An anion receptor that facilitates transmembrane proton-anion symport by deprotonating its sulfonamide N-H proton

Article abstract of DOI:10.1039/C8CC04044C

Indole-based amide-sulfonamide derivatives were synthesized. The X-ray crystal structure and chloride binding studies in solution showed a 1?:?1 stoichiometry. The ion transport efficiency directly correlated to the pK_a of the sulfonamide N-H p

Full text of DOI:10.1039/C8CC04044C

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An anion receptor that facilitates transmembrane proton-anion
symport by deprotonating its sulfonamide N−H proton
Sopan Valiba Shinde, and Pinaki Talukdar*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Indole-based amide-sulfonamide derivatives were synthesized. cell death.11
The X-ray crystal structure and chloride binding studies in solution
Prodigiosin also inspired the development of several
showed the 1:1 stoichiometry. The ion transport efficiency directly proton-chloride cotransporters, e.g. perenosins,12 tren
correlated to the pKa of the sulfonamide N−H protons. The amides,13 imidazole-appended amidopyrrole,14 tris-ureas and
mechanistic study indicated the proton-anion symport across the thioureas15 and bis(melamine)-linked bispidine16 which have
lipid bilayer membrane.
basic cores for protonation. Herein, we propose the design and
development of sulfonamide-based receptor that takes
advantage of its sulfonamide N-H proton acidity to cotransport
proton-anion across lipid bilayer membrane.
Anions play a significant role in a survival of cell by regulating
many vital processes, such as cellular pH, signal transduction,
osmotic balance, etc.1 Naturally, the anion transport across the
phospholipid bilayer is facilitated by membrane protein
machinery which assists in the anions transport as either the
mobile carrier or static channel.2 However, the malfunctioning
of these proteins underlies the number of medical
complications (i.e. channelopathies) such as Cystic fibrosis,
kidney disorders, epilepsy and myotonia.3 Many synthetic
small molecules has emerged mimicking the anion transport
behavior of specialized proteins. However, only a few of these
synthetic molecules display gating/switching behavior that is
seen in biological systems. The proton flux regulators e.g. V-
ATPase and Na+/H+ exchangers (NHE) regulate the unusual
acidic pH in the microenvironment of tumor cells and thereby
acting as a hallmark to protect tumor cells from weak basic
drugs.4 The activity of such weak basic drugs can be restored
by using a chemical agent, which is capable of deacidifying the
microenvironment of tumor cells.5 One of such most studied
carriers is prodigiosin,6 a red pigment isolated from the gram-
positive bacteria Serratia and Streptomyces.7 Prodigiosin and
its synthetic analogs are well documented for their
anticancer,6,8 immunosuppressive activity, toxicity against
fungi9 and malaria parasites.10 These molecules take
advantage of the basic nature of one ring nitrogen and bind to
proton-chloride through electrostatic and hydrogen bond
interactions, and facilitates the cotransport of the inorganic
acid across cell membranes thereby triggering the apoptotic
The structures of these molecules 1a−1g are shown in Fig.
1A. In this design, an o-phenylenediamine was connected to an
indole moiety at one end via carboxyamide linkage and ranges
of substituted phenyl rings at the other end via sulfonamide
linkage. It was envisaged that such a receptor would bind to an
anion through hydrogen bond interactions from three N-H
moieties (Fig. 1B). Upon transporting the anion across lipid
bilayer membrane, the receptor may also give up its
sulfonamide N-H proton depending on the acidity of the
proton and pH of the environment. Such an outcome is
feasible because Talukdar and co-workers have already
reported that the pKa of sulfonamide N-H protons dictates its
deprotonation, which gets reflected in the ion binding mode.17
The theoretically estimated pKa of sulfonamide N-H proton for
molecules 1a−1g are 5.59, 7.28, 6.8, 7.44, 7.28, 7.52 and 5.75,
respectively (Table 1).18 Under the acidic conditions, these
A
B
O
O
H
N
H
N
H
O
O
HN
N
NH
N
S
S
O
H
O
A
R
R
1a 1g
−
C
A− lipid membrane H+/A−
1a, R = 2,3,4,5,6-Pentafluoro
1b, R = -Br, 1c, R = -NO ,
p
p
H
H
H
H
2
H
−A
H
H
1d, R = p-Me, 1e, R = p-CF3,
1f, R = p-OMe,
1g, R = 2,4,6-Trifluoro
H
Fig. 1 Structures of receptors 1a−1g (A). Representative anion (A−) binding (B) and
transport across lipid vesicle (B).
