Pyridine/pyridinium symmetrical bisamides as functional materials: Aggregation, selective sensing and drug release

Article abstract of DOI:10.1039/c7nj03931j

Pyrrole and furan-based pyridine/pyridinium bisamides 1-4 have been designed and synthesized with a view to establishing new supramolecular gelators. The neutral gelators 1 and 2 were explored for cation binding. While the furan analogue 1 forms gel in the presence of Ag⁺ and Cu²⁺ ions in DMSO:H₂O (1:1, v/v), the pyrrole conjugate 2 exhibits metallogel formation selectively with Ag⁺ ions and corroborates the role of the heteroatom in the spacer that modulates the self assembly behavior of the gelators. As an application, the 1-Cu gel selectively distinguishes thiol-based amino acids from a series of other amino acids as well as effectively discriminates d-glucose from its C₂-epimer d-mannose by exhibiting gel to sol transformation. Additionally, encapsulation and subsequent release of the chemopreventive drug curcumin has been studied using the 1-Cu gel. Placement of a cholesterol unit onto the structures 1 and 2 resulted in charged structures 3 and 4 of which compound 4 produced an unambiguous visual readout of F^- and AcO^- ions by showing gel to sol transition.

Full text of DOI:10.1039/c7nj03931j

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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JOURNAL NAME
ARTICLE
Pyridine/pyridinium Symmetrical Bisamides as Functional
Materials: Aggregation, Selective Sensing and Drug release
Received 00th January 20xx,
Accepted 00th January 20xx
Santanu Panja, Sumit Ghosh and Kumaresh Ghosh*
DOI: 10.1039/x0xx00000x
Abstract: Pyrrole and furan-based pyridine/pyridinium bisamides 1-4 have been designed and synthesized with a view of
establishing new supramolecular gelators. The neutral gelators 1 and 2 were explored in cation binding. While the furan
www.rsc.org/
+
2+
2
analogue 1 forms gel in the presence of Ag and Cu ions in DMSO: H O (1:1, v/v), the pyrrole conjugate 2 exhibits
+
metallogel formation selectively with Ag ions and corroborates the role of the heteroatom in the spacer that modulates
the self assembly behavior of the gelators. As an application, the 1-Cu gel selectively distinguishes thiol-based amino acids
2
from a series of other amino acids as well as effectively discriminates D-glucose from its C -epimer D-mannose by
exhibiting gel to sol transformation. Additionally, encapsulation and subsequent release of the chemopreventive drug
curcumin has been studied by using the 1-Cu gel. Placement of cholesterol unit onto the structures 1 and 2 resulted in
-
-
charged structures 3 and 4 of which compound 4 produced unambiguous visual readout of F and AcO ions by showing gel
to sol transition.
2
6,31-36
scope of applications.
Introduction
Recently, the metallo-supramolecular gels originated from
interaction of metal ions with gelators has received attention
Recent years have witnessed great surge of interest in
exploiting self-assembled small organic molecules as functional
2
4,31,37-42
because of their wide applications in different areas.
In
1
-9
exploring this class of compounds, the use of pyridine
including other functionalities is worth mentioning. The
literature survey reveals that there are a number of
architectures which contain pyridyl ureas/amides as the
functional entities. While the pyridyl motif is engaged in metal
coordination, the other functionalities ureas/amides remain
engaged in making hydrogen bonded network to establish
materials. The self-aggregation properties of such molecules
enable them to immobilize solvents to form semisolid
viscoelastic materials, called gels. Various non-covalent
interactions such as hydrogen bonding, π-π stacking, van der
Waals interactions etc. incite the molecules to form
intermolecularly linked three dimensional aggregates in which
the solvent molecules are entrapped. In this regard, the
functional groups of the molecules that influence the self-
3
8-43
cross-linked networks in suitable solvents.
Metal
1
0-13
coordination of the pyridyl centre sometimes influences the
hydrogen bonding capabilities of the ligands (via C=O and N–H
groups) for which self-assembly is controlled in more
directional way. In this regard, different types of spacers that
hold the functional entities play decisive role in the formation
of assemblies. In addition to self-aggregation behaviors,
bisamides with other various architectures find application in
linking play important role.
Sometimes, the self
aggregation of the molecules are tuned by external stimulus
such as light, redox, pH, ions etc. This provides a scope to
develop stimuli responsive gels. Of various stimulus, ion
1
4-23
coordination draws attention for their visual detection.
Not
only visual detection but also emphasis has been given to such
special class of compounds for their potential applications in
4
4
2
4-30
asymmetric catalytic synthesis.
Despite of such
medicine to materials.
To establish these materials, a study
information/reports in the literature, there is enough scope to
deal with simple and easy to synthesizable molecular systems
for task-specific applications.
on correlation between gelling behaviour and structural
parameters of gelators is another domain of interest in
designing new functional molecular gelators that increase the
In this account, we wish to introduce some symmetrical,
neutral and charged pyridyl bisamides 1-4 that behave
excellently as functional materials in sensing and drug delivery.
Department of Chemistry, University of Kalyani, Kalyani-741235, India. Email:
ghosh_k2003@yahoo.co.in, Fax: +913325828282; Tel: +913325828750.
Of the different bisamides 1-4, compounds
1 and 2 possess
metal coordinating pyridyl nitrogens whereas quaternization
†
Electronic Supplementary Information (ESI) available: Gelation results, chemical
1
and thermal responsiveness, absorption spectra, FTIR and H NMR spectra, binding of those nitrogen atoms with cholesteryl unit resulted in
1
13
curves, and copies of H, C NMR and HRMS can be found in the supporting
information. See http://dx.doi.org/10.1039/b000000x/
charged structures
3
and
4. The gelling abilities of the
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compounds were studied thoroughly. The furan analogue
+
1
5a and 5b in the presence of Et
3
N in dry CH
and , respectively. On
the other hand, reaction of cholesterol with chloroacetyl
2 2
Cl at room
2+
forms gel in the presence of Ag and Cu ions in semi aqueous temperature afforded compounds
1
2
H
N
H
2
4
N
chloride gave compound
with the chloride
corresponding chloride salts which upon anion exchange using
NH PF in aqueous CH OH containing 10% DMF afforded the
desired compounds and , respectively, in appreciable yields.
