Synthesis of two phloroglucinol derivatives with cinnamyl moieties as inhibitors of the carbonic anhydrase isozymes I and II: an in vitro study

Article abstract of DOI:10.1080/14756366.2016.1181626

Two cinnamyl-substituted phloroglucinols, 4-p-methoxycinnamyl phloroglucinol (9) and 4,6-bis-p-methoxycinnamyl phloroglucinol (10) were synthesized. Two carbonic anhydrases, human carbonic anhydrase I and II (hCA I and II), were purified. Kinetic interact

Full text of DOI:10.1080/14756366.2016.1181626

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Synthesis of two phloroglucinol derivatives with
cinnamyl moieties as inhibitors of the carbonic
anhydrase isozymes I and II: an in vitro study
Serdar Burmaoğlu, Esra Dilek, Ali Osman Yılmaz & Claudiu T. Supuran
To cite this article: Serdar Burmaoğlu, Esra Dilek, Ali Osman Yılmaz & Claudiu T. Supuran
(2016): Synthesis of two phloroglucinol derivatives with cinnamyl moieties as inhibitors of
the carbonic anhydrase isozymes I and II: an in vitro study, Journal of Enzyme Inhibition and
Medicinal Chemistry, DOI: 10.1080/14756366.2016.1181626
To link to this article: http://dx.doi.org/10.1080/14756366.2016.1181626
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SHORT COMMUNICATION
Synthesis of two phloroglucinol derivatives with cinnamyl moieties as
inhibitors of the carbonic anhydrase isozymes I and II: an in vitro study
Serdar Burmaoglu1,2, Esra Dilek3, Ali Osman Yılmaz2, and Claudiu T. Supuran4
˘
2
1Tercan Vocational High School, Erzincan University, Tercan-Erzincan, Turkey, Department of Biochemistry, Faculty of Pharmacy, Erzincan
3
4
University, Erzincan, Turkey, Department of Chemistry, Faculty of Science, Atatu¨rk University, Erzurum, Turkey, and Neurofarba Department,
Section of Pharmaceutical and Nutriceutical Sciences, Universita degli Studi di Firenze, Sesto Fiorentino, Florence, Italy
Abstract
Keywords
Two cinnamyl-substituted phloroglucinols, 4-p-methoxycinnamyl phloroglucinol (9) and
4,6-bis-p-methoxycinnamyl phloroglucinol (10) were synthesized. Two carbonic anhydrases,
human carbonic anhydrase I and II (hCA I and II), were purified. Kinetic interactions between
these isozymes with 9 and 10 were investigated. These new compounds exhibited inhibitory
effects on the hCA I and II enzymes’ activity in vitro. The combination of the inhibitory effects of
both phloroglucinol and p-coumaric acid groups in a single compound was explored. However,
relative to the inhibitory effects of the two groups separately, compounds 9 and 10
demonstrated comparable inhibitory effects. More effective inhibitors of CAs could be created
by testing these compounds on other CA isozymes.
Enzyme inhibition, human CAI, human CAII,
phloroglucinol, synthesis
History
Received 28 March 2016
Revised 18 April 2016
Accepted 19 April 2016
Published online 10 May 2016
Introduction
p-Hydroxybenzoic acid (4) and its derivatives (5–8) are also
molecules derived from phenol. These compounds have attracted
the attention of many scientists due to their promising biological
features, especially their potent antioxidant properties (Figure 1),
which have been the subject of many studies. These compounds
have OH and OMe groups in the ortho and para positions on their
aromatic rings and have been reported to show strong antioxidant
Natural products have long been used as medicinal and disease-
preventing molecules. Now, in modern medicinal chemistry,
natural products and their derivatives are an increasing resource
for early drug discovery1. This has resulted in a surge in the
number of studies that identify active compounds from natural
plant sources and investigate their properties.
activity3,5,6
.
Natural phenolic compounds have a significant role in the
pharmaceutical industry. Their structures include one or more
hydroxyl group attached to their aromatic ring. The number of
hydroxyl groups and their position on the aromatic ring are
important. These compounds exhibit pharmacological antioxi-
dant, antiproliferative, anti-inflammatory and anticancer
properties2.