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1
receptors were expected to transport anions. However, in analysis, based on the H NMR titrations, showed a maximum
some cases the deprotonation of sulfonamide N-H proton was at the 0.5 mole fraction, confirming 1:1 binding stoichiometry
expected resulting in the proton-anion symport process (Fig. of
1C).
1
with Cl– (Fig. S24C). Mass spectrometric analysis also
supported 1:1 binding of 1d:Cl– (Fig. S47). The binding constant
Synthesis of 1a
acid Initially, the coupling of acid
phenylenediamine to get the compound
reaction of with BF3·OEt2 led to the deprotection of the Boc 3206.35
group to obtain free amine in 90% yield. Finally, the reaction
481.5 M‒1, respectively (Table 1). For 1b and 1c, Ka values
of amine with aryl sulfonyl chloride 6a 6g in pyridine-THF could not be determined due to their poor solubility in
−
1g was initiated from indole 2-carboxylic Ka values were calculated by fitting the titration data of Ha
with N-Boc-o- proton in the WinEQNMR2 program according to the 1:1
in 88% yield. The binding model. For 1a and 1d
1g, Ka values were > 104,
88.3, 4680.31 146.8, 1911.04 140.3 and 8187.78
3.
3
2
4
−
4
±
±
±
5
±
5
−
(1:3) mixture provided the receptor 1a
−
1g in 86-95% yields acetonitrile-d3. Overall, the trend of Ka values was dependent
of the acidity of Hc i.e. stronger the electron withdrawing
(Scheme S1−S4).
The crystal structure of 1e with Cl− was obtained by slow effect of the substituted benzene ring next to the sulfonyl
evaporation of acetonitrile solution of 1e in the presence of group, better is the binding with the Cl−. For the receptor 1d, a
excess tetrabutylammonium chloride (TBACl). The single comparison of halide-binding provided the binding sequence
crystal XRD structure showed the 2:2 kosmotropic of Cl− (Ka = 3206.35
± ±
88.3 M‒1) > Br− (263.39 6.02 M‒1) > I−
complexation of 1e and Cl−, stabilized by three bridged water (Ka could not be determined due to the insignificant change of
molecules (Fig. 2A, S22). The receptor 1e forms two N–H···Cl– chemical shift) suggesting higher selectivity towards Cl− (Fig.
hydrogen bonds (Nsulfonamide···Cl− and Ncarboxyamide···Cl− distances S29−S30). However, the titration of 1d with the basic anions F−
of 3.112(4) Å and 3.256(4) Å) with angles of 143.1° and 157.4°, and AcO− as TBA salts in acetonitrile-d3 resulted in
respectively. Each Cl– further forms one C–H···Cl– hydrogen deprotonation of the receptor (Fig. S31−S32).
bond with C···Cl distance of 3.765(4) Å and the C–H···Cl– angle
of 148.7°, respectively. Each Cl− also forms a hydrogen bond fluorometrically with the help of pH-sensitive 8-
The ion transport activity of 1a−1g was investigated
with one terminal water molecule (Cl−···OH2 distance of hydroxypyrene-1,3,6-trisulfonate dye (HPTS, pKa
= 7.2),
2.926(1) Å. At the same time, the complex is further stabilized entrapped into vesicles.21 The large unilamellar vesicles were
by the additional hydrogen bond interactions of this water prepared at pH = 7.0 from egg yolk phosphatidylcholine (EYPC)
with one sulfonyl oxygen atom (H2O···Osulfonamide distance lipid with entrapped HPTS to get EYPC-LUVs⊃HPTS.
