Synthesis of novel acridine bis-sulfonamides with effective inhibitory activity against the carbonic anhydrase isoforms I, II, IX and XII

Article abstract of DOI:10.1016/j.bmc.2015.09.022

By using a multi component reaction system (MCR), nitro acridine sulfonamides were obtained from cyclic-1,3-diketones, 4-aminobenzene sulfonamide and aromatic aldehydes. Some novel acridine bis-sulfonamides 6a-l were then synthesized by the reaction betwe

Full text of DOI:10.1016/j.bmc.2015.09.022

Bioorganic & Medicinal Chemistry 23 (2015) 6573–6580
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of novel acridine bis-sulfonamides with effective
inhibitory activity against the carbonic anhydrase isoforms I, II, IX
and XII
a
a
a
b
b,
⇑
_
Ibrahim Esirden , Ramazan Ulus , Burak Aday , Muhammet Tanç , Claudiu T. Supuran
,
Muharrem Kaya c,
⇑
a Chemistry Department, Faculty of Arts and Science, Dumlupınar University, 43100 Kütahya, Turkey
b Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, 50019 Sesto Fiorentino (Florence), Italy
c Biochemistry Department, Faculty of Arts and Science, Dumlupınar University, 43100 Kütahya, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2015
Revised 10 September 2015
Accepted 14 September 2015
Available online 15 September 2015
By using a multi component reaction system (MCR), nitro acridine sulfonamides were obtained from
cyclic-1,3-diketones, 4-aminobenzene sulfonamide and aromatic aldehydes. Some novel acridine bis-
sulfonamides 6a–l were then synthesized by the reaction between sulfonyl chlorides and the novel
amino-acridine sulfonamides 5a and 5b, obtained by reduction of nitro-acridine sulfonamide derivatives
4a and 4b. The newly synthesized compounds were investigated as inhibitors of 4 human carbonic
anhydrase isoforms (hCA, EC 4.2.1.1). Several of the compounds showed low micromolar inhibition
against the medically relevant isoforms hCA I, II, IX, and XII.
Keywords:
Carbonic anhydrase
Acridine
Ó 2015 Elsevier Ltd. All rights reserved.
Sulfonamide
Enzyme inhibition
Isoforms CA I, II, IX and VII
1. Introduction
possessing important biological functions as a coenzyme/cofactor.2
Thus there are many acridine-like compounds showing anti-
Acridines are planar tricyclic aromatic compounds which con-
tain nitrogen in the heterocyclic ring. Even if these heterocycles
were discovered the 19th century, some of their derivatives are
still under investigation. Acridine shows a similarity in its structure
cancer,3,4 or antimicrobial activity,5 whereas other such derivatives
were reported to act as effective b-channel opener in cardiovascu-
lar disease,6 in the photodynamic therapy,7 or as anti-Alzheimer’s
agents.8 Well-known drugs containing the acridine moiety include
Amsacrine, Asulacrine, Acronycine, Acridine carboxamide (DACA),
Proflavine and Ascididemin (Chart 1), and they have been used as
anti-cancer or anti-bacterial agents.12,13 Furthermore, many acri-
dine sulfonamides are known as strong carbonic anhydrase (CA,
EC 4.2.1.1) inhibitors (CAIs), potentially useful for the treatment
glaucoma9,10 or other conditions, which the activity of the CA iso-
forms are deregulated.11
CAs are responsible for the reversible hydration of carbon diox-
ide to bicarbonate.11 By catalyzing this simple reaction CAs partic-
ipate in many physiological processes such as regulation of
respiration and gas exchange, bone resorption, calcification, pH
and CO2 homeostasis, electrolyte secretion in a variety of tissues/
organs, biosynthetic reactions.11–13 This diversity of roles makes
to nicotinamide adenine dinucleotide (NADH),1
a molecule
Abbreviations: MCR, multi component reaction; CA, carbonic anhydrase; hCA,
human carbonic anhydrase; NADH, nicotinamide adenine dinucleotide; Amsacrine,
N-[4-(acridin-9-ylamino)-3-methoxyphenyl]methanesulfonamide; Asulacrine, 9-
[4-(methanesulfonamido)-2-methoxyanilino]-N,5-dimethylacridine-4-carboxam-
ide; Acronycine, 6-methoxy-3,3,12-trimethylpyrano[2,3-c]acridin-7-one; DACA,
N-[2-(dimethylamino)ethyl]acridine-4-carboxamide; Proflavine, acridine-3,6-di-
amine; Ascididemin, 9H-quino[4,3,2-de][1,10]phenanthrolin-9-one; CAIs, carbonic
anhydrase inhibitors; IR, infrared; NMR, nuclear magnetic resonance; HRMS, high
resolution mass spectroscopy; SAR, structure–activity relationship; DMSO, dimethyl
sulfoxide; LC, liquid chromatography; DBSA, p-dodecylbenzenesulfonic acid; TLC,
tine layer chromatography; mp, melting point; Lit, literature; ESI, electron spray
ionization; TEA, trimethylamine;
lM, micromolar; nM, nanomolar; KI, inhibition
constant.
different isoforms interesting drug targets for
a variety of
⇑
Corresponding authors. Tel.: +39 055 457 3005; fax: +39 055 457 3385 (C.T.S.);
tel.: +90 274 2652051; fax: +90 274 2652056 (M.K.).
E-mail addresses: claudiu.supuran@unifi.it (C.T. Supuran), muharrem.kaya@dpu.
edu.tr (M. Kaya).
conditions.14
The sulfonamides and their isosteres such as the sulfamates and
sulfamides, are established CAIs and are in clinical use for almost
http://dx.doi.org/10.1016/j.bmc.2015.09.022
0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.

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I. Esirden et al. / Bioorg. Med. Chem. 23 (2015) 6573–6580
Chart 1. Some drugs incorporating acridine moieties.
