearranges to an anhydride via the Baeyer–Villiger In accordance with the proposed mechanism in Scheme 2, the by-
2
2
2 2
O and the reaction mixture was
2
O
2
2 2
H O
22
reaction. Further hydrolysis generates an aniline, which under- products NBA and APM appeared on NMR (Fig. 1A), HPLC (Fig. S3,
23
goes a 1,6-elimination to liberate the diazeniumdiolate anion, ESI†) and mass spectra (Fig. S4, ESI†) after H O treatment. In sharp
2
2
accompanied by 4-nitrobenzoic acid (NBA) and 4-aminophenyl contrast, KA-NO-4 was very stable in PBS buffer (pH = 7.4) and bovine
methanol (APM). Finally, diazeniumdiolate anions decompose plasma in the absence of H O . More than 90% KA-NO-4 survived
2
2
quickly, although with various half-lives (Table 1), to yield NO.
even after 48 h (Fig. S5, ESI†). The nitro group within the
-initiated nucleophilic
in pyridine to give attack. Therefore, KA-NO-5 was synthesized (ESI†) as a non-nitro
-nitrophenylglyoxalic acid 1. (4-Aminophenyl)methanol was counterpart of KA-NO-4 for the following studies. MTT assays
The synthetic route to KA-NO is quite straightforward (Scheme 2). a-ketoamide fragment is requisite for H
-Nitroacetophenone was oxidized with SeO
2
2 2
O
22
4
4
coupled with acid 1 in EDCI and DIEA to afford a-ketoamide revealed that KA-NO-5 inhibited A549 cells to a much less extent
intermediates 2. After bromination of the hydroxyl group using than KA-NO-4 at the same concentration (Fig. 1C). Importantly, pre-
CBr and PPh , the active benzyl bromide derivative 3 underwent incubation of A549 cells with the H O scavenger, N-acetyl-cysteine
4
3
2 2
a SN2 nucleophilic attack by sodium diazeniumdiolates at (NAC) remarkably diminished the cytotoxicity of KA-NO-4, but not
low temperature to give the final products. Detailed synthetic KA-NO-5. As expected, KA-NO-5 was totally resistant to 10 eq. of H
procedures are shown in the ESI.† (Fig. 1D). Taken together, these results strongly supported that H
Considering the high amount of H specifically present in triggered activation was vital for the anticancer activity of KA-NO.
cancer cells, the cytotoxicity of KA-NO prodrugs was evaluated by Moreover, a group of reactive oxygen species (ROS), reactive nitrogen
measuring their IC50 values in four H -overproducing cancer cells species (RNS) and reactive sulfur species (RSS) were employed to
lines (A549, HL-60, HCT-116, and B16)
2 2
O
O -
2 2
2 2
O
2 2
O
1
7,18,24
plus one normal cell examine the H O -specific response of KA-NO-4 (Fig. 1E). It was
2
2
2
ꢀ
À
line (CCD 841 CoN). JS-K, a well-known O -2,4-dinitrophenyl found that only HO , ONOO and GSH slightly induced the
a
Table 1 IC50 values of KA-NO prodrugs on cancer and normal cells
IC50 (mM)
b
Compounds
t
1/2 (s)
A549
HL-60
HCT-116
B16
CCD 841 CoN
KA-NO-1
KA-NO-2
KA-NO-3
KA-NO-4
JS-K
o10
6.24 Æ 0.33
19.60 Æ 1.57
3.21 Æ 0.18
0.88 Æ 0.05
5.45 Æ 0.32
4.87 Æ 0.23
9.88 Æ 0.68
6.50 Æ 0.32
23.08 Æ 1.57
17.66 Æ 1.09
16.19 Æ 1.06
7.58 Æ 0.67
11.55 Æ 0.73
8.34 Æ 0.44
25.26 Æ 1.67
7.52 Æ 0.41
63.99 Æ 4.19
238.10 Æ 16.41
56.94 Æ 3.97
35.31 Æ 1.69
101.4 Æ 8.32
132 Æ 7
304 Æ 9
169 Æ 7
304 Æ 9
4.27 Æ 0.23
10.23 Æ 0.67
17.89 Æ 1.27
12.58 Æ 0.96
a
Cells were incubated with the indicated compounds at different concentrations for 72 h, and IC50 values were measured by MTT and CCK-8
b
assays. Mean Æ SD, n = 3. The half-lives of the corresponding sodium diazeniumdiolates to decompose at pH 7.4 and 25 1C to release NO were
assessed by UV spectra. Mean Æ SD, n = 3.
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Fig. 2 NO release and function from KA-NO prodrugs. (A) KA-NO pro-
drugs (50 mM) in PBS (pH 7.4, 10 mM)/MeCN (v/v, 80/20) solution were
treated with 10 eq. of H
was detected by Griess assay. Mean Æ SD, n = 3, **p o 0.01 vs. KA-NO-4.
B) A549 cells were treated with 6 mM of the indicated compounds for 8 h,
2 2
O at 37 1C for 8 h. The nitrite level in each group
(
or pretreated with NAC (20 mM) for 1 h, followed by treatment with
KA-NO-4 for 8 h. Intracellular nitrite levels were detected by Griess assay.