2.912(1) Å), central water molecule (H2O···OH2 distance 2.70(1) Subsequently, the extravesicular pH was raised to 7.8 by
Å) and Cortho–H of the trifluoromethylphenyl ring 3.24(1) Å). adding NaOH. The collapse of the pH gradient, upon addition
Additionally, the Hirshfield surface analysis19 also confirmed of a transporter was monitored by measuring the fluorescence
these hydrogen bonding interactions (Fig. S23). The indolic NH intensity of HPTS at λem = 510 nm (λex = 450 nm). Finally,
was engaged in the homodimerization with another molecule vesicles were lysed by adding Titron X−100 to achieve the
of 1e through NH···O=C hydrogen bond making it unavailable complete collapse of the applied pH gradient. The synthetic
for the anion binding.
receptors 1b and 1d−1f with a pKa (of sulfonamide NH proton)
The solution phase anion binding abilities of receptors greater than 7.0 exhibited significant fluorescence intensity
1g were evaluated by 1H NMR titration20 at 298 K in enhancement indicating transport of ions across the EYPC-
1a−
acetonitrile-d3 by titrating tetrabutylammonium (TBA) halides. LUVs. Comparison of ion transport activity at identical
Titration data showed significant downfield shifts of all three concentration (c = 10 μM) provided the activity sequence: 1d
NH signals e.g., Δδ = 1.72, 2.57 and 1.75 ppm for Ha, Hb and Hc, 1b 1e 1f 1c 1a 1g (Fig. 3A). Although, 1a has lower pKa
respectively for 1d (Fig. 2B), indicating the hydrogen bond than 1f, its higher ion transport activity could be attributed to
>
>
>
>
>
>
interactions of these protons with chloride ion. Job’s plot
its better membrane permeability (logP = 4.95). The dose-
response activity compound 1b 1f also provided the EC50 (the
−
concentration required to reach the 50% activity) and Hill
coefficient n values (Table 1). The Hill coefficient n values, in
general, suggested the involvement of two molecules in the
active transporter formation. For compound 1d (40 μM), no
leakage of the ANTS dye from EYPC-LUVs⊃ANTS/DPX was
observed, confirming the vesicle integrity in the presence of
the 1d (Fig. S40).
Subsequently, the most active compound 1d was selected
to investigate the ion selectivity and transport mechanism. The
selectivity studies performed on compound 1d by varying the
extravesicular ions in HEPES buffer solution.22 As expected,
insignificant change in ion transport activity was observed
upon varying metal chlorides (i.e. MCl, where, M+ = Li+, Na+, K+,
Rb+, and Cs+) in extravesicular buffer solution (Fig. S41B−S41C).
Fig. 2 Side view of the X-ray crystal structure of [1e·Cl−][Bu4N+] (A). Chemical shift
change in NH protons of 1d upon titration with TBACl (0 – 10 equiv.) (B).
2 | J. Name., 2012, 00, 1-3
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Table 1 Summary of the chloride stability constants Ka (M−1) of receptors 1a-1g calculated at 298 K and pKa values of receptors 1a−1g.
Transporter
R
2,3,4,5,6-Pentafluoro
p-Br
logP
4.94
4.99
4.16
4.73
5.10
4.06
4.65
pKa of sulfonamide NHa
Ka (M-1)b
>104
EC50 (µM)
ND
n
1a
1b
1c
1d
1e
1f
5.59
7.28
6.8
ND
ND
4.01
1.70
1.02
2.18
1.67
2.30
ND
p-NO2
ND
13.41
2.33
p-CH3
7.44
7.28
7.52
5.75
3206.35 ± 88.3
4680.31 ± 146.8
1911.04 ± 140.3
8187.78 ± 481.5
p-CF3
5.82
p-OCH3
7.56
1g
2,4,6-Trifloro
ND
aCalculator plugin of MarvinSketch program was used for calculating logP and pKa. bBinding constants were obtained based on 1:1 binding model for sulfonamide NH proton.