Phenol (1) and phenolic compounds (2–3) are widely used in
the health sector for creating prodrugs and drugs3. Phloroglucinol
(3) is a phenolic compound with three hydroxyl groups attached to
its aromatic ring (Figure 1). Due to its biological properties,
phloroglucinol (3) is used in medicine, cosmetics, paints, and
pesticides4.
Thus far, no negative effects have been reported for
phloroglucinol (3). On the contrary, based on its catalase
activation properties, phloroglucinol (3) has been reported to
exhibit protective activity against oxidative stress resulting from
H2O2 in cells. They also show protective effects against cell injury
caused by the oxidative stress resulting from gamma radiation4.
Carbonic anhydrases (CAs; carbonate hydrolyases, EC 4.2.1.1)
are a family of metalloenzymes with 16 isoforms in mammals.
Their most important function is catalyzing the reversible
hydration of carbon dioxide in a two-step reaction to yield
bicarbonate and protons. CAs are a well-characterized type of pH
regulatory enzyme found in most tissues including erythrocytes7,8
.
Many such CA isozymes have these functions show effect with
the potency to be inhibited/activated for the treatment of disease
such as glaucoma, edema, obesity, osteoporosis, epilepsy and
cancer8–10
.
Recent studies have investigated the interaction between CA I
and II isozymes and various derivatives of phenols; benzenes with
different substituents; and bisphenols with antioxidant properties
and their various derivatives, and salicylic acid derivatives11–14
.
Various natural and unnatural phenolic compounds have been
reported to have anticancer, anticarcinogenic, antibacterial,
antimutagenic, antiviral properties and anti-inflammatory
activitiy11–15
.
Methods
Chemical synthesis
˘
Address for correspondence: Serdar Burmaoglu, Tercan Vocational High
Commercially available reagents and solvents were of analytical
grade or were purified by standard procedures prior to use.
Reactions were monitored via thin-layer chromatography (TLC).
School, Erzincan University, 24800, Tercan-Erzincan, Turkey. Tel: +90-
446-441-3627. Fax: +90-446-441-3672. E-mail: sburmaoglu@
erzincan.edu.tr

˘
S. Burmaoglu et al.
2
J Enzyme Inhib Med Chem, Early Online: 1–5
Figure 1. Chemical structures of phenolic compounds and synthesized compounds.
The 1H NMR and 13C NMR spectra were recorded on a 400 (100) 4-p-Methoxycinnamyl phloroglucinol (9)
MHz Varian spectrometer using CDCl3 and Acetone-d6. Column
To a suspension of NaH (35 mg, 0,87 mmol) in dry THF (4 mL),
chromatography was performed on silica gel 60 (70–230 mesh
ASTM), and TLC was carried out on silica gel (254–366 mesh
ASTM). Melting points were determined on a capillary melting
apparatus (Buchi 530) and are uncorrected. Infrared (IR) spectra
were obtained from solutions in 0.1-mm cells with a Perkin-Elmer
spectrophotometer (Waltham, MA). Elemental analyzes were
performed on a Leco CHNS-932 apparatus.
phloroglucinol (3) (100 mg, 0,79 mmol) was added under N2 atm.
After 5 min, a solution of 13 (179 mg, 0,79 mmol) in dry THF
(4 mL) was added to the mixture. The reaction was stirred until
complete by TLC analysis (17 h). The reaction was quenched
NH4Cl (10 mL) and then the mixture was neutralized with 2 M
HCl until pH 1–2. The reaction mixture was extracted with EtAOc
(3 ꢁ 30 mL). The organic phase was dried with Na2SO4 and the
solvent was evaporated under reduced pressure. The crude
product was purified by silica gel chromatography using
p-Methoxycinnamyl alcohol (12)
To
a
solution of 4-methoxy-cinnamaldehyde (11) (5 g, EtOAc/Hexane as eluent (5%) to yield 4-p-methoxycinnamyl
30.8 mmol) in EtOH (60 mL) at 0 ꢀC was added sodium phloroglucinol (9) as a cream solid (95 mg, 16%). Melting point:
borohydride (1.2 g, 30.8 mmol) in one portion. The resulting 183–184 ꢀC. Rf ¼ 0.083 (% 60 EtOAc/Hexanes). 1H NMR
mixture was stirred at rt for 30 min, then it was cooled again to (400 MHz, Aseton-d6) d 7.97 (bs, 1H), 7.85 (bs, 1H), 7.27–7.24
0 ꢀC and acetone (20 mL) was added. After stirring for 10 min, (m, 2H), 6.84–6.81 (m, 2H), 6.34 (d, J ¼ 16 Hz, 1H), 6.27–6.20
sat. aqueous ammonium chloride and water were added and the (m, 1H), 5.98 (s, 2H), 3.75 (s, 3H), 3.44 (d, J ¼ 5.2 Hz, 2H). 13C
mixture was extracted with EtOAc (3x60 ml). The combined NMR (100 MHz, Aseton-d6) d 158.9, 156.9, 156.8, 134.5, 131.2,
organic phases were dried over Na2SO4 and the solvent was 128.5, 127.6, 127.0, 114.0, 94.8, 54.7, 26.2. Anal. Calculated
removed under reduced pressure to the title alcohol (4 g, for (C16H16O4): C, 70.57; H, 5.92; O, 23.50; Found C, 70.52,
1
98%) as yellow solid. Rf: (0.16 20% EtOAc-Hexanes). H NMR O, 6.136.
