Binding interaction of a newly developed bisindole drug molecule with α-cyclodextrin: Face to face shielding of indole hoops

Article abstract of DOI:10.1039/c4ra06087c

Binding interactions of a newly developed drug molecule namely 3,3′-bis(indolyl)-4-chlorophenylmethane (BICPM) with α-cyclodextrin have been studied using steady state and picosecond time resolved fluorometric techniques. A significant increase both in st

Full text of DOI:10.1039/c4ra06087c

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Binding interaction of a newly developed bisindole
drug molecule with a-cyclodextrin: face to face
shielding of indole hoops
Cite this: RSC Adv., 2014, 4, 38206
a
b
c
Arabinda Mallick, Tapas Majumdar, Basudeb Haldar and Ujjal Kanti Royd
*
*
Binding interactions of a newly developed drug molecule namely 3,30-bis(indolyl)-4-chlorophenylmethane
(BICPM) with a-cyclodextrin have been studied using steady state and picosecond time resolved
fluorometric techniques. A significant increase both in steady state anisotropy (r) and in the average
rotational correlation time in the CD environments compared with that in a pure aqueous phase
indicates that the rotational dynamics of BICPM are substantially slowed down upon binding with the a-
cyclodextrin. Critical spectral analysis reveals the formation of two types of inclusion complex between
the fluorophore and a-cyclodextrin (a-CD) depending on the relative population of the two. The
stoichiometries and association constants of these complexes have been determined by monitoring the
fluorescence data. Hydrodynamic radii of the formed 1 : 2 probe-a-cyclodextrin supramolecular
complex have also been determined. From the determined hydrodynamic radii and from molecular
docking analysis it is argued that probably two CD cavity shields the indole moiety in a face-to-face manner.
Received 22nd June 2014
Accepted 7th August 2014
DOI: 10.1039/c4ra06087c
www.rsc.org/advances
a variety of organic molecules. Cyclodextrin complexation can
give benecial modication of guest molecules such as solu-
1. Introduction
bility enhancement, stabilization of labile guests, physical
isolation of incompatible compounds and control of volatility
and sublimation, stabilization of labile guests in terms of long-
term protection of color, odor and avor, and so forth the
cyclodextrin molecules have internal cavity accessible to the
guest molecules of proper dimension through an opening of
Cyclodextrins (CDs) are interesting microvessels capable of
embedding appropriately sized molecules and the resulting
supramolecules can serve as excellent miniature models for
nano-bio conjugates.1–5 These conjugates are drawing much
attention from chemists as well as biologists because of their
widespread application in the pharmaceutical industry; espe-
cially due to their importance as microvessels for selected drug
delivery. Spatially conned environments with a nano dimen-
sion offered by the cyclodextrins can modify the chemical
reactivity as well as dynamics of the guest molecule because of
change in the micropolarity and steric rigidity inside the cavity
compared to the situation in the bulk aqueous phase.1–16 Due to
the presence of primary and secondary hydroxyl groups point-
ing outside the cavity, the outer surface is hydrophilic whereas
the inner surface, lined with inside pointing C–H groups and
ether-like oxygens, is hydrophobic. Because of this particular
property, CDs are able to complex various organic compounds
in aqueous solution and are of special interest in pharmacology
and supramolecular chemistry.1–16 The most remarkable prop-
erty of the CDs is their ability to form inclusion complexes with
5–17
˚
4.5–5.3 A, for a-CD.