This data confirms that the cations are not involved in the rate quenching of intravesicular lucigenin fluorescence confirming
limiting steps of ion transport process by 1d. However, the the influx of Cl− (Fig. S43).
change of anions in the extravesicular buffer with sodium salts
−
The collapse of the applied pH during the HPTS assay can
−
(i.e. NaA, where A− = F−, Cl−, Br−, I−, NO3 , ClO4 , SCN−, and be achieved by either of M+/H+ antiport, OH−/A− antiport,
OAc−) showed a significant difference in ion transport activity M+/OH− symport, and H+/A− symport processes. The observed
providing the activity sequence: Cl− > OAc−
∼ ≥
F− Br− > SCN− > cation variation data ruled out the M+/H+ antiport and M+/OH−
−
−
NO3 > I− > ClO4 (Fig. 3B). The selectivity sequence indicated symport processes, and anion variation data are suggestive of
the involvement of extravesicular anions in the ion transport either OH−/A− antiport or H+/A− symport by 1d. The initial
process. The initial drop in the intravesicular pH in case of I− decrease of HPTS fluorescence, observed for A− = I− and ClO4
−
−
and ClO4 indicated the possibility of initial H+/A‒ influx or A‒ (Fig. 3B), is suggestive of H+ influx via H+/A− symport as one
/OH‒ antiport. The selectivity sequence neither fully concerted possible mechanism. To further cross-examine, the transport
the Hofmeister series (where the dehydration energy limits activity of 1d, in the in the presence of either FCCP (a proton
transport) nor a complete dependence on the anion size. Also, carrier) or valinomycin (a K+ carrier), was implemented.25 In
among the halides, the dehydration dominated quasi- the FCCP coupled assay, the compound 1d showed similar
Hofmeister series (i.e. Cl− > Br− > I−) was observed.23 This transport activity as in the absence of FCCP (Fig. 4A). The
indicates that both dehydration and carrier binding followed outcome corroborated to the dissipation of pH gradient
by membrane crossing are rate-limiting steps. The observation through the H+ efflux by H+/Cl− cotransport mechanism,
was also in agreement with the halide binding data of 1d instead of the OH− influx. The valinomycin25b (a K+ carrier)
obtained from NMR studies. The chloride ion transport activity performed by replacing the extravesicular Na+ with K+. The
of 1d across LUVs was further examined by monitoring the valinomycin coupled HPTS assay (with intravesicular NaCl and
fluorescence intensity of lucigenin dye (λem = 535 nm, λex = 455 extravesicular KCl) of 1d also showed ion transport that was
nm) entrapped along with nitrate inside EYPC-LUVs.24 The comparable to 1d alone (Fig. 4B). Therefore, no cooperative
addition of NaCl (33 mM) followed by 1d resulted in the
effect was seen between K+ influx by valinomycin and ion
transport by 1d, and the outcome further confirmed the H+/Cl−
symport mechanism of the amide-sulfonamide derivative.
To get more insight about the mechanism, HPTS assays
were carried out by varying the extravesicular anions and
without applying the pH gradient (i.e. pHin = pHout = 7.0). The
vesicles entrapped with NaCl were suspended in buffer
containing either of NaCl, NaBr, NaI, NaClO4 or Na2SO4 salts. In
the presence of extravesicular NaCl, the addition of 1d
resulted in the initial influx of HCl followed by slow dissipation
B
A
80
60
40
20
0
−
100
80
60
40
20
0
blank
ClO4
F−
SCN−
OAc−
Cl−
Br−
I−
NO3
−
IF
IF
-20
of the in situ generated pH gradient (Fig. 4C). In the presence
2−
k
f
1
100
200
t (s)
300
a
b
c
d
e
1
g
of poor permeating external SO42− (Hydration energy,
ꢁ
GSO
=
n
1
1
1
1
1
a
l
4
b
−1080 kJ mol−1)26 an immediate increase in HPTS fluorescence
was observed which indicate the H+/Cl− coefflux. For
Fig. 3 Comparison of ion transport activity of 1a−1g (10 ꢀM) across EYPC-LUVs⊃HPTS
recorded at 200 s after sample addition (A). Anion selectivity of 1d across EYPC-
LUVs⊃HPTS measured in presence of applied pH gradient (ꢁpH = 0.8) (B).
