Synthesis of novel heme-interacting acridone derivatives to prevent free heme-mediated protein oxidation and degradation

Article abstract of DOI:10.1016/j.bmcl.2011.04.127

Heme is an important prosthetic molecule for various hemoproteins and serves important function in living aerobic organisms. But degradation of hemoprotein, for example, hemoglobin during different pathological conditions leads to the release of heme, which is very toxic as it induces oxidative stress and inflammation due to its pro-oxidant nature. Thus, synthesis of compound that will detoxify free heme by interacting with it would be fruitful for the management of heme-induced pathogenesis. Here, we report the synthesis of a novel natural product arborinine and some other acridone derivatives, which interact with free heme. These acridones in vitro block heme-mediated protein oxidation and degradation, markers for heme-induced oxidative stress.

Full text of DOI:10.1016/j.bmcl.2011.04.127

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3563–3567
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel heme-interacting acridone derivatives to prevent free
heme-mediated protein oxidation and degradation
a
b
a
c,
⇑
Chinmay Pal , Milan Kumar Kundu , Uday Bandyopadhyay , Susanta Adhikari
a
Department of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
Department of Chemistry, University of Burdwan, Golapbag, Burdwan 713104, West Bengal, India
Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700 009, West Bengal, India
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Heme is an important prosthetic molecule for various hemoproteins and serves important function in liv-
ing aerobic organisms. But degradation of hemoprotein, for example, hemoglobin during different path-
ological conditions leads to the release of heme, which is very toxic as it induces oxidative stress and
inflammation due to its pro-oxidant nature. Thus, synthesis of compound that will detoxify free heme
by interacting with it would be fruitful for the management of heme-induced pathogenesis. Here, we
report the synthesis of a novel natural product arborinine and some other acridone derivatives, which
interact with free heme. These acridones in vitro block heme-mediated protein oxidation and degrada-
tion, markers for heme-induced oxidative stress.
Received 22 February 2011
Revised 12 April 2011
Accepted 27 April 2011
Available online 3 May 2011
Keywords:
Arborinine
Acridones
Synthesis
Ó 2011 Elsevier Ltd. All rights reserved.
Heme-binding
Protein oxidation
Oxidative stress
Heme is an important molecule for living aerobic organisms
which plays an essential role in drug detoxification, oxygen trans-
port, respiration, and signal transduction. It interacts with various
inactive apo-proteins giving rise to functional hemoproteins. In
hemoglobin and myoglobin, heme plays an important role in stor-
age and transport of oxygen whereas in cytochromes, it is involved
in energy generation, electron transport, and chemical transforma-
stimulating potassium loss and swelling hemin causes substantial
hemolysis. It impairs the erythrocytes ability to maintain cation
gradients and also induces hemolysis by a colloid–osmotic mecha-
1
1
2
nism. The hemolytic process induced by heme has at least two
phases. In the first phase, there is a massive loss of potassium,
which precedes the depletion of glutathione and ATP. In second
1
2
phase, massive loss of hemoglobin occurs. The aim of the work
tion. In catalases, heme functions in H
2 2
O degradation and in per-
oxidases, it serves different biological functions in presence of
2
–7
2
2
H O
2
.
Although heme is an important molecule in human, free
heme is responsible for oxidative stress, hemolysis and inflamma-
2
tion. Free heme offers toxic effects to tissues and organs through
oxidative stress by generating reactive oxygen species (ROS) and
redox-active iron of heme plays the central role for heme toxicity.
ROS damages lipid, protein, and DNA. Heme affects the function of
kidneys, neurones, cardiac cells, hepatocytes, and peripheral leuko-
cytes. Hemin in the aqueous phase frequently aggregates in the
membrane and promotes oxidation, which leads to the enhance-
ment of permeability and membrane disorder. Oxidation of mem-
brane components may promote cell lysis and death.8,9 Free heme
induces the conversion of low-density lipoprotein to cytotoxic oxi-
1
0
dized products. By oxidizing low- and high-density lipoproteins
hemin forms conjugated dienes, thiobarbituric acid reacting sub-
stances and F2-isoprostanes.11 By affecting red cell membrane,
⇑
Corresponding author. Tel.: +91 33 23509937; fax: +91 33 23519755.