Mean Æ SD, n = 3, **p o 0.01 vs. KA-NO-4. (C) A549 cells were treated
with the indicated concentration of KA-NO-4 for 24 h, or pretreated with
NAC (20 mM) or C-PTIO (50 mM) for 1 h, followed by treatment with
KA-NO-4 for 24 h. The levels of 3-NT Cyt-c were detected by Western blot.
way. NAC or C-PTIO preincubation hampered intracellular NO
generation indirectly or directly, and therefore reversed the
-DMSO (550 mL) and effect of KA-NO-4 on 3-NT Cyt-c formation.
1
Fig. 1
KA-NO-4 (40 mM) degradation in a mixture of d
O (50 mL) in the presence of H (10 eq.) at 37 1C. (B) Proton assign-
2 2
H O -induced activation of KA-NO-4. (A) H NMR analysis of
6
D
2
2 2
O
The nitration of mitochondrial proteins is supposed to lead to
alteration of protein function and cell apoptosis. The apoptotic
effects of KA-NO-4 were thus studied in A549 cells. KA-NO-4 dose-
dependently induced apoptosis of A549 cells (Fig. 3A and Fig. S7,
ESI†). Pretreatment of NAC or C-PTIO led to resistance of cancer cells
to KA-NO-4 induced apoptosis. Compound 3, NBA and APM had no
apoptosis-inducing activity (Fig. S8, ESI†). Moreover, KA-NO-4
ments of KA-NO-4, NBA and APM. (C) The effects of NAC on the
cytotoxicity of KA-NO-4 and KA-NO-5 in A549 cells. Mean Æ SD, n = 3,
*
*p o 0.01 vs. KA-NO-4. (D) Decomposition of KA-NO-4 and KA-NO-5
with or without H
2 2
O (10 eq.) as measured by HPLC (254 nm). (E) Selective
response of KA-NO-4 toward H
O .
2 2
decomposition of KA-NO-4. All the other species had no effects on arrested the cell cycle of A549 cells at G2/M phase (Fig. 3B and
the activation of KA-NO-4. Fig. S9, ESI†), decreased the membrane potential of mitochondria
An extracellular Griess assay was performed to evaluate the (DC ) (Fig. 3C and Fig. S10, ESI†), induced the cleavage of Caspase
amount of NO generation. Comparable nitrite levels were detected 3 and Caspase 9, increased the expression of Bax, and lowered
from the four H -responsive prodrugs, but not KA-NO-5, after the level of Bcl-2 (Fig. 3D and Fig. S11, ESI†). All these results
treatment with H for 8 h (Fig. 2A). Interestingly, the intracellular indicated that KA-NO-4 inhibited the growth of A549 cells via a
Griess assay indicated that the highest nitrite level in A549 cells mitochondrial-dependent apoptosis-inducing pathway, which
m
2 2
O
O
2 2
was generated by KA-NO-4 treatment, followed by KA-NO-1 and was blocked by NAC or C-PTIO due to H
KA-NO-3, and KA-NO-2 yielded the least nitrite amount (Fig. 2B).
This correlates well to the IC50 values in Table 1. NAC pretreatment
diminished the intracellular NO production of KA-NO-4. Collec-
tively, we assume that the four prodrugs own similar NO release
behaviour extracellularly. However, their intracellular NO donating
ability might vary possibly due to different cell membrane perme-
ability, leading to unequal cytotoxicity. The ability of KA-NO
prodrugs to release NO in A549 cells was also investigated using
2 2
O or NO scavenge.
26
a fluorophore probe DAF-FM DA. KA-NO prodrugs generated
modest to high fluorescence in A549 cells compared with the blank
control. Moreover, KA-NO-4 induced fluorescence in a dose-
dependent manner. Either NAC or C-PTIO pretreatment attenuated
the fluorescence from KA-NO-4 (Fig. S6, ESI†).
Once released, NO is known to react with the superoxide
À
À
anion (O
of nitrating many proteins including cytochrome C (Cyt-c). The
2
) to afford peroxynitrite (ONOO ), which is capable
nitration occurs at tyrosine residues to form 3-nitrotyrosine Fig. 3 Apoptotic effects of KA-NO-4. A549 cells were treated with
compounds at indicated concentrations for 24 h, or pre-incubated with
NAC (20 mM) or C-PTIO (50 mM) for 1 h, followed by treatment with 6 mM
KA-NO-4 for 24 h. Apoptosis rates (A), cell cycle phase distributions
(
3-NT). Therefore, the induced expression of 3-NT protein can
be regarded as a unique indicator of NO generation and
function. The ability of KA-NO-4 to nitrate Cyt-c in A549 cells
was investigated by Western blot (Fig. 2C). Clearly, KA-NO-4
2
7
(
B) and DC
m
(C) were measured by flow cytometry. Mean Æ SD, n = 3,
##
*
*p o 0.01 vs. blank, p o 0.01 vs. KA-NO-4 (6 mM). (D) The expressions
increased the level of 3-NT Cyt-c in a dose- and time-dependent of apoptosis-related proteins were visualized using Western blot.
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We appreciate the generous donation of sodium diazenium-
diolates and JS-K from Professor Zhangjian Huang at China
Pharmaceutical University. This work is supported by the
National Natural Science Foundation of China (21877052,
81602960), Natural Science Foundation of Jiangsu Province
(BK20180030, BK20161028), and the Fundamental Research
Funds for the Central Universities (JUSRP51712B).
Conflicts of interest
There are no conflicts to declare.
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2 2
O
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