6.
Salt formation reactions of
1 and
H
H
X
N
N
O
O
2
6
in dry DMF-CH CN produced the
3
- N
R
X
N
R
PF6-
PF6
O
O
O
O
N
N
3
; X = O
1
2
; X = O
; X = NH
O
O
4
6
3
4 ; X = NH
3
4
All the compounds were characterized by usual spectroscopic
techniques.
R =
H
H
H
(ii)
H
H
HO
OH (i)
Cl
N
Fig. 1. Structures of compounds
1
-
4
.
Cl
N
X
X
X
O
O
O
O
O
O
N
N
1 ; X = O
; X = NH
X = O , NH
solvents. In comparison, the pyrrole-based structure
2
exhibits
+
5a ; X = O
b ; X = NH
2
5
metallogel formation selectively in the presence of Ag ions
and thereby indicating the role of spacer in intermolecular
(iv)
O
(
iii)
R
OH
R
Cl
O
association. On the other hand, the charged structure
4
H
N
H
6
N
X
formed gel from DMSO:H O (1:1, v/v) and behaved as
2
O
O
-
-
N
R
PF -
6
N
R
R =
PF
-
6
excellent media to visual readout of F and AcO ions over a
series of other anions via gel to sol transition. Sensing of ions is
essentially important due to their environmental and
H
H
O
O
H
3; X = O
; X = NH
O
O
4
4
5,46
physiological significances.
Apart from ion recognition, the
Scheme 1. (i) SOCl
dry CH Cl
rt, 10h; (iv) a.
OH (1:10, v/v), H
2
2
, dry CH
Cl
2 2
,, reflux, 10h; (ii) 3-aminopyridine, Et
Cl
PF6, DMF:
3
N,
utility of the metallogels for some other purposes such as
discrimination of amino acids and carbohydrates demands
2
2
, rt, 16-18h; (iii) Chloroacetyl chloride, pyridine, dry CH
, dry DMF, dry CH CN, reflux, 3 days; b. NH
O.
2
2
,
6
3
4
precise attention owing to their close physical and chemical CH
3
4
7-50
properties.
Of the different amino acids, thiolated amino
acids L-cysteine and L-glutathione act as biomarkers of Aggregation and sensing studies on 1 and 2
5
1,52
cancer.
Moreover, in human body, transport pathways of Compounds 1 and 2 are structurally simple bispyridine amides
D-glucose is linked with cancer, cystic fibrosis, renal glycosuria with furan and pyrrole as linkers, respectively. It is noteworthy
etc. and of course to diabetes mellitus arises from the that such bisamides can assume different equilibrium
4
7,53
ineffective D-glucose transport.
gel has been noted to detect thiol containing amino acids from shown in Fig. 2.
a series of other amino acids and also to discriminate D- hydrogen bond donor or acceptor group influences the
In this context, the 1-Cu conformations (In–In, In–Out and Out–Out) in solution as
2
1,55
The nature of the linker or spacer with
glucose from its C -epimer D-mannose by exhibiting a clean gel population of the individual form. While the ‘In-In’ form of
2
1
is
is
to sol phase transformation.
stable through hydrogen bond formation, the same in 2
In addition, release of curcumin from
1-Cu gel matrix was considerably less favorable due occurrence of repulsive
followed to realize the possible application of the metallogel in interaction among the polar N-H bonds. Such conformational
drug delivery. It was observed that L-glutathione being more behaviors of the compounds are responsible for their
effective than L-cysteine released the encapsulated aggregation involving different modes of interactions.
chemopreventive drug curcumin from the 1-Cu gel matrix. The
(
a)
H
N
H
N
H
N
O
R
O
R
O
R
bioactivities (neuroprotection, chemo-, and cancer prevention)
of curcuminoids have gained attention as they not only have
anti-inflammatory activity but also induce endogenous
antioxidant defense mechanisms in the organism and
R
R
R
O
O
O
N
N
N
N
N
O
O
O
H
H
H
In-In
In - Out
Out - Out
(b)
H
N
H
N
O
R
O
R
H
N
5
4
O
R
N
H
R
R
R
influence gene expression as well as epigenetic mechanisms.
N
N
O
H
NH
O
O
H
However, although curcumin itself has very limited or low
toxicity, due to poor water solubility and bioavailability,
H
H
In-In
In - Out
Out - Out
5
3
method to increase their bioavailability is highly desirable.
Fig. 2. Possible different conformations of the bisamides
b).
1 (a) and 2
Hence the demetallation of curcumin encapsulated metallogel
by biomolecules provides a useful strategy for effective in vivo
analysis of drug therapy.
(
Thus the gelation propensities of
various polar and nonpolar solvents (Table 1S). Interestingly,
both the compounds and exhibited non-gelating
1 and 2 were investigated in
Results and discussion
1
2
behaviour, resulting in either solution or precipitation.
However, addition of metal salts to the semi aqueous solution
Synthesis
Compounds 1-4 were synthesised according to the Scheme 1.
Coupling of 3-aminopyridine with respective diacid dichlorides
of
1
and
2
caused instant gel formation. Among various metal
2
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+
2+
ions, only Ag and Cu induced gelation of
1
in THF, MeOH, closely spaced globular microstructures were observed for Ag-
(Fig. 4).
temperature. We also investigated the effect of other metal We believe that ligands
ions during gelation of in DMSO: H O (1:1, v/v). Interestingly arrangements out of different possibilities during gel
except Ag and Cu , other metal ions taken in the study were formation with metal ions (Fig. 1S). Strong metal chelation
found to be futile in bringing gelation of under similar involving the pyridyl motifs, presumably regulates the
conditions (Fig. 3A). This observation intimates that the visual formation of intermolecular hydrogen bonds between amide -
1,4-dioxane, DMF and DMSO in presence of water at room gel of 2
1
and 2 follow linear packing
1
2
+
2+
1
+
2+
sensing of Ag and Cu ions by
phase transformation.