70 years for the treatment of glaucoma, obesity, epilepsy and as
diuretics.15 The large use of CAIs for pharmaceutical applications
relies on the wide distribution of the 15 human (h) CA isoforms
within different tissues as well as on their implication in many
physiological/pathological conditions. Antiglaucoma CAI-drugs
mainly target CA II, IV and XII; the diuretics CA II, IV, XII and
XIV; the antiepileptic CA VII and XIV.11,14,16,17 The selective inhibi-
tion of the CA IX and XII isoforms results in antitumor and antime-
tastatic effects.13,14 In vivo experiments showed that silencing of
hCA IX reduces xenograft tumors to 40% of the volume along with
up-regulation response of the gene encoding for hCA XII. Silencing
of both hCA IX and hCA XII showed 85% reduction of tumor growth.
hCA IX is a 54–58 kDa trans-membrane protein consistent of a
cytoplasmic fragment, which exhibits phosphorylation sites, a
trans membrane section and an extracellular region. hCA IX
exposes its catalytic domain on the extracellular environment
and is further functionalised with glycosidic residues.18 It should
be stressed that currently a sulfonamide CA IX inhibitor (SLC-
0111) entered in Phase I clinical studies for the treatment of
hypoxic, advanced stage metastatic solid tumors.19,20
The main drawback associated to the use of CAIs is represented
by the lack of selectivity in inhibiting various isoforms by many of
the first and second generation CAIs, thus resulting in a plethora of
side effects.21,22 In this context many efforts have been made for
the development of specific CAIs, and some remarkable results
have been achieved in the last 15 years since the introduction of
the tail approach.20–22 Moreover novel CAIs classes such as the
polyamines,23 phenols,24 dithiocarbamates,25 xanthates,26 coumar-
ins, thiocoumarins, 2-thioxo-coumarins and coumarin oximes16,27–29
were identified and their inhibition mechanisms of many of these
compounds were determined by means of X-ray crystallography
CA II adducts.21,24,25
2. Results and discussion
2.1. Chemistry
The general synthetic method, three steps reaction shown in
Scheme 1, was used to prepare the nitro acridine derivatives (4a
and 4b), novel amino acridine compounds (5a and 5b) and novel
acridine bis-sulfonamide compounds (6a–l). For the first step
MCR method applied, and compounds 4a and 4b were obtained
by using dimedone (1), 4-aminobenzenesulfonamide (2), nitro aro-
matic aldehydes (3a and 3b)–molar ratio of 2:1:1 and DBSA, as
phase transfer catalyst, in one-pot reaction in water. For the second
step, new amino acridine derivatives (5a and b) were synthesized
by using excessive reduction reactive—aqueous sodium poly-sul-
fide—from nitro acridine compounds (4a and 4b) at reflux temper-
ature with high yields (respectively, 87% and 82%). For the final
step, the acridine bis-sulfonamide derivatives 6a–l were obtained
from various sulfonyl chlorides and amino acridines (5a, 5b) in
THF at room temperature in presence of triethylamine (TEA).30,31
All the products were characterized by melting point detection,
IR, NMR and HRMS analyses. In the IR spectra of the compounds 5a,
5b and 6a–l, the ANH2, ASO2NH2, ASO2NHR vibrations were
observed in the region between 3244 and 3467 cmÀ1. Aliphatic
CAH stretching bands were observed at 2954–2959 cmÀ1 and the
aromatic CAH stretching bands were observed at 3032–
3098 cmÀ1. Also, sharp peaks were observed for the carbonyl
groups in the region between 1623 and 1634 cmÀl for all the acri-
dine bis-sulfonamides.
For the 1H NMR spectra of compounds 5a, 5b and 6a–l singlet
peaks were observed between 0.60 and 0.90 ppm which belong
to protons of the methyl groups in position 3 and 6. For the com-
pounds 5a, 5b and 6a–l doublet or multiplet peaks were observed
in between 1.62 and 2.22 ppm belong to CH2 group protons of the
cyclohexene ring.32 For the compounds 6b, 6e, 6h and 6k singlet
peaks were observed in between 2.18 and 2.52 ppm belong to pro-
tons of the methyl group. For the compounds 6c and 6i the signal
of the methoxy protons of were observed at 3.80 and 3.70 ppm,
respectively. Also the signals of the CH protons were observed at
4.90 and 4.98 ppm and the signals for the aromatic protons were
observed between 6.30 and 8.36 ppm. For the compounds 5a, 5b
and 6a–l ASO2NH2 group protons were assigned as singlet peaks
Considering the interest in sulfonamide CAIs, in this study we
investigate a new class of acridine bis-sulfonamides which have
been designed by an approach of multicomponent reactions. The
structure of the novel compounds was confirmed by using spectral
analysis (FT-IR, 1H NMR, 13C NMR (APT) and HRMS) and they were
investigated the inhibition of human CA isoforms hCA I, II, IX and
XII. The structure–activity relationships (SAR) for the inhibition
of these isoforms with the acridine bis-sulfonamides are also
discussed.

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6575
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
C6H5 4-CH3C6H4 4-CH3OC6H4 4-BrC6H4 2,4,6-(CH3)3C6H2 2-Naphthyl C6H5 4-CH3C6H4 4-CH3OC6H4 4-BrC6H4 2,4,6-(CH3)3C6H2 2-Naphthyl
R
Scheme 1. Synthesis of novel acridine bis-sulfonamide compounds.
Table 1
a signal for the carbonyl group carbon peak between 195.34 and
195.63 ppm and the signal of carbon–carbon double bonds was
observed between 113.29 and 162.67 ppm.33 Also, aliphatic carbon
peaks were observed at 20.82–56.00 ppm. When the HRMS analy-
ses of all the molecules (5a, 5b and 6a–l) were examined, we
observed signals in line with the molecule ion peaks of the pro-
posed structures.