(400 MHz, CDCl3)
d
7.33 (d, J ¼ 8.6 Hz, 2H), 6.86
(d, J ¼ 8.6 Hz, 2H), 6.56 (d, J ¼ 15.8 Hz, 1H), 6.24 (dt, 4,6-Bis-p-methoxycinnamyl phloroglucinol (10)
J ¼ 15.8, 5.9 Hz, 1H), 4.30 (t, J ¼ 5.8 Hz, 2H), 3.81 (s, 3H).
To a suspension of NaH (35 mg, 0,87 mmol) in dry THF (4 mL),
The 1H NMR spectrum are in agreement with reported data by
West et al.16
phloroglucinol (3) (100 mg, 0.79 mmol) was added under N2 atm.
After 5 min, a solution of 13 (179 mg, 0.79 mmol) in dry THF was
added to the mixture. The reaction was stirred until complete by
TLC analysis (17 h). The reaction was quenched NH4Cl (10 mL)
p-Methoxycinnamyl bromide (13)
To a stirred solution of 12 (483 mg, 2.94 mmol) in Et2O (35 mL), and then the mixture was neutralized with 2 M HCl until pH 1–2.
PBr3 (0.14 mL, 1.47 mmol) was added at 0 ꢀC. The reaction was The reaction mixture was extracted with EtAOc (3 ꢁ 30 mL). The
stirred until complete by TLC analysis (30–45 min). The mixture organic phase was dried with Na2SO4 and the solvent was
was quenched with a saturated NaCl (40 mL) solution and evaporated under reduced pressure. The crude product was
extracted with Et2O (2 ꢁ 30 mL). The organic phase was dried purified by silica gel chromatography using EtOAc/Hexane as
with Na2SO4 and the solvent was evaporated under reduced eluent (5%) to yield 4,6-bis-p-methoxycinnamyl phloroglucinol
pressure to yield p-methoxycinnamyl bromide (13) as white solid (10) as a cream solid (36 mg, 10%). Melting point: 121–122 ꢀC.
1
(569 mg, 85%). 1H NMR (400 MHz, CDCl3) d 7.33 (d, J ¼ 8.6 Hz, Rf ¼ 0,2 (% 60 EtOAc/Hexanes). H NMR (400 MHz, CDCl3) d
2H), 6.86 (d, J ¼ 8.6 Hz, 2H), 6.60 (d, J ¼ 15.6 Hz, 1H), 6.26 7.29–7.24 (m, 4H), 6.84–6.80 (m, 4H), 6.48 (d, J ¼ 16.0 Hz, 2H),
(dt, J ¼ 15.6, 7.9 Hz, 1H), 4.17 (d, J ¼ 7.9 Hz, 2H), 3.82 (s, 3H). 6.23 – 6.15 (m, 2H), 6.02 (s, 1H), 5.36 (bs, 1H), 4.90 (bs, 1H),
1
The H NMR spectrum is in agreement with reported data by 3.79 (s, 6H), 3.54 (d, J ¼ 4.8, 4H). 13C NMR (100 MHz, CDCl3)
West et al.16
159.3, 154.5, 153.6, 130.9, 129.8, 127.6, 125.6, 113.9, 105.2,

DOI: 10.1080/14756366.2016.1181626
Synthesis of phloroglucinol derivatives with cinnamyl moieties
3
O
Br
OH
ii
H
i
MeO
MeO
MeO
11
12
13
OH
OH
HO
OH
OMe
Br
9
iii
OMe
HO
OH
OH
Phloroglucinol (3)
p-methoxy cinnamylbromide (13)
MeO
HO
OH
OMe
10
Scheme 1. Reagents and conditions: NaBH4, EtOH, 0 ꢀC, 30 min, 98%; (ii) PBr3, diethylether, 0 ꢀC, 1 h, 85%; (iii) Phloroglucinol (3), NaH, THF, rt,
17 h, 26%.