1 is possible through sol-gel NH and carbonyl functionalities that stabilize the networks. To
understand this, FTIR spectra of
and gel states were recorded. For
1
and
2 in their amorphous
1
, while in amorphous state
-
the stretching frequency for amide C=O appaeared at 1681 cm
A
1
-1
as sharp signal, in the gel state it was reduced to 1650 cm
and became broad (Fig. 2S). Moreover, stretching frequency
for the amide -NH of moved to the lower region by 43 and 54
1
+
2+
units in the gel states with Ag and Cu , respectively. These
findings undoubtedly confirmed the important roles of metal
chelation and hydrogen bonding during gelation. On the other
hand, stretching frequency of amide carbonyl in
2 slightly
B
moved to the higher value in gel state (Fig. 2S) which also
+
corroborated Ag coordination.
The selective metal ion interactions of
1 and 2 were also
understood in solution by UV. UV-vis titrations of the
-5
compounds (c = 2.50 x 10 M) were carried out with different
-3
metal ions (taken as perchlorate salts, c = 1.0 x 10 M) in
DMSO: H O (1:1, v/v). In UV-vis, compound initially exhibited
absorbtion maxima at 297 nm. During titration with Ag and
Fig. 3. Photograph showing the phase changes of (A) 1 and (B) 2 in
DMSO: H O (1:1, v/v, [gelator] = 5 mg/mL) in presence of 2 equiv.
amounts of different metal ions [c = 0.05 M in H O as perchlorate salt]
2
2
1
2
+
2
+
Cu
ions, the intensity of this peak was decreased
after 1h.
considerably without showing any other change in the
absorption spectra (Fig. 3S). Titration with other metal ions
On moving from compound
hetero atoms in the spacer, a significant change in the self
aggregation of in the presence of metal ions was noticed.
Here only Ag ions formed thick gel instantly and the other
1 to 2, representing the different
resulted in negligible change in the absorbance of
1 (Fig. 4S).
In case of 2, substantial decrease in the absorption at 306 nm
+
2
+
was observed during titration with Ag . However, a ratiometric
response in the absorption spectra with an isosbestic point at
2
+
metal salts including Cu led to precipitation (Fig. 3B). It is
mentionable that presence of less than 2 equiv. amounts of
2
+
4
6
30 nm was observed upon gradual addition of Cu along with
nm bathochromic shift in absorption spectrum (Fig. 3S). The
metal ions displayed partial gelation of both 1 and 2.
change in absorbance of
2 with other metal ions was negligible
The surface morphologies of the metallogels were studied by
SEM images which showed rod and globular like structures.
This depends on the nature of the gelators and the metal ions
(
Fig. 4S). The binding constant values were ascertained by non-
5
6
linear fitting of the absorption titration data and the 1:1
5
binding interaction was confirmed by job plots. From the
7
(
Fig. 4). While the Ag-gel of
exhibited non-twisted rod like networks, Cu-gel of
similar conditions revealed flower like matrices. In comparison,
1 from DMSO/H O (1:1, v/v)
2
+
-Ag ,
plots, the association constants for the complexes
+
-Ag and
1
1-
3
1
under
2
Cu ,
+
2+
2-Cu were estimated to be (1.61 ± 0.27) x 10
2
-1
3
M , (1.99 ± 0.29) x 10 M , (3.40 ± 0.27) x 10 M and (7.41 ±
-1
3
-1
3
-1
.32) x 10 M , respectively (Fig. 5S).
0
(
a)
(b)
(c)
(f)
1
2+
In H-NMR of
1
in the presence of equivalent amounts of Cu
and Ag ions, no significant changes in chemical shift values of
the amide protons (H ) as well as pyridine o-protons H were
+
a
b
observed. In presence of the indicated metal ions, small
upfield chemical shift for all types of protons was observed
+
(
Fig. 6S). In case of
in marked upfield chemical shift of protons H
other aromatic protons including pyrrole hydrogen H
Such change in chemical shift of the indicated protons in both
and defines the metal-ligand interaction in solution.
2
, addition of equiv. amount of Ag resulted
(
d)
(e)
a
, H
b
as well as
(Fig. 7S).
c
1
2
To examine the mechanical properties of the metallogels,
rheology experiments (Fig. 5) were performed where the
Fig. 4. SEM images of xerogel of 1. Ag (a and b), 1.Cu (c and d) and 2. variation of dynamic storage modulus G’ and corresponding
+
2+
+
2
Ag (e and f) prepared from DMSO:H O (1:1, v/v).
loss modulus G’’ were measured as a functions of strain and
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frequency. A nonlinear response of both G’ and G’’ were Application of Cu-gel of 1
observed with the applied strain amplitude at a fixed a) Biomolecule recognition
frequency (ω = 10 rad/s). With gradual increase in the applied Of the Cu- and Ag-gels of
1, the Cu-gel was explored in
stress both G’ and G’’ were deviated from linearity and beyond selective recognition of some amino acids and carbohydrates.
a certain stress a sharp fall of both G’ and G’’ values were Recognition and discrimination of amino acids and
observed indicating that the gel started to collapse. The stress carbohydrates are very much crucial due to their physiological
sweep experiments exhibited crossover points at yield stress relevance. However, owing to their close physical and chemical
+
2+
+
of 6 Pa, 10 Pa and 23 Pa for the 1-Ag , 1-Cu and 2-Ag gels, properties demands sophisticated tools for effective detection.