−
extravesicular Br−, I−, and NO3 , the quenching in the
fluorescence was observed suggesting the influx of H+/A−. The
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Izumi, T. Torigoe, H. Ishiguchi, H. Uramoto, Y. Yoshida, M.
Tanabe, T. Ise, T. Murakami, T. Yoshida, M. Nomoto and K.
Kohno, Cancer Treat. Rev., 2003, 29, 541-549.
6
7
8
R. Pérez-Tomás, B. Montaner, E. Llagostera and V. Soto-
Cerrato, Biochem. Pharmacol., 2003, 66, 1447-1452.
N. Darshan and H. K. Manonmani, J. Food Sci. Technol., 2015,
52, 5393-5407.
B. Díaz de Greñu, P. I. Hernández, M. Espona, D. Quiñonero,
M. E. Light, T. Torroba, R. Pérez-Tomás and R. Quesada,
Chem. Eur. J., 2011, 17, 14074-14083.
9
N. Someya, M. Nakajima, K. Hirayae, T. HIBI and K. Akutsu, J.
Gen. Plant Pathol., 2001, 67, 312-317.
Fig. 4 Ion transport activity of 1d (2.5 ꢀM) in the presence and the absence of FCCP (0.8
ꢀM) (A), and valinomycin (2.5 pM) (B). Anion selectivity without pH gradient (C).
10 R. K. Suryawanshi, C. D. Patil, H. P. Borase, C. P. Narkhede, B.
K. Salunke and S. V. Patil, Pestic. Biochem. Physiol., 2015,
123, 49-55.
anion symport mechanism is further confirmed by checking
the transport across EYPC-LUVs (inside 1 mM HPTS, 100 mM
NaNO3, HEPES 10 mM, pH 7.0). These vesicles were suspended
in the buffer (100 mM NaCl, 10 mM HEPES, pH = 7.0) and the
transport is monitored after the addition of 1d resulted in the
H+/NO3− efflux confirming the symport mechanism (Fig. S46).
In summary, we have synthesized 1H-indole-2-
carboxyamide-based anion receptors by further linking the
moiety to a sulfonamide with varied aryl groups. This class of
molecules was envisaged to bind anion, and transporting the
anion along with a proton by deprotonating its sulfonamide
group. The co-crystallization of 1b with TBACl revealed the
binding of two Cl− ions by two receptor molecules with the
help of multiple water molecules. The 1H-NMR titration
experiments also confirmed anion binding. All receptors
11 J. L. Sessler, L. R. Eller, W.-S. Cho, S. Nicolaou, A. Aguilar, J. T.
Lee, V. M. Lynch and D. J. Magda, Angew. Chem. Int. Ed.,
2005, 44, 5989-5992.
12 W. Van Rossom, D. J. Asby, A. Tavassoli and P. A. Gale, Org.
Biomol. Chem., 2016, 14, 2645-2650.
13 (a) L. A. Jowett, E. N. W. Howe, V. Soto-Cerrato, W. Van
Rossom, R. Pérez-Tomás and P. A. Gale, Sci. Rep., 2017, 7,
9397; (b) K. J. Winstanley, S. J. Allen and D. K. Smith, Chem.
Commun., 2009, 4299-4301.
14 P. A. Gale, M. E. Light, B. McNally, K. Navakhun, K. E. Sliwinski
and B. D. Smith, Chem. Commun., 2005, 3773-3775.