96.7, 55.7, 26.8. Anal. Calculated for (C26H26O5): C, 74.62; H,
6.26; Found C, 74.66, H, 6.506.
1NMR and 13C NMR spectra of synthesized compounds 9 and
10 are presented in supporting information (SI).
Enzymatic inhibition studies
Purification of carbonic anhydrase isozymes from human
erythrocytes by affinity chromatography
Erythrocytes suspension was obtained from the Blood Center of
the Research Hospital at Erzincan University. Sepharose 4B-L-
tyrosine-sulfonamide affinity chromatography was carried out as
previous study14. The human carbonic anhydrase (hCA I and hCA
II) isozymes were eluted with 1 M NaCl/25 mM Na2HPO4 (pH
6.3) and 0.1 M CH3COONa/0.5 M NaClO4 (pH 5.6), respectively.
The absorbance of the protein in the column effluents was
determined spectrophotometrically at 280 nm. All procedures
were performed at 4 ꢀC12,17
.
CA inhibition assay
Carbonic anhydrase activity was assayed by following the change
in absorbance at 348 nm of 4-nitrophenylacetate (NPA) to 4-
nitrophenylate ion over a period of 3 min at 25 ꢀC using a
spectrophotometer (CHEBIOS UV–VIS) according to the method
described by Verpoorte et al.18 The enzymatic reaction, in a total
volume of 3.0 mL, contained 1.4 mL of 0.05 M Tris–SO4 buffer
(pH 7.4), 1 mL of 3 mM 4-nitrophenylacetate, 0.5 mL H2O and
0.1 mL enzyme solution. A reference measurement was obtained
by preparing the same cuvette without enzyme solution. The
inhibition effects of 9 and 10 were examined. Different inhibitor
concentrations were used. Control cuvette activity in the absence
of inhibitor was taken as 100%. For each inhibitor an Activity%-
[Inhibitor] graph was drawn.
Figure 2. Polyacrylamide gel electrophoresis (PAGE) of the purified CA
isozymes. Lane 1: standard proteins (62–16.5 kDa), lane 2: hCA I and
lane 3: hCA II.
Both cinnamyl-substituted phloroglucinols were obtained by
stirring phloroglucinol (3) with p-methoxycinnamyl bromide
(13) in the presence of NaH. The p-methoxycinnamyl bromide
(13) was prepared in two steps from p-methoxycinnamaldehyde
(11). The 1H-NMR spectrum of 9 displayed a doublet of doublets
(dd) at d 3.44 for methylene protons and a singlet for the two
aromatic protons in the phloroglucinol ring (d 5.98). The 1H-
NMR spectrum of 10 displayed a dd at d 3.54 for methylene
protons and a singlet for the aromatic proton in the phloroglucinol
ring (d 6.02). In this study, we compared the effects of two new
synthesized compounds with the effects of phenolic compounds
from previous studies on the hCA I and II isozymes. For this
purpose, we extracted and purified hCA I and II from human
Protein determination
Protein during the purification steps was determined spectro-
photometrically at 595 nm according to the Bradford method,
using bovine serum albumin as the standard as previous
study14,19–21
.
Results and discussion
The first ever synthesis of the cinnamyl-substituted phlorogluci-
nol derivatives
9 and 10 is summarized in Scheme 1.

˘
S. Burmaoglu et al.
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J Enzyme Inhib Med Chem, Early Online: 1–5
Table 1. Summary of the purification procedure for hCA I and hCA II.