2
respectively. Trend of these crossover points is in agreement Due to thiol responsive behaviour of Cu gel of 1, initially a
+
with the solution phase binding interaction. However, in series of amino acids with or without thiol group were tested
frequency sweep experiment at a fixed strain of 1%, both G’ for their selective sensing. When aqueous solutions of
and G’’ were frequency invariant over the entire range studied different amino acids (c = 0.03 M) were added to the gel
2
+
and the values of G’ were more than 2 to 8 times higher than derived from
2
1 with 2 equiv. amounts of Cu in DMSO:H O
those of G’’ at any frequency, signifying dominant elastic (1:1, v/v), L-cysteine disrupted the gel into a colorless solution
character of the metallogels.
within 15 mins (Fig. 6). Under identical conditions, other amino
acids including L-methionine caused negligible effect on the
gel state. This occurred presumably due to strong coordination
G' -Ag
G'' -Ag
1
1
G' -Ag
G'' -Ag
1
000000
1000000
1
1
2+
G' -Cu
G'' -Cu
G' -Cu
G'' -Cu
1
1
1
1
of L-cysteine with the Cu ion that caused demetallion
G' -Ag
G'' -Ag
G' -Ag
G'' -Ag
2
2
2
2
100000
100000
involving the thiol group. Similar results were also obtained for
other thiol containing amino acids like DL-homocysteine and L-
glutathione but they took ~1h to produce off-white colored
precipitation (Fig. 10S). To understand the interaction of
1
0000
10000
1000
1000
1
00
copper ensemble of
amounts of Cu(ClO
1
, prepared by mixing
1 with 2 equiv.
100
1
0
0.1
1
10
100
)
2
in DMSO:H O (1:1, v/v), with the amino
2
0
.01
0.1
1
10
100
4
Ang. Frequency (rad/sec)
%
strain
acids, UV-vis titrations were performed. As can be seen from
Fig. 11S, the ensemble shows measurable interaction only with
L-cysteine, DL-homocysteine and L-glutathione by exhibiting
increase in absorption in the region 290 nm to 300 nm. Other
amino acids in the study weakly decreased the absorption.
Fig. 5. Rheology experiments of the metallogels of
O (1:1, v/v).
1 and 2 in DMSO:
H
2
In order to determine the thermal stability of the gels, gel
melting temperature (Tgel) was measured in DMSO: H O (1:1,
2
v/v) on keeping the metal concentration fixed (2 equiv.) and
plotted against the gelator concentration (Fig. 8S). For all the
cases, there was a sharp increase in Tgel with gelator’s
2
+
concentration. Similar to greater interaction of
1 with Cu
+
2+
than Ag in solution, compound
1
formed stable gel with Cu
than Ag with slight lower mgc value. Compound , on the
other hand, was found to form gel with Ag at minimum
concentration of 2.2 mg/mL in DMSO: H O (1:1, v/v) having Tgel
+
2
+
2
of 60 °C. The gels were thermo reversible and gave distinct
phase changes upon heating and cooling (Fig. 8S). Similar gel
to sol transition was also observed in the presence of external
chemical stimulus at room temperature. Addition of 2 equiv.
-
amounts of Cl ions to the Ag-metallogels of
1 and 2 caused
rapid destruction of the gels within 2h by scavenging the
+
intermolecularly bound Ag ions from the gel matrices. Further Fig. 6. Pictorial representation on chemical responsiveness of the Cu
2+
+
2+
2
1 ([gelator] = 5 mg/mL with 2 equiv. of Cu in 1:1 DMSO: H O)
gels of
addition of Ag ions to the broken gels endows the ligands
and to become thick after 1h by attending required
structural feature responsible for gelation (Fig. 9S). On the
other hand, Cu-gel of
upon successive addition of excess amounts of 1- k. L-glutamic acid].
1
in the presence of 2 equiv. amounts of different amino acids (c = 0.03
M) and C-2 epimeric carbohydrates D-glucose and D-mannose (c = 0.03
M) [a. glycine, b. L-valine, c. L-alanine, d. L-phenylalanine, e. L-proline,
2
1
exhibited gel-sol reversible transition f. L-cysteine, g. L-lysine, h. L-threonine, i. L-hystidine, j. L-methionine,
2
+
-
dodecanethiol and Cu , respectively (Fig. 9S). Addition of Cl
ions to the Cu-
metallogels of
1
1
gel did not cause sol formation. Thus the Beside amino acids, the use of carbohydrates in bringing gel to
behaved differently with respect to the sol phase transition was followed. Carbohydrates, associated
-
externally added chelating agents and Cl ions, in this context, with biological molecular recognition processes, are important
+
2+
can discriminate the Ag and Cu -metallogels. Of the Cu- and targets for their selective recognition or detection. In this
Ag-gels, the Cu-gel was used to investigate its scope of regard, several synthetic receptors which do function in
solution are known in the literature. But the use of
5
8
application.
4
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metallogel in this aspect is unknown. Interestingly, in the presence of L-cysteine and L- glutathione was monitored. For
2
+
present endeavour, the 1-Cu gel effectively distinguished D- such study, initially the gel was prepared by mixing of
glucose from its C-2 epimer D-mannose. While addition of D- curcumin followed by the addition of 2 equiv. amounts of Cu
glucose ruptured the gel into sol by complexing the chelated in DMSO-H O (1:1, v/v). Thus the Cu-gel containing curcumin
1 with
2
+
2
2
+
Cu ions (after 3h), under similar conditions D-mannose did showed different morphology (nano rods) as well as an
o
not show any effect on gel to sol transition (Fig. 6). Moreover, increase in gel melting temperature (by 6 C) with respect to
under identical conditions, D-xylose, D- galactose, D-ribose, D- the Cu-gel of 1 without curcumin (Fig. 7A).
glucosamine etc., brought gel to sol conversion and effectively When aqueous solutions of L-cysteine and L- glutathione were
distinguished D-mannose from them. We presume that the added on the top of the gel at room temperature, the light
presence of axial OH at C2 in D-mannose does not allow its green colored gel started to disintegrate resulting in yellow
2
+
coordination with Cu in gel matrix. This is in contrast to the colored solution (due to release of curcumin) (Fig. 7A). A time
others in the present study. Thus the demetallation from 1- dependent UV-vis study was performed by taking certain
2
+
Cu gel could be an effective strategy in recognition of thiol amount of the supernatant solution periodically to monitor the
containing amino acids and in discrimination of two C-2 kinetics of the drug release experiment. With time, the
epimeric carbohydrates.
intensity of the peak at 435 nm for curcumin was gradually
increased. After 50 mins analysis revealed ~92% release of the
drug into the solution with L-cysteine (Fig. 12S). Interestingly,
b) Drug delivery
Development of suitable systems for delivery of hydrophobic L- glutathione was established to be more effective than L-
drugs is a challenging aspect in bioscience because of their cysteine as it responded for a long period of time (greater than
3
5,59
poor solubility in water.