CA inhibition data for compounds (4a, 4b), (5a, 5b), (6a-l) and standard inhibitors
against human isozymes hCA I, II, IX and XII by a stopped flow CO2 hydrase assay32
Entry
–R
KI (
l
M)
hCA I
hCA II
hCA IX
hCA XII
4a
4b
5a
5b
6a
6b
6c
6d
6e
6f
—
—
—
—
5.1
0.69
2.5
0.64
0.89
0.65
0.50
0.10
0.96
0.37
0.60
0.48
0.47
0.38
0.39
0.25
0.45
0.43
0.50
0.012
1.02
0.42
1.00
0.92
0.58
0.10
0.44
1.12
0.09
0.28
0.11
0.10
0.80
0.25
0.09
0.81
0.025
0.35
0.50
0.61
0.03
0.64
0.53
0.92
0.86
0.26
0.37
1.02
0.78
0.92
0.56
0.52
0.83
0.006
8.87
2.09
4.55
6.92
6.53
5.62
3.89
8.91
4.27
4.31
5.38
6.52
6.53
0.25
2.2. Carbonic anhydrase inhibition
C6H5
4-CH3C6H4
4-CH3OC6H4
4-BrC6H4
2,4,6-(CH3)3C6H2
2-Naphthyl
C6H5
4-CH3C6H4
4-CH3OC6H4
4-BrC6H4
2,4,6-(CH3)3C6H2
2-Naphthyl
—
The new compounds reported here and the standard drug
acetazolamide were assayed as inhibitors of four cytosolic human
isoforms, hCA I, II, IX and XII (Table 1).34
The new derivatives were rather ineffective inhibitors of the
widespread cytosolic isoform hCA I, with inhibition constants in
6g
6h
6i
the range of 0.69–8.91 lM (acetazolamide, the standard sulfon-
6j
amide CAI has a KI of 250 nM against this isoform). There are few
important variations in order to be able to discuss SAR. It was
observed that increasing of the bulkiness of the tails for the com-
pound series 4a, 4b, and 6a–f (Chart 2) resulted with slight increas-
ing of KI values, that is, decreasing on inhibitory effect, in the range
6k
6l
AAZ*
*
Acetazolamide (AAZ) was used as a standard inhibitor for all CAs investigated
here. KI-s are means from 3 different assays. Standard errors were in the range of
5–10% of the reported values (data not shown).
of 0.69–6.92 lM. On the contrary the opposite effect of bulkiness
was observed that for the compound series 5a, 5b, and 6g–l,
(Chart 2), with inhibition constants varying in the range of
between 7.61 and 7.63 ppm and the compounds 6a–f and 7a–f
were assigned as singlet peaks between 9.90 and 10.25 ppm. The
13C NMR (APT) spectra of the compounds 5a, 5b and 6a–l displayed
2.5–8.91
lM. It should be noted that position of the tails
(sulfonyl groups) on the main scaffold (for 6a–f, are -para and for
KIs for hCA I
10
9
8
7
6
5
4
3
2
1
0
8.91
6.92
4.31
6.52
5.62
6.53
3.89
6.53
5.38
4.55
4.27
2.09
1
2
3
4
5
6
6a
6g
Chart 2. Change in the KI values for 6a–f (red line) and 6g–l (blue line).

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I. Esirden et al. / Bioorg. Med. Chem. 23 (2015) 6573–6580
KIs hCA II
1.2
1.1
1
0.96
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0.6
0.5
0.47
0.45
0.48
0.38
0.37
0.25
0.43
0.39
2
0.1
1
3
4
5
6
6a
6g
Chart 3. Change in the KI values for 6a–f (red line) and 6g–l (blue line).
KIs hCA IX
1.12
1.2
1.1
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0.81
0.8
0.58
0.44
0.28
0.25
0.09
0.11
1
0.1
0.1
2
0.09
5
3
4
6
6a
6g
Chart 4. Change in the KI values for 6a–f (red line) and 6g–l (blue line).
KIs hCA XII
1.2
1.1
1
1.02
0.64
0.92
0.86
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0.83
0.37
0.92
0.78
0.53
0.56
0.52
0.26
1
2
3
4
5
6
6a
6g
Chart 5. Change in the KI values for 6a–f (red line) and 6g–l (blue line).

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I. Esirden et al. / Bioorg. Med. Chem. 23 (2015) 6573–6580
6577
6g–l are -meta) also influence the KI values. However, a salient
feature of all these sulfonamides is their rather flat SAR, probably
due to the extreme bulkiness of the tails that they incorporate
and which probably extend out of the active site.
For the dominant cytosolic isoform hCA II, as for isoform CA I, it
was observed that the new derivatives were rather ineffective inhi-
bitors, showing a limited range of inhibitory power, with a varia-
advanced technology research center of Dumlupınar University
(ILTEM).
4.2. General procedure for preparation of nitro-acridine
sulfonamide compounds (4a, 4b)
A mixture of a dimedone 1 (0.280 g, 2 mmol), 4-aminobenzene-
sulfonamide (0.172 g, 1 mmol) 2, -meta and -para substitute
nitrobenzaldehydes (3a and 3b) (0.106 g, 1 mmol), and p-dodecyl-
benzenesulfonic acid (DBSA) (0.033 g, 10 mmol %) in 40 mL H2O
was stirred and refluxing for 24 h. The progress of the reaction
was monitored by TLC. After, the reaction is completed, the mix-
ture was cooled to room temperature solid filtered off and washed
with H2O. The products (4a and 4b) were purified and recrystal-
lized from ethanol.10
tion of KI between 0.10 and 0.96 lM. However, the KI values
were slightly lower for on hCA II when compared with other CA
isoforms and any important effect of bulkiness of tail was not
observed for this isoform (Chart 3). It is suggested that due to
the fact hCA II has a wide entrance to active site, probably the
hydrophobic and hydrophilic interactions of these tails with the
active site were not highly effective, and leading in fact to the flat
SAR mentioned above also for isoform hCA I.
The transmembrane isoform hCA IX was inhibited better than
the cytosolic ones, with KIs ranging between 90 nM and 1.12
(Table 1). However the isoform which was better inhibited was
hCA XII (a transmembrane one as hCA IX), with KIs ranging
between 30 nM and 1.02 lM. The small range of inhibitory power
l
M
4.2.1. 4-(3,3,6,6-Tetramethyl-9-(4-nitrophenyl)-1,8-dioxo-1,2,3,
4,5,6,7,8-octahydroacridin-10(9H)-yl)benzenesulfonamide (4a)
As yellow solid (ethanol), mp 298–300 °C (Lit. >250),30 yield
93%.
of these compounds against the two transmembrane isoforms may
be due to the fact that the variations in the structure are at rather
distant parts of the tail from the primary sulfonamide, and we
hypothesize that these parts of the molecules lay outside the active
site, affording thus for less specific interactions with amino acid
residues crucial for the binding of inhibitors. It is thus probable
that the bulky scaffold of these sulfonamides does not make a lot
of favorable contacts with the enzyme active site, whereas the sec-
ondary sulfonamide moiety is too far away for assuring the right
interactions with the residues at the entrance of the cavity, which
would lead to isoform-selective CAIs (Charts 4 and 5).13–15
4.2.2. 4-(3,3,6,6-Tetramethyl-9-(3-nitrophenyl)-1,8-dioxo-1,2,3,
4,5,6,7,8-octahydroacridin-10(9H)-yl)benzenesulfonamide (4b)
As yellow solid (ethanol), mp 256–257 °C (Lit. >250)30 yield
89%.