15 N. Busschaert, M. Wenzel, M. E. Light, P. Iglesias-Hernández,
R. Pérez-Tomás and P. A. Gale, J. Am. Chem. Soc., 2011, 133
,
14136-14148.
16 S. V. Shinde and P. Talukdar, Angew. Chem. Int. Ed., 2017, 56
,
showed ion transport activity in the order 1d
> 1b > 1e > 1f >
4238-4242.
1c > 1a > 1g. The detailed mechanistic investigation with the
17 (a) A. Roy, O. Biswas and P. Talukdar, Chem. Commun., 2017,
53, 3122-3125; (b) T. Saha, M. S. Hossain, D. Saha, M. Lahiri
and P. Talukdar, J. Am. Chem. Soc., 2016, 138, 7558-7567.
18 Marvin 5.8.0, ChemAxon 2012 (http://www.chemaxon.com).
19 (a) M. J. Turner, J. J. McKinnon, S. K. Wolff, D. J. Grimwood, P.
R. Spackman, D. Jayatilaka and M. A. Spackman,
CrystalExplorer17 (2017); (b) J. J. McKinnon, A. S. Mitchell
most efficient transporter demonstrated the proposed proton-
anion symport process. This class of molecules may be useful
in targeting the solid tumors by promoting intracellular
acidification.
We thank SERB, Govt. of India (EMR/2014/000873B and
EMR/ 2016/001897) for funding. S.V.S. thanks CSIR for the
research fellowship.
and M. A. Spackman, Chem. –Eur. J., 1998, 4, 2136-2141; (c)
J. J. McKinnon, D. Jayatilaka and M. A. Spackman, Chem.
Commun., 2007, 3814-3816.
Conflicts of interest
20 L. Fielding, Tetrahedron, 2000, 56, 6151-6170.
21 K. Kano and J. H. Fendler, Biochim. Biophys. Acta, Biomembr.,
1978, 509, 289-299.
There are no conflicts to declare.
22 N. Sakai and S. Matile, J. Phys. Org. Chem., 2006, 19, 452-
Notes and references
460.
1
2
R. Hesketh, J. Cell Sci., 2000, 113, 2925-2926.
S. S. Mansy, Cold Spring Harbor Perspect. Biol., 2010,
a002188.
23 (a) A. V. Jentzsch, D. Emery, J. Mareda, S. K. Nayak, P.
Metrangolo, G. Resnati, N. Sakai and S. Matile, Nat.
Commun., 2012, 3, 905; (b) Y. Zhang, P. S. Cremer, Curr.
Opin. Chem. Biol., 2006, 10, 658-663
24 B. A. McNally, A. V. Koulov, B. D. Smith, J.-B. Joos and A. P.
Davis, Chem. Commun., 2005, 1087-1089.
2,
3
4
(a) B. Schwappach, Nat. Cell Biol., 2000,
2, E169; (b) D.
Bockenhauer, Curr. Opin. Pediatr., 2001, 13, 142-149.
E. P. Spugnini, P. Sonveaux, C. Stock, M. Perez-Sayans, A. De
Milito, S. Avnet, A. G. Garcia, S. Harguindey and S. Fais,
Biochim. Biophys. Acta, Biomembr., 2015, 1848, 2715-2726.
(a) O. Tredan, C. M. Galmarini, K. Patel and I. F. Tannock, J.
Natl. Cancer Inst., 2007, 99, 1441-1454; (b) N. Raghunand
25 (a) R. Benz and S. McLaughlin, Biophys. J., 1983, 41, 381-398;
(b) P. Bhattacharyya, W. Epstein and S. Silver, Proc. Natl.
Acad. Sci. U.S.A., 1971, 68, 1488-1492.
5
26 Y. Marcus, J. Chem. Soc., Faraday Trans., 1991, 87, 2995-
2999.
and R. J. Gillies, Drug Resist. Updat., 2000, 3, 39-47; (c) H.
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