E-mail address: adhikarisusanta@yahoo.com (S. Adhikari).
Scheme 1a. Chemical synthesis of 1,2,3-trimethoxy-10-methylacridin-9 (10H)-one
(4) by Hughes et al.
0
960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.127

3
564
C. Pal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3563–3567
Scheme 1b. Chemical synthesis of arborinine (1).
is to synthesize novel acridone derivatives that interact with heme
for the treatment of heme-induced oxidative stress as well as path-
ogenesis. Recent studies have shown that acridone scaffold can
interact with heme. Therefore, synthesis of novel acridone deriv-
atives will be beneficial for heme-induced oxidative stress if they
interact with heme. In this work, total synthesis of arborinine (1)
and some acridone derivatives are described and their heme-bind-
ing abilities and thereby binding constants are evaluated. These
molecules can prevent also heme-induced oxidative stress by pro-
tecting protein from heme-induced oxidative damage.
Acridone alkaloids which have been isolated from various plant
sources are known to possess wide varieties of biological activities
including anticancer, antimicrobial, antiviral and antiparasitic
1
3
14
properties. Arborinine, (1-hydroxy-2,3-dimethoxy-10-methylac-
ridin-9(10H)-one) (1), a well known acridone alkaloid, has been
isolated from plants that belongs to the Rutaceae family has several
1
5–17
biological effects.
Literature survey reveals that 1,2,3-trimeth-
oxy-10-methylacridin-9(10H)-one (4) as reported in Scheme 1b
1
8,19
was synthesized by Hughes et al.
from 2-(3,4,5-trimethoxy-
phenylamino) benzoic acid (2) in 15% yield only ( Scheme 1a).
Table 1
Structure and % of yields of the synthesized acridones
Substrate
Intermediate
Product
Yields (%)
Time (mins)
30
8
7
5
4
45
60
68
7
8
6
6
0
5
35
55
50
29 (over all)
Reactions were performed at 80 °C for 30 min-1 h using Eaton’s reagent as cyclizing agent. Yields refer to the purified products characterized by difference spectroscopic
method and binding constants were calculated from nonlinear curve-fitting methods.

C. Pal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3563–3567
3565
sodium methoxide in dry methanol. When 1,2,3-trimethoxy-9-
methoxyacridine was heated in a sealed tube with methyl iodide
at 100 °C for 4 h, it isomerised to 1,2,3-trimethoxy-10-methylacri-
din-9(10H)-one (4). The harsh reaction conditions have made the
synthesis and isolation of pure product difficult. Therefore, it is in-
deed necessary to develop an efficient and high yielding methodol-
ogy for the synthesis of arborinine for extensive biochemical
studies.
In this work we have synthesized arborinine (1) and some other
1
4,20,22
acridone derivatives using Eaton’s reagent,
2 5
a mixture of P O
and CH SO H, to promote effectively the key cyclization of anthra-
3
3
nilic acid derivatives in high yields. The synthetic method is very
mild, efficient and scalable. Heme binding abilities and binding
constants of arborinine and other substituted acridones containing
2 2
electron withdrawing (–CO H, –NO ) groups as well as electron
Scheme 2. Chemical synthesis of acridones (2a–e).
donating substituents (–OMe, –Cl) were also investigated in order
to understand the effect of substituent in the present study. These
compounds can protect heme-induced oxidative stress by prevent-
ing heme-mediated protein oxidation (carbonyl formation) and
degradation.