4.3. General procedure for preparation of amino-acridine
sulfonamide compounds (5a, 5b)
Na2SÁ9H2O (1 mmol) and sulfur (2 mmol) were dissolved by
boiling in 20 ml of water. This solution (sodium poly-sulfur) was
then added dropwise to a stirred solution of warm nitro acridine
compounds (4a, 4b) (1 mmol) in ethanol–water. The progress of
the reaction was monitored by TLC. Once the reaction is completed,
the mixture was cooled to room temperature and solid filtered off
and washed with H2O.10
3. Conclusion
There are still many important drug design aspect to be
addressed for obtaining isoform-selective and more effective sul-
fonamide CAIs. Considering our interest in sulfonamides, herein
we investigate a new series of acridine bis-sulfonamides which
have been obtained by using multicomponent reaction techniques.
The new series of acridine bis-sulfonamides was synthesized with
effective yields. The compounds were characterized by physico-
chemical methods and tested for their in vitro inhibition activity
against the CA isoforms I, II, IX and XII. Several compounds showed
low micromolar inhibition against the pharmacologically relevant
isoforms hCA I, II, IX, and XII. The prepared compounds containing
both acridine ring and sulfonamide group are thought to be of
interest because sulfonamides are used in the treatment of many
diseases, possessing antimicrobial, antimalarial, antiglaucoma,
and anticancer properties.
4.3.1. 4-(9-(4-Aminophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,
3,4,5,6,7,8-octahydroacridin-10(9H)-yl)benzenesulfonamide (5a)
As white solid (ethanol), mp 257–258 °C, yield 87%. IR (cmÀ1):
3458 and 3371 w (ANH2), 3040 w (ArAH), 2954 w (CAH), 1626 s
(C@O), 1577 s (C@C), 1363 and 1152 s (SO2); 1H NMR (300 MHz,
DMSO-d6) d (ppm): 0.70 (s, 6H, 2Â ACH3), 0.90 (s, 6H, 2Â ACH3),
1.71 (d, 2H, J = 17.2 Hz, ACH2), 2.00 (d, 2H, J = 16.1 Hz, ACH2),
2.18 (d, 4H, J = 16.5 Hz, 2Â ACH2), 4.80 (s, 2H, ANH2), 4.90 (s,
1H, ACH), 6.43 (d, 2H, J = 8.4 Hz, ArAH), 6.95 (d, 2H, J = 8.4 Hz,
ArAH), 7.62–7.68 (m, 4H, ArAH and ASO2NH2), 8.03 (d, 2H,
J = 8.7 Hz, ArAH); 13C NMR (75 MHz, DMSO-d6) d (ppm): 26.53,
29.79, 30.92, 32.44, 41.33, 50.17, 114.07, 114.23, 122.88, 128.35,
132.46, 133.49, 134.46, 138.42, 146.87, 149.81, 195.57; HRMS
(QTOF-ESI): m/z calcd for
C29H33N3O4S: 519.2192; found:
4. Experimental
4.1. Chemistry
518.2321 [MÀH]À.
4.3.2. 4-(9-(3-Aminophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,
3,4,5,6,7,8-octahydroacridin-10(9H)-yl)benzenesulfonamide (5b)
As white solid (ethanol), mp 218–219 °C, yield 82%. IR (cmÀ1):
3368 and 3272 w (ANH2), 3066 w (ArAH), 2957 w (CAH), 1628 s
(C@O), 1574 s (C@C), 1334 and 1155 s (SO2); 1H NMR (300 MHz,
DMSO-d6) d (ppm): 0.70 (s, 6H, 2Â ACH3), 0.90 (s, 6H, 2Â ACH3),
1.72 (d, 2H, J = 17.2 Hz, ACH2), 2.02 (d, 2H, J = 16.0 Hz, ACH2),
2.16–2.22 (m, 4H, 2Â ACH2), 4.90 (s, 1H, ACH), 5.10 (s, 2H,
ANH2), 6.30–6.33 (m, 1H, ArAH), 6.50 (d, 2H, J = 7.7 Hz, ArAH),
6.89 (t, J = 7.7 Hz, 1H, ArAH), 7.61 (s, 2H, ASO2NH2), 7.64 (d, 2H,
J = 8.7 Hz, ArAH), 8.03 (d, 2H, J = 8.7 Hz, ArAH); 13C NMR
(75 MHz, DMSO-d6) d (ppm): 26.56, 29.56, 32.59, 32.97, 41.41,
49.80, 112.84, 121.53, 122.67, 127.92, 130.23, 131.04, 134.73,
The chemicals used in the synthesis of acridine bis-sulfonamide
derivatives were obtained from Merck and Aldrich Chemical Com-
pany. All chemicals and solvents used for the synthesis were of
spectroscopic reagent grade.
Melting points were measured on a Bibby Scientific Stuart Dig-
ital, Advanced, and SMP30. Fourier Transform Infrared (FT-IR)
spectra were recorded on Bruker Optics, ALPHA FT-IR spectrome-
ter. The 1H NMR and 13C NMR spectra were obtained in DMSO-d6
with Bruker DPX-300 as solvents with tetramethylsilane as the
internal reference. The mass analyses were performed on an Agi-
lent Technologies 6530 Accurate-Mass Q-TOF LC/HRMS at the

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I. Esirden et al. / Bioorg. Med. Chem. 23 (2015) 6573–6580
141.34, 145.34, 147.88, 148.51, 150.99, 195.63; HRMS (QTOF-ESI):
4.4.4. 4-Bromo-N-(4-(3,3,6,6-tetramethyl-1,8-dioxo-10-(4-sulfa-
moylphenyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9-yl)phenyl)
benzenesulfonamide(6d)
m/z calcd for C29H33N3O4S: 519.2192; found: 518.2271 [MÀH]À.