Thus depending on the cavity size, CDs
are capable of encapsulating guest molecules of different
dimensions. Fluorometric techniques have been used exten-
sively to understand the nature of the host–guest interac-
tions.6,9,10 Few studies have revealed the formation of inclusion
complexes of 1 : 1 and 1 : 2 type.6,12,17–21 Such preference in the
formation of the well-dened nano conjugates in micro-
heterogeneous environments is of much interest to present day
science. In this direction 1 : 2 probe-CD complex draws special
attention because it can acts as the starting building block for
the preparation of nanocapsule of desired dimension.17,22
Numerous bis(indolyl) methanes and their derivates, a new
kind of aza-heterocycles, have been isolated from various
terrestrial and marine natural sources. These natural products
have novel structures and exhibit important biological activi-
ties.23–25 Therefore, there is a great interest in the synthesis of
the bisindole compounds, occurring naturally or not. It has also
been exploited as an efficient uorosensor for sensing essential
trace metals. The uorophore, BICPM, used in the present
experiment belongs to the group of such bioactive bisindole
family and serving as a proper model drug. The indole nucleus
seems to be a promising basis for design and synthesis of new
aDepartment of Chemistry, Kashipur Michael Madhusudan Mahavidyalaya, Purulia,
West Bengal -723132, India. E-mail: ampcju@yahoo.co.in
bDepartment of Chemistry, University of Kalyani, Nadia, West Bengal -741235, India
cDepartment of Chemistry, Vivekananda Mahavidyalaya, Sripally, Burdwan, West
Bengal -713103, India. E-mail: pcbhaldar@yahoo.co.in
dDepartment of Chemistry, Desh Bandhu Mahavidyalaya, Chittaranjan, West Bengal
-713331, India
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derivatives able to ght against many health disorders
including the nervous system. Very recently Yan et al. reported
the potent activity of indoloquinones against the human
pancreatic cancer.25 Since most of the drug molecules are
hydrophobic in character, they always look for a hydrophobic
shelter. a-Cyclodextrin (a-CD) bears the responsibility in the
present case. Complexation of such biologically potent mole-
cules with different biomimetic environments attracts interest
of the researchers because of the molecule's ability to achieve
specic chemical efficiency as a result of organization in the
reaction media. An important parameter for the understanding
of such a complexation process is the determination of the
stoichiometry and the binding constant. Particular attention
has been given on the probe-CD stoichiometries and the
binding constants.
G ¼ IHV/IHH
(2)
The terms I refer to parameters similar to those mentioned
above for the horizontal position of the excitation polarizer
where G is the correction factor for the detector sensitivity to the
polarization detection of the emission.27 Average orescence
lifetimes hsi for bi-exponential iterative tting were calculated
from the decay times and the pre-exponential factors using the
following relation.
hsi ¼ a1s1 + a2s2
(3)
where a terms denote the decay constant of the respective
component while the s terms refers to the corresponding
lifetime.
The ground state structure of the BICPM molecule has been
optimized utilizing density functional theory (DFT) combining
hybrid B3LYP functional and 6-311+G basis set in acetonitrile as
solvent using the Gaussian 09 programme suite.28 Conductor
polarizable continuum model (CPCM) has been used to incor-
porate the solvent effect in ground state geometry optimization.
The crystal structures of a-CD has been obtained from
protein complexes (pdb id: 2ZYM) available in Protein Data
Bank (PDB). The a-CD has been then extracted and added all the
hydrogens and Gasteiger charges to prepare it for docking. The
PDB structure of BICPM has been derived from the optimized
structure. BICPM has been considered as a ligand and a-CD as a
receptor for docking studies. The molecular docking has been
carried out applying the Lamarckian Genetic Algorithm (LGA),
inculcated in the docking program Auto Dock 4.2.29 The CD has
2. Experimental section
3,30-Bis(indolyl)-4-chlorophenylmethane (BICPM) (Scheme 1)
was synthesized in the laboratory simply by condensation of
4-chlorobenzaldehyde and indole using the method mentioned
elsewhere.26 It was puried by column chromatography and the
purity of the compound was checked by thin layer chromato-
graphy (TLC). The compound was further vacuum sublimed
before use. a-CD (Fluka) were used as received without further
purication. Triply distilled water was used for making the
experimental solutions.
Shimadzu U3500 absorption spectrophotometer was used
for the absorption spectral studies. Fluorescence lifetimes were
determined from time resolved intensity decay by the method of
time correlated single-photon counting (TCSPC).27 The pulse
duration of the excitation source response is 40 ps. The decay
curves were analyzed using IBH decay analysis soware.
Goodness of ts was judged by the visual inspection of the
residuals of the tted function to the data. The lifetimes were
measured in degassed solution of the probe at ambient
temperature. The steady state uorescence anisotropy was
performed with a Hitachi spectrouorimeter F-4010 model.
Excitation and emission bandwidths were 5 nm. Steady state
anisotropy, r, was dened by:
3
˚
been laid over a three dimensional grid box (60 ꢁ 54 ꢁ 48) A
˚
with 0.375 A spacing. The output from Auto Dock has been
analyzed using PyMOL soware.30
3. Results and discussion
3.1 Steady state and time resolved measurements
Fig. 1 displays the uorescence emission prole of BICPM upon
addition of gradual amount of a-cyclodextrin indicating the
interaction between the drug and cyclodextrin.
Gradual addition of a-cyclodextrin to the aqueous solution of
(1) BICPM leads to the signicant decrease in emission intensity
along with the bathochromic shi in the emission maxima.