An example is curcumin, a 2h) to release 87% of the drug (Fig. 7B). Figure 7C, in this
naturally occurring yellow colored phenol that exhibits regard, corroborates the steady release of curcumin from the
therapeutic efficacy against carcinogenesis and tumor growth. composite gel matrix with time in the presence of L-
The working-effectivity is linked with its limited solubility in glutathione. Hence, L- glutathione is observed to be a
5
4
water and very low bioavailability. Alongside, the challenging promising agent in releasing curcumin through the gradual
2
+
hurdle for development of a delivery system is to impart target disruption of Cu -gel. Thus the noncovalent approach in
specificity for the tumor cells. Thus target-specific delivery formulation of self-assembled metallo-supramolecular
system is highly demanding to improve the bioavailability of architectures followed by the demetallation technique using
the hydrophobic drugs. Moreover in cancer cell relative biomolecules may be a useful strategy to fabricate new
concentration of L-cysteine and L-glutathione remains as molecular systems for effective in vivo analysis of
[
51,52]
2+
high.
gelation of
Keeping these in mind, while the Cu -induced encapsulation and subsequent release of drugs.
was used in loading curcumin, its release in
1
Compounds 3-4 and their gelation and anion binding studies
Structural tuning of the bisamides and led to the organic
salts and , respectively. Compounds and are the
1
2
(
A)
3
4
3
4
fascinating integration of cholesteryl units with the pyridyl
amide motifs, flanked by rigid aromatic spacer. The different
conformational behaviors of the amides as shown in Fig. 2,
may introduce cross-linked hydrogen bonded network in
solution for which gelation may take place. Thus the gelation
nature of compounds
solvents and only the pyrrole-based salt
colored gel in DMSO:H O (1:1, v/v) (Table 2S). Under similar
conditions, the nongelation tendency of the furan analogue 3
3
and
4
was studied in a variety of
Curcumin
5 mins
15 mins
1
0
0
0
0
.2
.9
.6
.3
.0
(B)
1.2
4
formed light yellow
(
C)
30 mins
2
45 mins
0
.9
.6
6
7
0 mins
5 mins
90 mins
05 mins
120 mins
presumably signified the subtle role of the heteroatom in the
aromatic spacer in forming intermolecular association during
gelation.
0
1
1
1
35 mins
40 mins
L- glutathione
L-cysteine
0.3
150 mins
2
The DMSO:H O (1:1, v/v) gel of 4 exhibited thermoreversible
0
.0
0
30
60
90
120
150
3
50
400
450
500
550
Time (mins)
phase transition and at mgc (48 mg/mL) the Tgel value was
o
recorded to be 62 C (Fig. 13S). SEM image revealed the
Wavelength (nm)
Fig. 7. (A) Photograph showing the phase change of the curcumin
encapsulated Cu-gel of upon treatment with (a) L- glutathione and
b) L-cysteine along with the SEM image (scale bar 200 nm) of the
curcumin loaded gel; (B) Change in absorbance of the supernatant
formation of rock-like porous surface (Fig. 8A). We presume
that such morphology is due to packing arrangement of the
molecules shown in Fig. 14S. Here also the molecules can
1
(
solutions obtained from L- glutathione and L-cysteine responsive attain more stable out-out conformation in solution where the
release of curcumin from the composite gel with time; (C) UV-vis amide –NHs and pyridinium ortho-protons (H ) are the
spectra of the resulting supernatant solution obtained from L-
o
possible hydrogen bond donors that encourage the
glutathione responsive release of curcumin from the composite gel at
different time intervals (the dotted line indicates the absorbance of
curcumin before loading).
intermolecular aggregation. This is in accordance to our
2
1,60
previous observation.
To support this proposition, FTIR
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-
was recorded in its amorphous and gel states (Fig. mentionable that, although F -sensitive gelators are
spectra of
4
60-66
-
AcO responsive LMWGs are heardly reported.
67
1
5S). The lowering of stretching frequency of both amide and numerous,
-1
-1
-
ester carbonyl by 29 cm and 3 cm respectively, indicates the Thus gelator
formation of a number of intermolecular hydrogen bond To understand the affinity of
contacts during gelation. Moreover, the role of cholesterol solution, UV-vis titrations of (c = 2.5 x 10 M) was carried out
units in stabilizing such hydrogen bonded network through in DMSO. Compound initially exhibited strong absorbtion at
hydrophobic-hydrophobic interactions cannot be ignored. 325 nm. During titration with F and AcO ions, the intensity of
Compound consisting of pyridinium amide was responsive this peak was gradualy decreased and a new band at 343 nm
4
is a new insight in visual detection of AcO ions.