4.4. General procedure for preparation of acridine bis-
sulfonamide derivatives (6a–l)
As white solid (ethanol), mp 235–236 °C, yield 97%. IR (cmÀ1):
3377 w (ANH2), 3095 w (ArAH), 2957 w (CAH), 1627 s (C@O),
1579 s (C@C), 1363 and 1159 s (SO2); 1H NMR (300 MHz, DMSO-
d6) d (ppm): 0.70 (s, 6H, 2Â ACH3), 0.90 (s, 6H, 2Â ACH3), 1.70
(d, 2H, J = 17.2 Hz, ACH2), 1.99 (d, 2H, J = 15.9 Hz, ACH2), 2.17 (d,
4H, J = 16.5 Hz, 2Â ACH2), 4.92 (s, 1H, ACH), 6.95 (d, 2H,
J = 8.5 Hz, ArAH), 7.17 (d, 2H, J = 8.5 Hz, ArAH), 7.61 (s, 2H, ASO2-
NH2), 7.58–7.71 (m, 6H, ArAH), 8.02 (d, 2H, J = 8.5 Hz, ArAH), 10.20
(s, 1H, ANH); 13C NMR (75 MHz, DMSO-d6) d (ppm): 26.42, 29.67,
31.78, 32.50, 41.41, 49.94, 113.45, 120.85, 127.10, 127.82, 128.73,
129.03, 131.14, 132.67, 135.40, 139.30, 141.57, 142.87, 145.15,
150.10, 195.50; HRMS (QTOF-ESI): m/z calcd for C35H36BrN3O6S2:
737.1229; found: 760.1125 [M+Na]+.
4-Amino-acridine sulfonamide 5a (0.520 g, 1 mmol), benzene
sulfonyl chloride (0.177 g, 1 mmol), and 0.5 mL dry triethylamine
(TEA) were stirred in dry 5 mL THF for 5 h at room temperature.
After the solvent was removed under in vacuo and washed with
H2O.31
4.4.1. N-(4-(3,3,6,6-Tetramethyl-1,8-dioxo-10-(4-sulfamoylphe-
nyl)-1,2,3,4,5,6,7,8,9,10-decahydro acridin-9-yl)phenyl)benzen-
esulfonamide (6a)
As white solid (ethanol), mp 208–210 °C, yield 90%. IR (cmÀ1):
3375 w (ANH2), 3075 w (ArAH), 2959 w (CAH), 1623 s (C@O),
1589 s (C@C), 1362 and 1153 s (SO2); 1H NMR (300 MHz, DMSO-
d6) d (ppm): 0.70 (s, 6H, 2Â ACH3), 0.90 (s, 6H, 2Â ACH3), 1.70
(d, 2H, J = 17.2 Hz, ACH2), 1.98 (d, 2H, J = 16.0 Hz, ACH2), 2.16 (d,
4H, J = 16.5 Hz, 2Â ACH2), 4.93 (s, 1H, ACH), 6.95 (d, 2H,
J = 8.5 Hz, ArAH), 7.15 (d, 2H, J = 8.5 Hz, ArAH), 7.46–7.70 (m, 7H,
ArAH), 7.61 (s, 2H, ASO2NH2), 8.01 (d, 2H, J = 8.6 Hz, ArAH),
10.10 (s, 1H, ANH); 13C NMR (75 MHz, DMSO-d6) d (ppm): 26.46,
29.65, 31.72, 32.50, 41.41, 49.95, 113.49, 120.60, 126.96, 127.80,
128.62, 129.55, 131.13, 133.21, 135.74, 140.14, 141.57, 142.56,
145.15, 150.08, 195.50; HRMS (QTOF-ESI): m/z calcd for C35H37N3-
O6S2: 659.2124; found: 682.2021 [M+Na]+.
4.4.5. 2,4,6-Trimethyl-N-(4-(3,3,6,6-tetramethyl-1,8-dioxo-10-
(4-sulfamoylphenyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9-yl)
phenyl)benzenesulfonamide (6e)
As white solid (ethanol), mp 239–240 °C, yield 93%. IR (cmÀ1):
3467 and 3388 w (ANH2), 3172 w (ANH), 3035 w (ArAH), 2958
w (CAH), 1623 s (C@O), 1582 s (C@C), 1360 and 1146 s (SO2); 1H
NMR (300 MHz, DMSO-d6) d (ppm): 0.70 (s, 6H, 2Â ACH3), 0.90
(s, 6H, 2Â ACH3), 1.70 (d, 2H, J = 17.2 Hz, ACH2), 1.98 (d, 2H,
J = 15.9 Hz, ACH2), 2.16 (d, 4H, J = 16.6 Hz, 2Â ACH2), 2.21 (s, 3H,
ACH3), 2.47 (s, 6H, 2Â ACH3), 4.90 (s, 1H, ACH), 6.85 (d, 2H,
J = 8.5 Hz, ArAH), 6.95 (s, 2H, ArAH), 7.14 (d, 2H, J = 8.5 Hz, ArAH),
7.61 (s, 2H, ASO2NH2), 7.64 (d, 2H, J = 8.6 Hz, ArAH), 8.01 (d, 2H,
J = 8.6 Hz, ArAH), 9.90 (s, 1H, ANH); 13C NMR (75 MHz, DMSO-
d6) d (ppm): 20.84, 22.91, 26.50, 29.64, 31.79, 32.50, 41.40, 49.95,
113.52, 120.65, 127.79, 128.62, 131.11, 132.16, 134.58, 135.50,
139.00, 141.59, 142.27, 142.44, 145.15, 150.07, 195.50; HRMS
4.4.2. 4-Methyl-N-(4-(3,3,6,6-tetramethyl-1,8-dioxo-10-(4-sulfa-
moylphenyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9-yl)phenyl)
benzenesulfonamide (6b)
As white solid (ethanol), mp 230–231 °C, yield 92%. IR (cmÀ1):
3357 w (ANH2), 3033 w (ArAH), 2959 w (CAH), 1631 s (C@O),
1590 s (C@C), 1365 and 1159 s (SO2); 1H NMR (300 MHz, DMSO-
d6) d (ppm): 0.70 (s, 6H, 2Â ACH3), 0.90 (s, 6H, 2Â ACH3), 1.70
(d, 2H, J = 17.3 Hz, ACH2), 1.98 (d, 2H, J = 16.0 Hz, ACH2), 2.16 (d,
4H, J = 16.5 Hz, 2Â ACH2), 2.31 (s, 3H, ACH3), 4.92 (s, 1H, ACH),
6.95 (d, 2H, J = 8.5 Hz, ArAH), 7.15 (d, 2H, J = 8.5 Hz, ArAH), 7.28
(d, 2H, J = 8.1 Hz, ArAH), 7.58 (d, 2H, J = 8.3 Hz, ArAH), 7.61 (s,
2H, ASO2NH2), 7.66 (d, 2H, J = 8.5 Hz, ArAH), 8.01 (d, 2H,
J = 8.5 Hz, ArAH), 10.05 (s, 1H, ANH); 13C NMR (75 MHz, DMSO-
d6) d (ppm): 21.41, 26.46, 29.65, 31.72, 32.51, 41.41, 49.95,
113.51, 120.34, 127.03, 127.81, 128.61, 130.01, 131.14, 135.89,
137.35, 141.58, 142.38, 143.53, 145.15, 150.08, 195.52; HRMS
(QTOF-ESI): m/z calcd for
C38H43N3O6S2: 701.2593; found:
724.2482 [M+Na]+.