Similar type of observation was also noticed by Kondo et al.31
At a particular concentration of CD, the probe exists in two
forms (free and bound), and the emission maximum is, though
presumably, an average of the band maxima for the probe in
water and in the completely bound state. The emission maxima
of the uorophore bound to different CD were obtained from
the plateaus in the plot of the emission maximum versus
concentration of the CD (Fig. 2). A critical look at Fig. 2 envis-
ages two plateaus are observed. The intermediate plateau in the
lower concentration range is assigned to correspond to the 1 : 1
while the nal one corresponds to the 1 : 2 probe-CD complex.
The forthcoming sections, while dealing with different aspects
of the probe-CD binding interactions, will conrm this propo-
sition of formation of both 1 : 1 and 1 : 2 inclusion complexes
r ¼ (IVV ꢀ GIVH)/(IVV + 2GIVH
)
where IVV and IVH are the intensities obtained with the excita-
tion polarizer oriented vertically and the emission polarizer
oriented vertically and horizontally, respectively. The G factor
was dened as:
Scheme 1 Schematic representation of preparation of BICPM.
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Fig. 1 (a) Emission spectra of BICPM as a function of a-cyclodextrin concentration (lexc ¼ 295 nm) (b) variation of fluorescence intensity with a-
cyclodextrin concentration. [BICPM] ¼ 5.65 ꢁ 10ꢀ6 M.
that at a higher a-cyclodextrin concentration range. From the
analysis of the uorescence data, we found that at lower a-CD
concentration plot of 1/DF against 1/[CD] and at higher a-CD
concentration plot of 1/DF against 1/[CD]2 are linear justifying the
validity of eqn (4) in the lower concentration range and eqn (5) in
the higher concentration range of a-CD. Thus, we conclude that a
1 : 1 BICPM–a-CD complex is formed at lower a-cyclodextrin
concentration while a 1 : 2 BICPM–a-CD complex is formed at
higher a-CD concentration. A similar type of observation was
noticed in our previous works for the probe norharmane6,18 and
also by Kim et al.33 for the probe 4-biphenylcarboxylic acid.
Fig. 4 represents the respective plots in the segmented a-
cyclodextrin concentration ranges. Once the stoichiometry is
established, the association constants (K) are determined from
Fig. 2 Plot of emission maxima of BICPM as a function of a-cyclo-
dextrin concentration.
the individual plots. The extracted values are obtained as 61.46
molꢀ1 and 24.52 ꢁ 103 molꢀ2 for 1 : 1 and 1 : 2 complexes
respectively with a-CD. The determined values (15%) fall within
the normal range of values reported earlier for such type of
complexations.6,18 A remarkably high association constant value
with a-CD, in contrast with the formation of only a 1 : 1
for the 1 : 2 BICPM–a-CD complexation signies a compact
packing of the probe within the cavity space of the two a-CD
coming from the opposite sides.6
complex.
In order to determine the stoichiometries of the inclusion
complexes, the dependence of the BICPM uorescence on
a-cyclodextrin concentration was analyzed with added a-CD,
using Benesi–Hildebrand equations32 for 1 : 1 and 1 : 2
complexes (eqn (4) and (5) respectively).
To investigate these CD binding events further time resolved
uorescence studies have been performed in the presence and
absence of CD. Excited-state lifetime measurements provide
sensitive parameters for exploring the existence of single or
multiple species.28 For the same reason that the emission
spectra of the uorophores are sensitive to the local environ-
ment, their uorescence lifetimes reect intermolecular inter-
actions. BICPM encapsulation within CD cavity can be looked
into through time-resolved measurements.18,31 It allows one to
see how the rotational time constant affected upon encapsula-
tion of the probe within the CD cavities.31,34 It is seen that the
uorescence decays of BICPM in water and CDs are far from
single exponential. In water, and in the CD environments the
uorescence decays of BICPM are biexponential. Extraction of
meaningful rate constants in such heterogeneous systems is
really difficult. In order to realize the effect of the encapsulation
of the uorophore on the rotational correlation time, we
preferred to use the mean uorescence lifetime dened by eqn
(3) instead of placing too much emphasis on the magnitude of
ꢀ
ꢁ
1
1
1
1
¼
þ
(4)
DF DFmax
K½CDꢂ DFmax
!