The methodology involved thermal cyclization of 2 to 1,2,3-tri-
methoxy-9-chloroacridine under harsh condition at 135–145 °C
with phosphorous oxychloride. The chloroacridine was converted
into 1,2,3-trimethoxy-9-methoxyacridine by refluxing with
Figure 1. shows interaction of arborinine and acridones with heme. Optical soret spectroscopy for arborinine–hemin (A) and acridone–hemin (B–F) interaction at different
concentration of acridones (5–40 M) (i, 5 M; f, 40 M)
l
l
l

3
566
C. Pal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3563–3567
Table 2
Heme binding constant and IC50
synthesized acridones (1, 2a–e)
(lM) for inhibiting protein carbonyl formation of the
Compound Heme-binding constant
(M-1) M ± SEM
IC50 (lM) for inhibiting protein
carbonyl formation M ± SEM
K
a
*
4
4
4
4
*
1
2
2
2
2
2
(3.9 ± 0.12 ) Â 10
42 ± 2.2
*
*
a
b
c
d
e
(2.4 ± 0.09 ) Â 10
55 ± 3.7
*
*
(2.7 ± 0.08 ) Â 10
44 ± 2.9
*
*
(3.8 ± 0.15 ) Â 10
43 ± 2.3
4
(4.6 ± 0.17) Â 10
36 ± 1.8
41 ± 2.1
*
4
*
(4.3 ± 0.16 ) Â 10
Values are the means ± SEM of at least three experiments.
*
P < 0.05 versus 2d.
The chemical synthesis of arborinine (1) is outlined in Scheme
1
3
K
b. Ullmann condensation between 2-chlorobenzoic acid and
,4,5-trimethoxyaniline in presence of Cu powder, Cu
2
O and
2
1
2
CO in diglyme, under reflux for 5 h, provided the 2-(3,4,5-tri-
3
methoxyphenylamino) benzoic acid (2) in 64% yield. However, the
similar condensation between anthranilic acid and 5-iodo-1,2,3-
Figure 2. Protective effect of acridones (1, 2a–e) on heme-mediated protein
oxidation (carbonyl formation). The details of the methodology were described
trimethoxybenzene resulted only 38% yield. Compound 2 was trea-
2 2
under ‘Materials and methods’. ### = P <0.001 versus BSA + heme + H O system.
ted with Eaton’s reagent1
3,22
at 80 °C for 50 min to afford the cy-
clized product 1,2,3-trimethoxyacridin-9(10H)-one (3) in 65%
yield. It is important to mention here that when similar cycloacy-
lation reaction was carried out in presence of polyphosphoric acid
(
PPA) as reported by others,23 compound 3 was obtained in 15%
yield only. Moreover, high viscous nature of PPA makes reaction
difficult to handle for large scale operations. An alternative route
for acridones based on 1,4-dipolar cycloaddition of N-lithiated
ethyl anthranilates, which function as 1, 4 dipole equivalents with
arynes is also reported.24 However, the method involves initial
generation of anion in presence of strong base, LDA at À78 °C fol-
lowed by addition of haloarenes into the reaction mixture at
–
40 °C. Treatment of compound 3 with sodium hydride in pres-
ence of methyl iodide provided compound 4, which on selective
Figure 3. Protective effect of acridones on heme-mediated protein degradation.
Lane 1; control protein, Lane 2; Heme- mediated protein degradation, Lane 3,4,5;
acrridones (1, 2e, 2d) recover the heme- mediated protein degradation. The details
of the methodology were described under ‘Materials and methods’.
2
1,23
de methylation
in presence of ethanolic hydrochloric acid pro-
vided arborinine (1) in 80% yield after silica gel column chromatog-
raphy. The presence of the l-OH group, which forms an
intramolecular hydrogen bond with the peri-carbonyl function,
1
was detected in its H NMR spectrum at d 14.69. The spectral data
is in accord with that reported in literature.16 Eaton’s cycloacyla-
tion reactions were extended to various substituted acridones
We check whether acridones can prevent the heme-mediated
protein oxidation (carbonyl formation) and degradation using
2
5–29
31
(2a–e)
in order to explore the effect of various substituents
2 2
standard protein BSA. Heme in presence of H O produced exten-
as depicted in Scheme 2 and we have found that it is an excellent
method and the reaction is complete within 30 min to 1 h with 68–
sive protein carbonyl (measured by absorbance at 362 nm in pres-
ence of DNPH) in BSA as a result of oxidative modification (Fig. 2).