4.4.6. N-(4-(3,3,6,6-Tetramethyl-1,8-dioxo-10-(4-sulfamoylphe-
nyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9-yl)phenyl)naphtha-
lene-2-sulfonamide (6f)
As white solid (ethanol), mp 243–245 °C, yield 95%. IR (cmÀ1):
3382 w (ANH2), 3249 w (ANH), 3032 w (ArAH), 2957 w (CAH),
1625 s (C@O), 1582 s (C@C), 1363 and 1153 s (SO2); 1H NMR
(300 MHz, DMSO-d6) d (ppm): 0.60 (s, 6H, 2Â ACH3), 0.80 (s, 6H,
2Â ACH3), 1.66 (d, 2H, J = 17.2 Hz, ACH2), 1.93 (d, 2H, J = 15.9 Hz,
ACH2), 2.13 (d, 4H, J = 16.5 Hz, 2Â ACH2), 4.90 (s, 1H, ACH), 6.99
(d, 2H, J = 8.5 Hz, ArAH), 7.13 (d, 2H, J = 8.5 Hz, ArAH), 7.61 (s,
2H, ASO2NH2), 7.60–7.71 (m, 5H, ArAH), 7.97–8.08 (m, 5H, ArAH),
8.36 (s, 1H, ArAH), 10.20 (s, 1H, ANH); 13C NMR (75 MHz, DMSO-
d6) d (ppm): 26.37, 29.61, 31.74, 32.45, 41.36, 49.90, 113.45,
120.66, 122.41, 127.78, 128.03, 128.22, 128.27, 128.64, 129.29,
129.62, 129.73, 131.10, 131.96, 134.64, 135.71, 137.16, 141.55,
142.58, 145.13, 150.03, 195.45; HRMS (QTOF-ESI): m/z calcd for
(QTOF-ESI): m/z calcd for
C36H39N3O6S2: 673.2280; found:
696.2194 [M+Na]+.
4.4.3. 4-Methoxy-N-(4-(3,3,6,6-tetramethyl-1,8-dioxo-10-(4-sul-
famoylphenyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9-yl)phenyl)
benzenesulfonamide (6c)
As white solid (ethanol), mp 215–216 °C, yield 94%. IR (cmÀ1):
3393 w (ANH2), 3064 w (ArAH), 2958 w (CAH), 1626 s (C@O),
1584 s (C@C), 1361 and 1151 s (SO2); 1H NMR (300 MHz, DMSO-
d6) d (ppm): 0.65 (s, 6H, 2Â ACH3), 0.85 (s, 6H, 2Â ACH3), 1.70
(d, 2H, J = 17.2 Hz, ACH2), 1.99 (d, 2H, J = 16.0 Hz, ACH2), 2.17 (d,
4H, J = 16.5 Hz, 2Â ACH2), 3.80 (s, 3H, AOCH3), 4.93 (s, 1H, ACH),
6.95 (d, 2H, J = 8.5 Hz, ArAH), 6.99 (d, 2H, J = 8.9 Hz, ArAH), 7.15
(d, 2H, J = 8.5 Hz, ArAH), 7.61 (s, 2H, ASO2NH2), 7.63–7.66 (m,
4H, ArAH), 8.02 (d, 2H, J = 8.5 Hz, ArAH), 9.98 (s, 1H, ANH); 13C
NMR (75 MHz, DMSO-d6) d (ppm): 26.46, 29.65, 31.69, 32.50,
41.41, 49.95, 56.00, 113.51, 114.68, 120.28, 127.80, 128.58,
129.20, 131.12, 131.80, 136.01, 141.58, 142.28, 145.15, 150.07,
162.75, 195.51; HRMS (QTOF-ESI): m/z calcd for C36H39N3O7S2:
689.2229; found: 712.2138 [M+Na]+.
C
39H39N3O6S2: 709.2280; found: 732.2168 [M+Na]+.