1
1
1
1
¼
þ
(5)
2
DF DFmax
DFmax
K½CDꢂ
where DF ¼ Fx ꢀ F0, Fx and F0 represent uorescence intensities
of BICPM in the presence and absence of CD respectively. DFmax
is the maximum change in uorescence intensity and K is the
binding constant for at the formation of the complex. Typical
double reciprocal plots are shown in Fig. 3 for BICPM–a-CD
complex. Fig. 3 reveals that neither eqn (4) nor eqn (5) is valid
for the entire range of concentration of a-CD.
This rules out the formation of a single type of BICPM–a-
cyclodextrin complex and indicates that the BICPM–a-CD stoi-
chiometry in the lower CD concentration range is different from
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Fig. 3 Double reciprocal plots for the 1 : 1 and 1 : 2 BICPM–a-CD complexation including the full concentration range of CD studied (5–40 mM)
in both the plots.
Fig. 4 Segmented double reciprocal plot for BICPM–a-cyclodextrin complexation. Benesi–Hildebrand plot for (a) 1 : 1 binding in the lower CD
concentration region of 5–20 mM and (b) 1 : 2 binding in the higher CD concentration region of 25–40 mM.
˚
˚
individual components of the multiexponential decays. calculated end-to-end lengths of 12 A and 8.9 A. It is apparent
A complete treatment of the complex and multiexponential that BICPM is too bulky to t entirely in the a-CD cavity (internal
˚
˚
uorescence decays of BICPM in a-CD is, by itself, rigorous and diameter 5.7 A and depth ꢃ6.0 A). But the two uorescing
will be addressed at a later time. The calculated average lifetime indole rings hanging from the cholorobenzene unit each having
˚
˚
values of BICPM in water and in CD environments are tabulated calculated length 6.5 A and transverse cross-section 5.4 A may
in Table 1. Analysis of each individual decay function was get shelter partially inside the CD cage.
judged from the reduced c2 values.
For host–guest interaction it is very crucial to know the
binding mode and to get this picture it is very important to have
a clear idea about the shape, size and length around different
dimensions of the probe molecule. For this purpose the ground
state geometry of BICPM molecule has been optimized theo-
retically (Scheme 2) using density functional theory with the
hybrid functional B3LYP and 6-311+G basis set with solvent
effect of acetonitrile in CPCM model. On the basis of that
Table 1 Decay Parameters of BICPM in the absence and presence of
a-CDa
[a-CD]
mM
a1
s1 (ps) a2
s2 (ps) hsi (ps) hsci (ps) c2
0.0
50.0
52.30 181
70.80 225
47.70 432
29.20 527
3.01
3.13
43.00
283.00
1.09
1.10
a
Where a1 and a2 are the decay constants, s1 and s2 are the lifetimes, hsi
is the average lifetime in picosecond, hsci is the average rotational
correlation time in picoseconds.
Scheme 2 Optimized geometry of BICPM and its length in different
dimension.
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Comparing the a-CD cavity dimension with the molecular
size of the probe molecule one can argue that only a part of
BICPM; actually one hanging arm enters within the a-CD cavity
as shown in Scheme 3. Hence in case of 1 : 1 complexation a
part of the probe; second hanging arm remains exposed to the
bulk aqueous phase. This open part is also amenable to
complex formation with another a-CD leading to the formation
of a 1 : 2 inclusion complex between BICPM and a-CD (Scheme 3).
This type of complexation basically encapsulates the uorescing
moiety of the probe molecule from all around removing the
solvent water molecules, which is essential for the uorescence
properties. Hence signicant decrease in the uorescence
intensity is observed.
Fig.
complexes.
5
Calculated figures of 1 : 1 and 1 : 2 BICPM-CD inclusion
uorescence lifetime and reects the extent of restriction
imposed on the dynamic properties of the probe by the micro-
environment.12 Thus, an increase in the rigidity of the
surrounding environment of the uorophore results in an
increase in the uorescence anisotropy. Fig. 6 presents the
variation of uorescence anisotropy (r) of BICPM in a-CD
environments.
It is important to consider the possibility of face to tail or tail to
tail encapsulation mode also. The following section has been
devoted in this connection. The optimized ground state structure
of the BICPM probe molecule provides the width of the single
˚
indole part 5 A as can be easily observed from the Scheme 2. On
˚
the other hand, the face opening of a-CD is ꢃ5.3 A and the tail
In the presence of lower concentrations of a-CD (for the 1 : 1
complexation), small changes in the uorescence anisotropy
values are observed. This indicates that the probe experiences
only a bit of restriction imposed by the a-CD environments. This
is rationalized considering that a part of the uorophore
molecule remains exposed to the bulk aqueous phase. Inter-
estingly, in the presence of higher concentrations of a-CD, there
is a large enhancement in the uorescence anisotropy reecting
a greater degree of motional restriction in this environment.