However, in presence of arborinine (1) and acridone (2a–e) the
protein carbonyl formation decreases significantly. Among all the
8
5% yield (Table 1). The regioselectivity and spectral data of com-
2
8,29
pounds 2d and 2e are in accord with that reported in literature.
The interaction of acridones (2a–e, 1) with heme was deter-
mined at pH 7.4. A solution of heme at pH 7.4 showed a broad peak
derivatives, compounds
36 ± 1.8 M), and 2e (IC50 41 ± 2.1
activity (Fig. 2 and Table 2). To further demonstrate protective ef-
fect of 1, 2d, 2e against heme–H system, oxidative protein deg-
radation was followed in presence or absence of 1, 2d, 2e. In
presence of heme and H , BSA was damaged as evident from de-
1
(IC50 42 ± 2.2
lM), 2d (IC50
l
lM), shows greater protecting
at 362 nm that indicates dimers of the l-oxo type or the l-hematin
30
type predominate under our in vitro conditions. The addition of
acridones clearly perturbed the heme spectrum (Fig. 1), a finding
indicative of an interaction between the acridones and the heme.
2 2
O
2 2
O
Titration with increasing concentration of acridones (5–40
l
M)
creased band intensity in sodium dodecyl sulfate polyacrylamide
gel electrophoresis (SDS–PAGE) as shown in Figure 3. But in pres-
ence of compounds 1, 2d and 2e the protein band remains intact
(Fig. 3). It is of worth mentioning that these compounds did not
into the heme solution produced spectra with reduction in the
heme Soret molar absorptivity and a shift of the Soret band to long-
er wavelengths. The binding of acridones to heme was measured
by optical spectroscopy ( Fig. 1) and the apparent K
the binding of acridones to heme were calculated from the plot
of 1/ 362 against 1/[acridones] (Table 2 and Fig. 1 in the Supple-
a
values for
2 2
interact with H O (data not shown). From these experiments we
can conclude that acridones (1, 2a–e) can suppress or nullify the
D
A
pro-oxidant activity of heme. General method for synthesis and
3
2,33
mentary data). From the heme binding study of abrorinine and
other acridone derivatives (Fig. 1 and Table 1) it is evident that
haloacridone, 2d shows the highest heme binding capacity
biological evaluation of arborinine (1)
e)
data.
and acridones (2a–
3
2,33
and their spectral data are described in the Supplementary
4
À1
[K
a
= (4.6 ± 0.17) Â 10 M ] (Table 2). Acridone having an electron
In summary, we reported here an efficient and practical strategy
for the synthesis of arborinine and other acridone derivatives. We
have measured their heme-binding affinities and calculated
withdrawing group (–COOH) showed heme-binding ability, almost
equal to the haloacridone (Table 2).

C. Pal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3563–3567
3567
binding constants of heme-acridones as well as heme-arborinine
complex and these compounds attenuates heme-mediated protein
oxidation (carbonyl formation) and degradation, markers for
heme-induced oxidative stress. Thus, these molecules will be fruit-
ful in heme-induced oxidative stress as well as heme-induced
pathology.
26. Stankiewicz-Drogon, A.; Palchykovska, L. G.; Kostina, V. G.; Alexeeva, I. V.;
Shved, A. D.; Boguszewska-Chachulska, A. M. Bioorg. Med. Chem. 2008, 16,
8846.
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2
2
7. He, Z.; Bu, X.; Eleftheriou, A.; Zihlif, M.; Qing, Z.; Stewart, B. W.; Wakelin, L. P.
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0. Brown, S. B.; Shillcock, M.; Jones, P. Biochem. J. 1976, 153, 279.