4.4.7. N-(3-(3,3,6,6-Tetramethyl-1,8-dioxo-10-(4-sulfamoylphe-
nyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9-yl)phenyl)benzene-
sulfonamide (6g)
As white solid (ethanol), mp 182–184 °C, yield 84%. IR (cmÀ1):
3384 w (ANH2), 3266 w (ANH), 3068 w (ArAH), 2956 w (CAH),
1633 s (C@O), 1584 s (C@C), 1364 and 1161 s (SO2); 1H NMR
(300 MHz, DMSO-d6) d (ppm): 0.70 (s, 6H, 2Â ACH3), 0.90 (s, 6H,
2Â ACH3), 1.68 (d, 2H, J = 17.3 Hz, ACH2), 1.97 (d, 2H, J = 16.0 Hz,
ACH2), 2.15–2.22 (m, 4H, 2Â ACH2), 4.98 (s, 1H, ACH), 6.81–6.83
(m, 1H, ArAH), 7.00–7.09 (m, 2H, ArAH), 7.20 (s, 1H, ArAH), 7.61
(s, 2H, ASO2NH2), 7.43–7.72 (m, 7H, ArAH), 8.05 (d, 2H,
J = 8.5 Hz, ArAH), 10.20 (s, 1H, ANH); 13C NMR (75 MHz, DMSO-d6)

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I. Esirden et al. / Bioorg. Med. Chem. 23 (2015) 6573–6580
6579
d (ppm): 26.65, 29.67, 32.31, 32.44, 41.45, 49.96, 113.30, 118.27,
119.67, 124.49, 126.90, 127.75, 128.87, 129.53, 131.06, 133.17,
138.05, 140.08, 141.60, 145.24, 147.57, 150.16, 195.38; HRMS
DMSO-d6) d (ppm): 0.70 (s, 6H, 2Â ACH3), 0.90 (s, 6H, 2Â ACH3),
1.68 (d, 2H, J = 17.4 Hz, ACH2), 1.96 (d, 2H, J = 16.1 Hz, ACH2),
2.18 (s, 3H, ACH3), 2.14–2.22 (m, 4H, 2Â ACH2), 2.52 (s, 6H, 2Â
ACH3), 4.95 (s, 1H, ACH), 6.73 (d, 1H, J = 7.9 Hz, ArAH), 6.94–
7.07 (m, 5H, ArAH), 7.62 (s, 2H, ASO2NH2), 7.68 (d, 2H, J = 8.5 Hz,
ArAH), 8.04 (d, 2H, J = 8.5 Hz, ArAH), 10.10 (s, 1H, ANH); 13C
NMR (75 MHz, DMSO-d6) d (ppm): 20.82, 22.96, 26.72, 29.65,
32.22, 32.43, 41.46, 49.93, 113.29, 116.98, 119.47, 124.02, 127.73,
128.79, 131.14, 132.17, 134.41, 137.87, 138.97, 141.59, 142.20,
145.26, 147.58, 150.12, 195.35; HRMS (QTOF-ESI): m/z calcd for
(QTOF-ESI): m/z calcd for
C35H37N3O6S2: 659.2124; found:
658.2239 [MÀH]À.
4.4.8. 4-Methyl-N-(3-(3,3,6,6-tetramethyl-1,8-dioxo-10-(4-sulfa-
moylphenyl)-1,2,3,4,5,6,7,8,9,10-decahydro acridin-9-yl)phenyl)
benzenesulfonamide (6h)
As white solid (ethanol), mp 190–192 °C, yield 86%. IR (cmÀ1):
3396 w (ANH2), 3252 w (ANH), 3098 w (ArAH), 2959 w (CAH),
1632 s (C@O), 1585 s (C@C), 1363 and 1156 s (SO2); 1H NMR
(300 MHz, DMSO-d6) d (ppm): 0.70 (s, 6H, 2Â ACH3), 0.90 (s, 6H,
2Â ACH3), 1.68 (d, 2H, J = 17.4 Hz, ACH2), 1.97 (d, 2H, J = 16.0 Hz,
ACH2), 2.15–2.22 (m, 4H, 2Â ACH2), 2.28 (s, 3H, ACH3), 4.98 (s,
1H, ACH), 6.81 (d, 1H, J = 7.6 Hz, ArAH), 6.99–7.08 (m, 2H, ArAH),
7.19 (s, 1H, ArAH), 7.25 (d, 2H, J = 8.1 Hz, ArAH), 7.58 (d, 2H,
J = 8.1 Hz, ArAH), 7.62 (s, 2H, ASO2NH2), 7.66 (d, 2H, J = 8.5 Hz,
ArAH), 8.04 (d, 2H, J = 8.5 Hz, ArAH), 10.10 (s, 1H, ANH); 13C
NMR (75 MHz, DMSO-d6) d (ppm): 22.85, 26.60, 29.69, 32.29,
32.43, 41.46, 49.96, 113.32, 118.12, 119.56, 124.37, 126.96,
127.75, 128.84, 129.98, 131.10, 137.27, 138.19, 141.60, 143.42,
145.24, 147.53, 150.16, 195.39; HRMS (QTOF-ESI): m/z calcd for
C
38H43N3O6S2: 701.2593; found: 700.2733 [MÀH]À.
4.4.12. N-(3-(3,3,6,6-Tetramethyl-1,8-dioxo-10-(4-sulfamoylph-
enyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9-yl)phenyl)naph-
thalene-2-sulfonamide (6l)
As white solid (ethanol), mp 207–208 °C, yield 90%. IR (cmÀ1):
3387 w (ANH2), 3244 w (ANH), 3064 w (ArAH), 2958 w (CAH),
1632 s (C@O), 1585 s (C@C), 1334 and 1156 s (SO2); 1H NMR
(300 MHz, DMSO-d6) d (ppm): 0.60 (s, 6H, 2Â ACH3), 0.80 (s, 6H,
2Â ACH3), 1.62 (d, 2H, J = 17.3 Hz, ACH2), 1.88 (d, 2H, J = 16.0 Hz,
ACH2), 2.10–2.18 (m, 4H, 2Â ACH2), 4.95 (s, 1H, ACH), 6.86 (d,
1H, J = 7.9 Hz, ArAH), 6.96–7.07 (m, 2H, ArAH), 7.23 (s, 1H, ArAH),
7.63 (s, 2H, ASO2NH2), 7.58–7.75 (m, 5H, ArAH), 7.95–8.06 (m, 5H,
ArAH), 8.33 (s, 1H, ArAH), 10.25 (s, 1H, ANH); 13C NMR (75 MHz,
DMSO-d6) d (ppm): 26.41, 29.61, 32.30, 32.37, 41.42, 49.88, 113.29,
118.40, 119.93, 122.39, 124.33, 127.76, 127.99, 128.11, 128.25,
128.92, 129.27, 129.68, 131.10, 131.96, 134.65, 137.12, 137.94,
141.56, 145.23, 147.56, 150.10, 195.34; HRMS (QTOF-ESI): m/z
calcd for C39H39N3O6S2: 709.2280; found: 708.2390 [MÀH]À.