This situation is well-explainable from the model of the 1 : 2
probe–a-CD inclusion complex. To ensure that the observed
change in the steady-state anisotropy of BICPM in the a-CD
environments is not due to any change in the lifetime, the
apparent (average) rotational correlation times (sc) were calcu-
lated using Perrin's equation12 for BICPM in the a-CD envi-
ronments at their saturation level where r0, r, and sf are the
limiting anisotropy for the complexed molecule, steady-state
anisotropy, and mean uorescence lifetime of the uo-
rophore, respectively.
˚
opening is ꢃ4.5 A. So it is quite rational that the formation of
inclusion complex (IC) between BICPM and a-CD is only possible
through the face if is either 1 : 1 or 1 : 2. Hence the possibility of
face to tail and tail to tail ICs may be discarded from the theo-
retical point of view. Additional supports in this direction can be
produced from the docking model, which clearly shows a face-to-
face insertion of the indole moiety (Fig. 5).
Fluorescence anisotropy is a property that is dependent upon
rotational diffusion of the uorophore as well as the
Scheme 3 Schematic representation (not to scale) of 1 : 1 and 1 : 2 Fig. 6 Variation of steady state fluorescence anisotropy as a function
BICPM–a-CD inclusion complexes.
of a-CD concentrations.
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ꢂ ꢃ
active drug molecule in a-cyclodextrin cavities. The results
reveal that the photophysical behavior of BICPM is modied
signicantly upon encapsulation of the probe in the a-cyclo-
dextrin. The variation of the uorescence properties with the
addition of the CDs reveal formation of both 1 : 1 and 1 : 2
complexes. Signicant increase in the average rotational
correlation time in the CD environments compared with that in
a pure aqueous phase indicates that the rotational dynamics of
BICPM is substantially slowed down upon binding with the a-
cyclodextrin. The hydrodynamic radii of the 1 : 2 probe-a-
cyclodextrin inclusion complexes have been determined to be
sf r
sc ¼
(6)
r0 ꢀ r
Although ideally Perrin's equation is not applicable in a
microheterogeneous environment, one can use it, to a good
degree of accuracy, considering the mean uorescence lifetime
of the system. Using eqn (6), we have determined the sc values in
water as well as in a-CD environments, taking r0 ¼ 0.4, sc
increases appreciably with the addition of the CD. A signicant
increase in sc in a-CD environments (Table 1) establishes that
the observed change in the anisotropy values (Fig. 5) were not
due to lifetime-induced phenomena and reinforces our earlier
prediction that there is an increase in rotational restriction
experienced by the probe molecule.35,36 As a matter of fact,
connement of a probe in a-CD cavity increases the hydrody-
namic diameter of the system (the sum of the lengths of the
host, i.e., the CD, and the guest), and this causes enhancement
of the rotational correlation time. Since measurements of the
rotational correlation time can provide valuable information
regarding the effective volume and dimension of the inclusion
complexes (considering the measured, very small difference in
the lifetime and assuming that the macroscopic viscosity is the
same in all of the solutions containing CDs) as compared with
the free probe or CD molecule, this parameter has been
employed to gather additional evidence in support of the stoi-
chiometry of the inclusion complexes formed between the
BICPM and CD. In the presence of high concentrations of a-CD
(50.0 mM), the determined rotational correlation times 2.83 ns
is much larger than the corresponding values in the bulk water
0.83 ns. This observation indicates the change in hydrodynamic
dimension of the probe due to formation of supramolecules. To
get an idea about the approximate size of the inclusion
complexes formed between BICPM and CD, we can take the
help of the Stokes-Einstein-Debye equation.37,38
˚
7.344 A.
Acknowledgements
A.M. is greatly indebted to the University Grants Commission
(UGC), Govt. of India for nancial supports through Minor
Research Project (PSW-115/13-14, ERO ID NO SKB-010) and
UKR acknowledges nancial support from DST-New Delhi (SR/
FT/CS-137/2011 dated 12.07.2012). T.M. acknowledges Univer-
sity Grants Commission (UGC), Govt. of India for the UGC-BSR
Start-up grant (no. F.20-35/2013(BSR) dated 09.12.2013) and
DST PURSE programme to University of Kalyani.
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