4
towards the basic anions in
-
5
4
4
-
-
4
towards anionic substrates in the gel state. For this, a series of was simultaneously appeared with significant intensity leading
anions (as tetrabutylammonium salts) were undertaken. When to the formation of isosbestic point at 333 nm (Fig. 18S).
concentrated solutions of the anions were added on the top of Titration with other anions produced no significant change in
the gel, the gel state of
4 was rapidly ruptured into sol the absorbance of 4. Figure 19S represents the absorption
-
-
selectively in the presence of F and AcO ions within 2h. Other profile where ratiometric increase in absorption at 343 nm
-
-
anions produced negligible perturbation on the gel state of
4
distinguishes F and AcO ions from the other anions and
Fig. 8B). We believe that, F and AcO ions, owing to their high corroborates their selective detection in the solution phase
or moderate basicity, strongly interact with the pyridinium too. The absorption titration data were fitted to the Benesi-
-
-
(
6
8
amides through hydrogen bonding and charge-charge Hildebrand plots and the linear nature of the plots suggested
interactions. As a result, the intermolecular hydrogen bonded 1:1 binding (Fig. 20S). From the plots, the association constants
4
network is destroyed and sol formation occurs. This were also calculated and they were found to be 3.61 x 10 M
-1
2
1
4
-1
-
-
observation is in contrast to our earlier observation where and 5.01 x 10 M , for F and AcO ions respectively (Fig. 20S).
the isophthaloyl spacer of similar structure were non-
-
-
and AcO ions in gel to sol
responsive to both
transformation.
F
Conclusions
In conclusion, the gelation propensities of 3-aminopyridine-
based designed bisamides 1-4 have been thoroughly
investigated. The gelation characteristics of the bisamides are
dependent on the nature of the linker/spacer that signifies the
role of hydrogen bond donor and acceptor in forming the
aggregation in solution. Among the gelators, neutral
(A)
compounds
1 and 2 show gelation/aggregation in the presence
of the metal ions. In the study, while the furan analogue
2+
1
+
formed gel in the presence of Ag and Cu ions in aqueous
DMSO, under identical conditions the pyrrole analogue
(B)
2
+
exhibited selective gelation with Ag ions and validates their
visual sensing. Thus the spacer with heteroatom bearing
different hydrogen bonding features governs the molecular
arrangements and exhibit different metal coordination
attributes in solution.
The gel phases of the gelators show variety of applications. It is
Fig. 8. (A) SEM images of xerogel of
Photographs showing the phase changes of the DMSO: H
gel of (48 mg/mL) upon addition of 4 equiv. amounts of different
4
anions (c = 0.2 M, (a) F , (b) Cl , (c) Br , (d) I , (e) AcO , (f) H PO , (g)
4
from DMSO: H
2
O (1:1, v/v); (B)
established that Cu-gel of
selective detection of thiolated amino acids and in
discrimination of D-glucose from its C -epimer D-mannose
1 is significantly useful material in
2
O (1:1, v/v)
4
-
-
-
-
-
-
2
2
-
-
HSO
4
, (h) NO
3
) after 2h.
involving gel to sol phase transformation. Sugar discrimination
by design-based gelator through gel-sol or sol-gel transition is
1
However, H-NMR spectra of
4
in the presence of equiv. of enormous interest and in the present context, the Cu-gel of
draws attention. More importantly, Cu gel of has been
interaction. Due to hydrogen bond induced broadening, it was successfully applied in encapsulation and release of curcumin.
-
-
amount of F and AcO ions were recorded to understand the
1
1
1
-
difficult to record H-NMR spectrum with F ion. However, with Thorough study reveals that L-glutathione is a promising
-
AcO ion, the disapearance of the signals at 12.09 ppm and candidate in slow releasing of curcumin via slow rupturing of
1
0.97 ppm for amide –NHs (H
respectively, along with 0.20 ppm downfield chemical shift of On the other hand, charged compounds
the pyridinium o-protons supported the significant attachment of cholesteryl unit onto the pyridine ring nitrogens
intermolecular interaction (Fig. 16S). behave differently in gelation. While in aqueous DMSO
Importantly, F -induced ruptured gel was recovered upon compound behaved as nongelator, compound produced
addition of Fe (Fig. 17S) due to complexation induced light yellow colored gel indicating the role of the heteroatom
a
) and pyrrole –NH (H
b
)
curcumin encapsulated Cu-gel.
3
and 4 derived from
-
3
4
3
+
-
scavenging of
F
ions from the medium. This study of the aromatic linker in gelation. The gel of
4
has been
-
discriminates F from AcO ions visually. In this aspect, it is established to be useful in anion sensing. The gel state is
-
6
| J. Name., 2012, 00, 1-3
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ARTICLE
-
selectively ruptured into sol in the presence of F and AcO cooled to room temperature and excess solvent and thionyl
-
-
ions. The F -induced ruptured gel was recovered only upon chloride were evaporated off in vacuo to give pyrrole diacid
3
addition of Fe and this was convenient in discriminating of F chloride 5b, which was used directly in the next step without
+
-
-
from AcO ions visually.
characterization. The crude acid chloride 5b was dissolved in dry
CH Cl (20 mL) and was added dropwise over 10 mins to the
solution of 3-aminopyridine (0.4 g, 4.25 mmol) in CH Cl (15 mL)
2
2
2
2
Experimental
Materials
containing triethylamine (700 µL). The reaction mixture was stirred
at room temperature for 12 h. After completion of reaction, solvent
Cholesterol, Chloroacetyl chloride, pyridine and thionyl chloride was removed under reduced pressure and water was added to the
were purchased from Spectrochem. Tetrabutylammonium salts of residue. The aqueous layer was extracted with CHCl -MeOH mixture
3
anions and metal perchlorates used in the study were purchased solvent (CHCl -MeOH = 2:1 v/v; (25 mL x 3)) and dried over
3
from Sigma-Aldrich and were carefully handled. All solvents used in anhydrous Na SO . Purification of the crude mass by silica gel
2
4
the synthesis were purified, dried and distilled as required. Solvents column chromatography using CHCl : MeOH (9:1, v/v) as eluent
3
0
1
used in NMR experiments were obtained from Aldrich. Thin layer gave the compound 2 (0.29 g, yield: 48%), mp 310 C, H NMR (400
chromatography was performed on Merck precoated silica gel 60- MHz, CDCl containing one drop d -DMSO): δ 12.08 (s, pyrrole -NH),
3
6
1
13
F
254 plates. H and C NMR spectra were recorded using Bruker 400 10.05 (s, 2H), 8.94 (s, 2H), 8.33-8.28 (m, 4H), 7.31-7.28 (m, 2H), 7.11
MHz instrument using TMS as internal standard. High resolution (s, 2H); C NMR (100 MHz, d -DMSO): δ 158.9, 144.8, 141.9, 136.1,
mass data were acquired by the electron spray ionization (ESI) 129.5, 127.4, 124.1, 114.0; FT-IR: ν cm (KBr): 3323, 2977, 1633,
technique on XEVO GS-2 QTOf Waters mass spectrometer. FTIR 1550, 1422, 1282; HRMS (TOF MS ES ): Calcd for (M+H) : 308.1148,
1
3
6
-1
+
+
measurements of all the compounds and dried gels (xerogels) were Found: 308.1147.