C
36H39N3O6S2: 673.2280; found: 672.2375 [MÀH]À.
4.4.9. 4-Methoxy-N-(3-(3,3,6,6-tetramethyl-1,8-dioxo-10-(4-sul-
famoylphenyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9-yl)phe-
nyl)benzenesulfonamide (6i)
As white solid (ethanol), mp 187–189 °C, yield 87%. IR (cmÀ1):
3386 w (ANH2), 3247 w (ANH), 3088 w (ArAH), 2956 w (CAH),
1634 s (C@O), 1587 s (C@C), 1363 and 1155 s (SO2); 1H NMR
(300 MHz, DMSO-d6) d (ppm): 0.65 (s, 6H, 2Â ACH3), 0.85 (s, 6H,
2Â ACH3), 1.68 (d, 2H, J = 17.2 Hz, ACH2), 1.97 (d, 2H, J = 16.0 Hz,
ACH2), 2.18–2.22 (m, 4H, 2Â ACH2), 3.70 (s, 3H, AOCH3), 4.98 (s,
1H, ACH), 6.82–7.09 (m, 5H, ArAH), 7.16 (s, 1H, ArAH), 7.62–
7.68 (m, 6H, ArAH and ASO2NH2), 8.05 (d, 2H, J = 8.5 Hz, ArAH),
10.00 (s, 1H, ANH); 13C NMR (75 MHz, DMSO-d6) d (ppm): 26.61,
29.66, 32.28, 32.44, 41.45, 49.97, 55.98, 113.32, 114.65, 118.21,
119.66, 124.33, 127.74, 128.81, 129.13, 131.11, 131.74, 138.26,
141.59, 145.24, 147.51, 150.14, 162.67, 195.38; HRMS (QTOF-
ESI): m/z calcd for C36H39N3O7S2: 689.2229; found: 688.2352
[MÀH]À.
4.5. CA inhibition
An Applied Photophysics stopped-flow instrument has been
used for assaying the CA catalyzed CO2 hydration activity by using
method of Khalifah.33 Phenol red (at a concentration of 0.2 mM)
has been used as indicator, working at the absorbance maximum
of 557 nm, with 20 mM Hepes (pH 7.5) as buffer, and 20 mM Na2SO4
(for maintaining constant the ionic strength), following the initial
rates of the CA-catalyzed CO2 hydration reaction for a period of
10–100 s. The CO2 concentrations ranged from 1.7 to 17 mM for
the determination of the kinetic parameters and inhibition con-
stants. For each inhibitor at least six traces of the initial 5–10% of
the reaction have been used for determining the initial velocity.
The uncatalyzed rates were determined in the same manner and
subtracted from the total observed rates. Stock solutions of inhibi-
tor (0.1 mM) were prepared in distilled-deionized water and dilu-
tions up to 0.01 nM were done thereafter with the assay buffer.
Inhibitor and enzyme solutions were preincubated together for
15 min at room temperature prior to assay, in order to allow for
the formation of the E–I complex. The inhibition constants were
obtained by non-linear least-squares methods using PRISM
(www.graphpad.com), and non-linear least squares methods, val-
ues representing the mean of at least three different determina-
tions, as described earlier by us.35,36 All enzymes used were
recombinant ones, produced in Escherichia coli as reported ear-
lier.37,38 CA IX and XII were the catalytic domain only. The concen-
trations of the enzymes in the assay system were: 11.4 nM for hCA
I; 7.5 nM for hCA II, 8.6 nM for hCA IX and 10.6 nM for hCA XII,
respectively.
4.4.10. 4-Bromo-N-(3-(3,3,6,6-tetramethyl-1,8-dioxo-10-(4-sul-
famoylphenyl)-1,2,3,4,5,6,7,8,9,10-decahydro acridin-9-yl)phe-
nyl)benzenesulfonamide (6j)
As white solid (ethanol), mp 196–198 °C, yield 94%. IR (cmÀ1):
3383 w (ANH2), 3248 w (ANH), 3078 w (ArAH), 2959 w (CAH),
1633 s (C@O), 1583 s (C@C), 1338 and 1159 s (SO2); 1H NMR
(300 MHz, DMSO-d6) d (ppm): 0.65 (s, 6H, 2Â ACH3), 0.85 (s, 6H,
2Â ACH3), 1.67 (d, 2H, J = 17.2 Hz, ACH2), 1.97 (d, 2H, J = 15.9 Hz,
ACH2), 2.15–2.22 (m, 4H, 2Â ACH2), 4.95 (s, 1H, ACH), 6.86 (d,
1H, J = 7.9 Hz, ArAH), 7.02–7.15 (m, 3H, ArAH), 7.62 (s, 2H, ASO2-
NH2), 7.60–7.70 (m, 6H, ArAH), 8.05 (d, 2H, J = 8.5 Hz, ArAH), 10.25
(s, 1H, ANH); 13C NMR (75 MHz, DMSO-d6) d (ppm): 26.52, 29.69,
32.33, 32.43, 41.45, 49.93, 113.95, 118.67, 120.10, 124.59, 127.06,
127.78, 128.99, 129.05, 131.04, 132.65, 137.62, 139.17, 141.55,
145.24, 147.64, 149.80, 195.36; HRMS (QTOF-ESI): m/z calcd for
C
35H36BrN3O6S2: 737.1229; found: 736.1343 [MÀH]À.
4.4.11. 2,4,6-Trimethyl-N-(3-(3,3,6,6-tetramethyl-1,8-dioxo-10-
(4-sulfamoylphenyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9-yl)
phenyl)benzenesulfonamide (6k)
Acknowledgements
As white solid (ethanol), mp 203–204 °C, yield 88%. IR (cmÀ1):
3239 w (ANH), 3077 w (ArAH), 2957 w (CAH), 1632 s (C@O),
1584 s (C@C), 1333 and 1151 s (SO2); 1H NMR (300 MHz,
This research was financed in part by Dumlupınar University
Research Fund (Grant No. 2012-38) and by an EU FP7 Project
(Dynano).

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I. Esirden et al. / Bioorg. Med. Chem. 23 (2015) 6573–6580
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M. B.; Roskelley, C. D.; Overall, C. M.; Minchinton, A.; Pacchiano, F.; Carta, F.;
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2015.09.022.
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