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Acknowledgments
We thank Council of Scientific and Industrial Research (CSIR),
New Delhi, for providing grants through Suprainstitutional Project
32. Experimental section: General procedure for Ullmann condensation.
Method A: To a magnetically stirred solution of aromatic amine (containing
electron donating group) (1 equiv, 12.9 mmol) and 2-chlorobenzoic acid
(
SIP 0007) and offering Research fellowship to C.P. M.K.K. thank-
(
2
1 equiv, 12.9 mmol) in diglyme was added powdered Cu (catalytic), Cu O
fully acknowledges University of Burdwan for providing fellowship
to carry out the work.
(catalytic) and K CO3 (1.2 equiv, 15.4 mmol) successively. The reaction mixture
was heated under reflux (5 h) until completion of reaction as indicated by TLC.
2
The solvent was removed by distillation in vacuo, and the crude mass was
triturated with 1% aqueous NaOH solution. The whole mixture was filtered off
and the alkaline solution was washed with ether. The ether layer was
separated, and the aqueous layer was acidified with 6N HCl, and then
extracted with chloroform. The combined organic extracts was washed with
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.04.127.
brine, dried (Na
was purified using silica gel column chromatography to provide the pure
compound. Method B: mixture of aromatic amine (containing electron
withdrawing group) (1 equiv, 12.9 mmol), 2-chlorobenzoicacid (1 equiv,
2.9 mmol), CO (1.2 equiv, 15.4 mmol), powdered Cu (catalytic), in
isopentyl alcohol was heated under reflux for 4–5 h. After which 1 M K CO
2 4
SO ), evaporated to dryness in vacuo and the crude residue
A
References and notes
1
K
2
3
2
3
1.
2.
3.
4.
Ponka, P. Am. J. Med. Sci. 1999, 318, 241.
was added to this solution and filtered to remove the insoluble particles. Then
the aqueous layer was acidified with 2 M HCl, extracted with chloroform and
dried over Na SO . The solvent was removed under vacuo and the crude
Kumar, S.; Bandyopadhyay, U. Toxicol. Lett. 2005, 157, 175.
Bandyopadhyay, U.; Biswas, K.; Banerjee, R. K. Toxicol. Lett. 2002, 128, 117.
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Biochem. J. 1992, 284, 305.
2
4
residue was chromatographed over a silica gel column to give the pure
compound.
General procedure for cyclization.
5
.
.
Bandyopadhyay, U.; Bhattacharyya, D. K.; Chatterjee, R.; Banerjee, R. K.
Biochem. J. 1995, 306, 751.
Bandyopadhyay, U.; Chatterjee, R.; Chakraborty, T. K.; Ganguly, C. K.;
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To an oven dried round bottom flask equipped with magnetic stirrer, reflux
condenser, CaCl2 guard tube, diarylamine 2-carboxylic acid (6.92 mmol) was
taken. Eaton’s reagent (P O –CH SO H) (8 mL) was added and the reaction
6
2
5
3
3
7
8
.
.
mixture was heated at 80-100 °C for 30 min-1 h until completion of reaction as
indicated by TLC. The reaction mixture was allowed to come to room
temperature and added slowly to the saturated aqueous NaHCO3 solution.
9
6.
9
.
Vincent, S. H. Semin. Hematol. 1989, 26, 105.
Then, the solution was extracted with chloroform, dried over Na SO4 and
2
1
0. Jeney, V.; Balla, J.; Yachie, A.; Varga, Z.; Vercellotti, G. M.; Eaton, J. W.; Balla, G.
Blood 2002, 100, 879.
evaporated to dryness under vacuo. The crude residue was purified by silica gel
column chromatography to afford the pure product.