-
carried out using a Perkin-Elmer L120-00A spectrometer (νmax in cm
)
1
using KBr cell and KBr pellets, respectively. Scanning electron Chloro-acetic
microscopy (SEM) images were obtained on EVO LS-10 ZEISS 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
instrument. Fluorescence and UV-Vis studies were performed using cyclopenta[a]phenanthren-3-yl ester (6):
Horiba Fluoromax 4C spectrofluorimeter and Shimadzu UV-2450 To a stirred solution of cholesterol (0.5 g, 1.29 mmol) in 20 mL dry
acid
17-(1,5-dimethyl-hexyl)-10,13-dimethyl-
2
4
spectrophotometer, respectively.
2 2
CH Cl was added chloroacetyl chloride (0.16 mL, 1.93 mmol) and
pyridine (0.05 mL, 0.65 mmol) under nitrogenous atmosphere. The
mixture was allowed to stir for 10 h at room temperature. After
completion of reaction, the solvent was evaporated and the crude
Synthesis
2
5
N ,N -di(pyridin-3-yl)furan-2,5-dicarboxamide (1):
To a stirred solution of furan-2,5-diacid (0.3 g, 1.92 mmol) in dry was extracted with CHCl (3 × 30 mL). The organic layer was washed
3
CH Cl (20 mL), thionyl chloride (2.3 g, 19.34 mmol) was added several times with water and separated and dried over Na SO .
2 2
2 4
0
dropwise at 0 C followed by addition of two drops of dry DMF. The Evaporation of the solvent gave white solid compound.
resulting solution was refluxed for 12h. The reaction mixture was Recrystallization from petroleum ether afforded pure product 6
69
o
1
cooled to room temperature. Excess solvent and thionyl chloride (0.58 g, yield 96%), mp 148 °C (lit. 156 - 159 C). H NMR (400
were evaporated off in vacuo to give furan diacid chloride, which MHz, CDCl3 ) δ 5.37 (m, 1H), 4.72 (m, 1H), 4.03 (s, 2H), 2.36 (m, 2H),
−1
was used directly in the next step without characterization. The 2.02–0.85 (m, 38H), 0.67 (s, 3H); FTIR (KBr, cm ): 2939, 2907, 2821,
crude diacid chloride 5a was dissolved in dry CH Cl (20 mL) and 1753, 1620, 1195.
was added dropwise over 10 mins to the solution of 3-
aminopyridine (0.4 g, 4.25 mmol) in CH Cl (15 mL) containing Compound 3:
2
2
2
2
triethylamine (700 µL). The reaction mixture was stirred at room Compounds 1 (0.50 g, 1.62 mmol) and 6 (1.879 g, 4.06 mmol) were
temperature for 18h. After completion of the reaction, solvent was taken in dry CH CN (30 mL) containing 15% DMF and the mixture
3
removed under vacuum. The residual mass was dissolved in 10 mL was refluxed for 3 days. The precipitate appeared was filtered off
of acetone followed by addition of 100 mL of water and the solution and washed with hot CH CN and diethyl ether successively to get
3
was stirred for 30 minutes. The pH of the medium was adjusted to corresponding dichloride salt (1.72 g, yield: 86%, 1.39 mmol) which
8
-9 by adding NaHCO
3
. Then the precipitate was separated by was further subjected to anion exchange reaction using NH PF6
4
0
filtration to have pure compound 1 (0.35 g, yield: 59%), mp 150 C, (0.67 g, 4.17 mmol) aqueous MeOH (containing 10% DMF) under
1
H NMR (400 MHz, d
H), 8.24 (d, 2H, J = 8 Hz), 7.48 (s, 4H); C NMR (100 MHz, d
DMSO): δ 156.3, 148.4, 144.9, 141.8, 135.5, 128.7, 124.5, 117.0; FT- using diethyl ether afforded pure compound 3 (1.74 g) in 86% yield,
6
-DMSO): δ 10.80 (s, 2H), 8.99 (s, 2H), 8.38 (s, hot condition. After stirring the mixture for 30 min, the resulting
13
2
6
-
precipitate was filtered. Repeated crystallization of the precipitate
-1
0
1
IR: ν in cm (KBr): 3475, 3093, 1681, 1652, 1560, 1480, 1290, 1008; mp 238 C. H NMR (d -DMSO, 400 MHz): δ 11.87 (s, 2H), 9.44 (s,
HRMS (TOF MS ES ): Calcd for (M+H) : 309.0988, Found: 309.0974.
6
+
+
2H), 8.78 (d, 2H, J = 8 Hz), 8.58 (d, 2H, J = 4 Hz), 8.0 (t, 2H, J = 8 Hz),
7
.39 (s, 2H), 5.48 (s, 4H), 5.13 (s, 2H), 4.39 (m, 2H), 2.30-0.67 (m,
2
5
13
N ,N -di(pyridin-3-yl)-1H-pyrrole-2,5-dicarboxamide (2):
To a stirred solution of pyrrole-2,5-diacid (0.3 g, 1.93 mmol) in dry 139.5, 139.0, 137.7, 137.0, 128.4, 123.0, 118.3, 76.5, 61.3, 56.5,
CH Cl (20 mL), thionyl chloride (2.3 g, 19.34 mmol) was added 56.0, 49.8, 42.3, 37.9, 36.7, 36.5, 36.1, 35.6, 31.7, 31.6, 28.2, 27.8,
86H); C NMR (d -DMSO, 100 MHz): δ 166.2, 156.6, 148.2, 142.0,
6
2
2
0
-1
dropwise at 0 C followed by addition of two drops of dry DMF. The 27.6, 24.3, 23.6, 23.1, 22.8, 21.0, 19.3, 19.0, 11.7; FTIR (KBr) ν cm
:
resulting solution was refluxed for 12h. The reaction mixture was
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-
3
3
355, 2950, 1746, 1685, 1235; Mass (HRMS): Calcd. 1307.7698 for conditions in the concentration of 1.0 x 10 M. Solutions of
+
+
(M-PF
6
) found 1307.6294 (M-PF
6
) .