Sample type
Total volume (ml)
Activity (EU/ml)
Protein (mg/ml)
Specific activity (EU/mg)
% Yield
Purification factor
Haemolysate
CA-I
CA-II
48.00
9.60
4.80
169.00
498.00
891.60
19.67
0.57
0.12
8.59
873.70
7430.00
100.00
58.90
52.7
1.00
101.70
864.95
Table 2. Ki values for the hCA I and hCA II inhibition data for
compounds 1, 2, 4–10 and AZA by an esterase assay.
the compounds 4–8, with Ki values of 88.92 and 83.22,
respectively.
The synthesized compounds in this study were not found to be
better inhibitors than AZA, a clinically used sulfonamide.
However, comparing our results with studies on molecules that
were similar to the synthesized compounds, we found some
interesting results. The synthesized compounds 9 and 10 contain
both phloroglucinol and p-coumaric acid groups, which have both
been shown to have inhibition effects on different CA isozymes in
previous studies3,5. We had thought that when combined in a
single molecule, these two groups would either increase or reduce
each other’s effects. However, comparing our results with the
results obtained in previous studies, we found the inhibition
activities of our synthesized compounds to be comparable.
The pharmacological effects of the synthesized compounds 9
and 10 could be developed clinically for hCA I and II. Due to their
suitability for derivatization, these compounds could be used for
the design of novel inhibitors. In addition, compounds 9 and 10
could be improved to become more effective inhibitors by adding
groups to their structure with stronger inhibitory effects toward
the hCA I and II isozymes. The novel therapeutic applications of
these enzyme inhibitors or activators would be toward designing
prodrugs and drugs in the health sector.
Ki (mM)
Compounds
hCA I
hCA II
Phenol (1)
Pyrgallol (2)
p-Hydroxybenzoic (4)
p-coumaric acid (5)
Ferulic acid (6)
Gallic acid (7)
Syringic acid (8)
4-p-Methoxycinnamyl phloroglucinol (9)
4,6-bis-p-methoxycinnamyl
phloroglucinol (10)
Acetazolamide (AZA)
10.2*
7.41y
1061z
441z
408z
1052z
919z
77.00
n.d
5.5*
0.54y
675z
537z
210z
758z
695z
88.92
83.22
36x
3.7x
Mean from at least three determinations. Errors in the range of 3–5% of
the reported value (data not shown).
*From Ref.22–25
yFrom Ref.3
zFrom Ref.5
xFrom Ref.15
erythrocytes (Figure 2) and successfully synthesized compounds 9
and 10, which contained both phloroglucinol and cinnamyl
groups. Then, the effects of the synthesized compounds were
determined using the esterase activity method, with 4-nitrophenyl
acetate as the substrate from a previous study14. The purification
of hCA I was achieved with a 101.7-fold purification, a specific
activity of 873.70 EU mg/mL, and an overall yield of 58.90%;
hCA II was purified with a 864.95-fold purification, a specific
activity of 7430.00 EU mg/mL, and an overall yield of 52.70%
(Table 1). The inhibitory effects of 9 and 10 on enzyme activity
were tested under in vitro conditions. Lineweaver–Burk graphs
were drawn, from which the Ki values were calculated. These
results are given in Table 2.
In a previous study, the inhibition effect of compounds 1, 2,
and acetazolamide (AZA) on the rapid cytosolic isozyme, hCA
I, was investigated. These compounds showed a good inhibition
activity (Ki of 10.2, 7.41, and 36 mM, respectively) (Table
1)3,22–25. In this study, the inhibition effect of the synthesized
compound 9 was less than that of the compounds 1 and 2. In
another study, the inhibition effects of the compounds 4–8 on
the slow cytosolic isozyme, hCA I, were found to be moderate
to weak, with Ki values in the range of 408–1061 mM5. The
presence of a –COOH group and either one or three –OH
groups in the structure of these compounds changes their
inhibition effects. The inhibition effects of the synthesized
compound 9 were better than those of the compounds 4–8,
with Ki of 77.00 mM. Ki value for compound 10 couldn’t be
determined under the test conditions.
Declaration of interest
The authors report no declarations of interest. We thank the
Scientific and Technological Research Council of Turkey
(TUBITAK, Project number: 114Z554) and Erzincan University
(Project number: FEN-A-300614–0098) for their financial sup-
ports of this work.
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Supplementary material available online