1
1. Camejo, G.; Halberg, C.; Manschik-Lundin, A.; Hurt-Camejo, E.; Rosengren, B.;
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33. Spectral data for some key compound: 2-(3,4,5-Trimethoxyphenylamino)
benzoic acid (2): R : 0.41 (7.5% MeOH in CHCl ); mp: 125–127 °C; IR (neat)
f
3
1
1
1
mmax 3410.26, 1680.05, 1506.46, 1452.45, 1230.63, 1128.39; H NMR (600 MHz,
CDCl ) d 3.85 (s, 6H), 3.86 (s, 3H), 6.51 (s, 2H), 6.75 (ddd, 1H, J1 = 7.2 Hz,
3
J2 = 7.2 Hz, J3 = 1.2 Hz), 7.17 (dd, 1H, J1 = 8.4 Hz, J2 = 0.6 Hz), 7.36 (ddd, 1H,
J1 = 7.2 Hz, J = 7.2 Hz, J3 = 1.8 Hz), 8.04 (dd, 1H, J1 = 8.4 Hz, J2 = 1.8 Hz), 9.21 (b
2
13
1
1
1
1
4. Winter, R. W.; Kelly, J. X.; Smilkstein, M. J.; Dodean, R.; Bagby, G. C.; Rathbun, R.
K.; Levin, J. I.; Hinrichs, D.; Riscoe, M. K. Exp. Parasitol. 2006, 114, 47.
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Tetrahedron 1961, 16, 251.
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s, 1H); C NMR (150 MHz, CDCl ) d 56.15 (2C), 61.02, 101.42 (2C), 110.08,
3
114.15, 116.96, 132.54, 135.05, 135.26, 136.15, 149.40, 153.79 (2C), 173.41;
+
HRMS (ESI) m/z (M+Na) calcd for C16H17NO Na: 326.1004, found: 303.1005.
5
Arborinine (1): R : 0.49 (3% MeOH in CHCl ); mp: 168–170 °C; IR (neat) mmax
f
3
1
3448.49, 2931.60, 1641.31, 1591.16, 1556.45,1253.64; H NMR (600 MHz,
CDCl ) d 3.78 (s, 3H), 3.86 (s, 3H), 3.95 (s, 3H), 6.22 (s, 1H), 7.23 (t, 1H,
3
J = 7.2 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.66 (ddd, 1H, J1 = 7.2 Hz, J21= 7.2 Hz,
3
J3 = 1.2 Hz), 8.39 (dd, 1H, J1 = 8.4 Hz, J2 = 1.2 Hz), 14.69 (s, 1H); C NMR
1
1
2
8. Hughes, G. K.; Ritchie, E. Aust. J. Sci. Res. 1951, A4, 430.
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(150 MHz, CDCl ) d 34.14, 56.00, 60.82, 86.68, 105.82, 114.56, 120.78, 121.52,
3
126.67, 130.17, 133.97, 140.56, 142.02, 156.22, 159.32, 180.85; HRMS (ESI) m/z
+
(M+Na) calcd for C16H15NO Na: 308.0899, found: 308.0897. Acridin-9(10H)-
4
7
2, 4276.
1. Su, T. L.; Kohler, B.; Chou, T. C.; Chun, M. W.; Watanabe, K. A. J. Med. Chem.
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one (2a) R : 0.41 (7.5% MeOH in CHCl ); IR (neat) mmax, 2993.78, 1636.45,
f
3
1
2
1559.42, 1473.73; H NMR (300 MHz, DMSO-d ) d 7.25 (t, 2H, J = 6.9 Hz), 7.54
6
1
(d, 2H, J = 7.8 Hz), 7.71 (d, 2H, J = 6.9 Hz), 8.23 (d, 2H, J = 7.8 Hz), 11.74 (s, 1H);
13
2
2
2
2
2. Eaton, P. E. C. G. R.; Lee, J. T. J. Org. Chem. 1973, 38, 4071.
6
C NMR (75 MHz, DMSO-d ) d 117.35 (2C), 120.50 (2C), 121.01 (2C), 126.03
3. Su, T. L.; Dziewiszek, K.; Wu, T. S. Tetrahedron Lett. 1991, 32, 1541.
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(2C), 133.46 (2C), 140.90 (2C), 176.80; MS (ESI) m/z calcd for C13H NO: 195.07;
9
+
found: 218.06 [M+Na]