respective compounds (2 mL) were taken in the cuvette and to this
solutions different guest solutions were added individually in
different amounts. Upon addition, the change in absorbance of the
Compound 4:
Compound 4 was prepared according to the same reaction compounds was recorded. A similar study was performed to
2
+
-5
procedure as followed for the synthesis of compound 3. In this case, determine the interaction of the ensemble of 1.Cu (c = 2.5 x 10
-3
the amounts taken for compounds 2 and 6 were 0.55 g (1.79 mmol) M) with the amino acids (c = 1 x 10 M).
and 2.08 g (4.49 mmol), respectively. After filtration and washing
with diethyl ether, corresponding dichloride salt was obtained as Method for Job plot
white mass (1.86 g, yield: 84%). To the methanolic solution (20 mL The stoichiometry was determined by the continuous variation
containing 10% DMF) of the dichloride salt (1.86 g, 1.509 mmol), method (Job Plot). In this method, solutions of host and guests of
-5
4 6
NH PF
(0.724 g, 4.44 mmol) was added and the reaction mixture equal concentrations (c = 2.5 x 10 ) were prepared in the desired
was stirred under warming condition for 30 min. After reducing the solvent. Then host and guest solutions were mixed in different
volume of the reaction mixture, excess amount of water was added. proportions maintaining a total volume of 3 mL of the mixture. The
A white precipitate appeared which was filtered and washed with related compositions for host:guest (v/v) were 3:0, 2.8:0.2; 2.5:0.5,
diethyl ether to afford desired dihexafluorophosphate analogue 4 2.2:0.8, 2:1, 1.8:1.2, 1.5:1.5, 1:2, 0.8:2.2, 0.5:2.5, 0.2:2.8. All the
0
1
(
1.58 g) in 72% yield, mp 236 C. H NMR (d
6
-DMSO, 400 MHz): δ prepared solutions were kept for 1 h with occasional shaking at
2.67 (s, 1H), 11.19 (s, 2H), 9.57 (s, 2H), 8.78 (brd, 2H), 8.69 (brd, room temperature. Then absorbance of the solutions of different
H), 8.22 (brt, 2H), 7.23 (s, 2H), 5.72 (s, 4H), 5.37 (s, 2H), 4.62 (m, compositions was recorded. The concentration of the complex i.e.,
1
2
2
1
-1
H), 2.37-0.67 (m, 86H); FTIR (KBr) ν cm : 3387, 2951, 1749, 1691, [HG] was calculated using the equation [HG] = ΔA/A
247; Mass (HRMS): Calcd. 1306.7858 (M-PF
6
) ; found 1306.7793 ΔA/A
0
x [H] where
0
+
indicates the relative absorbance intensity and [H]
+
) .
(
M-PF
6
corresponds the concentration of pure host. Mole fraction of the
guest (X ) was plotted against concentration of the complex [HG].
G
Gelation test and SEM imaging
In the plot, the mole fraction of the guest at which the
The respective amounts of compounds 1-4 were dissolved in concentration of the host-guest complex concentration [HG] is
desired solvents (such as DMSO/H O, DMF/H O, MeOH/H
O, 1,4- maximum, gives the stoichiometry of the complex.
dioxane/H O etc. in 1:1 ratio, shown in Table 1S) (1 mL) forming a
2
2
2
2
homogeneous solution, slightly warmed and then allowed to cool
slowly to room temperature to form a gel. Increase in amount of
water in organic solvent led to precipitation. To study the effect of
metal ions, required amount of metal solutions (in water) were
added to the DMSO solution of compounds 1-2. All the gels were
tested by an inversion of vial method. Samples of gels for SEM
imaging were dried under vacuum and then coated with a thin layer
of gold metal.
Acknowledgements
We thank DST, West Bengal, for financial support under the
project (sanc. No. 755(Sanc.)/ST/P/S&T/4G-3/2014 dated
2
7.11.2014). SP thanks CSIR, New Delhi, India for a fellowship.
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Stimuli responsive drug release experiment
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of DMSO. 0.1 mL of this solution was then transferred to the vial
containing 5 mg of compound 1 in 0.4 mL of DMSO. Then 0.5 mL
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,
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. F. Fages, Low Molecular Mass Gelators, Topics in Current
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Wiley-VCH, Weinheim, 2008.
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2
+
aqueous solution of Cu (0.06 M) was added to it and the mixture
was kept undisturbed for few mins to get the light green colored
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mL of 0.03 M aqueous solution of L-glutathione and L-cysteine were
added individually. With time, the gel started to disintegrate and
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2
1
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Stock solution of the compounds 1, 2 and 4 were prepared in
-5
respective solvents in the concentration of 2.50 x 10 M. Stock
solutions of metal ions and anions were prepared under similar
1
8
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7NJ03931J
Journal Name
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New Journal of Chemistry
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DOI: 10.1039/C7NJ03931J
GRAPHICAL ABSTRACT
Pyridine/pyridinium Symmetrical Bisamides as Functional Materials:
Aggregation, Selective Sensing and Drug release
Santanu Panja, Sumit Ghosh and Kumaresh Ghosh*
We report the design, synthesis and gelation behavior of some 3-amino pyridine/pyridinium-based bisamides. As
application, the gels are useful in visual detection of cations, anions, biomolecules and in drug release.
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