Cucurbituril-resisted acylation of the anti-tuberculosis drug isoniazid via a supramolecular strategy

Article abstract of DOI:10.1039/c0ob00114g

A chemical investigation reveals that the resistance to acylation of an anti-tuberculosis drug, isoniazid is a consequent result of the inclusion or exclusion of cucurbit[n]urils (n = 6 or 7). The ¹H NMR spectra analysis shows that the differen

Full text of DOI:10.1039/c0ob00114g

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PAPER
Cucurbituril-resisted acylation of the anti-tuberculosis drug isoniazid via a
supramolecular strategy†
Hang Cong,a,b Chun-Rong Li, Sai-Feng Xue, Zhu Tao,* Qian-Jiang Zhu and Gang Wei*
a
a,b
a
b
c
Received 12th May 2010, Accepted 29th October 2010
DOI: 10.1039/c0ob00114g
A chemical investigation reveals that the resistance to acylation of an anti-tuberculosis drug, isoniazid
1
is a consequent result of the inclusion or exclusion of cucurbit[n]urils (n = 6 or 7). The H NMR spectra
analysis shows that the different interaction models of the isoniazid with the two cucurbiturils are
dependent on the cavity size of the hosts. Quantum chemistry calculations with density functional
theory method indicate that the interaction of the isoniazid with both cucurbiturils is through
thermodynamic stabilization in both the gas phase and aqueous solution through hydrogen bonding on
the portal carbonyls of the cucurbiturils. Electronic absorption titration spectra suggest the hosts and
guest interact in a ratio of 1 : 1 with moderate binding constants. Acylation kinetics of isoniazid with
various acylating agents in the presence of the cucurbiturils revealed that resistance is only dependent
on the host–isoniazid ratio, and independent on the size of the cucurbiturils and the species of acylating
agents.
Introduction
and prophylactic treatments. The metabolic pathway of this drug
involves acetylation of INH by arylamine N-acetyltransferase
Cucurbit[n]urils (Q[n], n = 5–8 or 10) are a set of macro-
(
NAT), which is a drug-metabolizing enzyme that is able to transfer
cyclic compounds synthesized with glycoluril and formaldehyde
an acetyl group from acetyl coenzyme A (Scheme 1) onto the
1
(
Scheme 1). The cavity of Q[n] can encapsulate and recognize
7
terminal nitrogen of the drug. The N-acetylation reaction can
the amines and azaheterocyclic compounds via hydrophobic
effects, size effects, as well as ion–dipole interactions at the
portals of Q[n]. The supramolecular characterization of the
Q[n] hosts provided platforms for the design and functionaliza-
tion of host–guest complexes involving Q[n] components. With
a potential application in drug-delivery, the special inclusion
complexes of drug molecules have been extended with Q[n] as
the host to increase chemical stability. Herein, the powerful
bactericidal agent against tuberculosis (TB), isonicotinic acid
hydrazide, commonly known as isoniazid (INH, Scheme 1),
has been stabilized by supramolecular interactions with Q[6]
and Q[7].
directly inactivate INH during therapy, and the metabolite is
8
believed to be responsible for the hepatotoxic effects observed. In
2
general, two phenotypes can occur depending on the N-acetylation
rate of INH in the body, these are referred to as slow and fast
acetylators. Fast acetylators have been significantly associated
3
8,9
with INH resistance. It is therefore of great importance to
effectively control the N-acetylation of INH. In this study, we used
a supramolecular strategy to chemically investigate the resistance
to acetylation of INH encapsulated by Q[6] and Q[7], with the aim
of developing these as a potential drug-carrier of INH, ensuring
its resistance to acetylation.
4
INH was first introduced for the effective treatment of TB in
5
1
952. It is estimated that about one-third of the world’s popula-
Experimental section
tion is currently infected with TB and 2–3 million deaths are caused
by this disease every year. INH is a front-line antibiotic that
6
Materials and instruments
has become one of the principal agents used in both therapeutic
Cucurbit[n]urils (n = 6 or 7) were prepared and purified according
10
to the methods developed in our laboratory. The chemical
agents isoniazid, acetic anhydride (1), benzoyl chloride (2),
benzenesulfonyl chloride (3) and p-toluenesulfonyl chloride (4)
were purchased from Alfa Aesar (Tianjing) Chemical Co., Ltd.
and used without further purification. The acylating agents S,N-
diacetylcysteine (5) and S-acetylcysteine (6) were synthesised
a
Institute of Applied Chemistry, Guizhou University, Guiyang, 550025,
P. R. China. E-mail: ecnuc@163.com; Fax: +86-851-3620906; Tel: +86-
8
51-3623903
b
Key Laboratory of Macrocyclic and Supramolecular Chemistry of Guizhou
Province, Guiyang, 550025, P. R. China
c
CSIRO Materials Science and Engineering, P.O. Box 218 Lindfield, NSW
2
070, Australia. E-mail: Gang.Wei@csiro.au
Electronic supplementary information (ESI) available: Kinetics plots,
11
referring to literature.
H NMR spectra were recorded at 20 C on a VARIAN INOVA-
400 spectrometer in D O. UV-vis absorption spectra of the guest
†
1
◦
details of initial rate calculation and coordinates of the optimized
structures. See DOI: 10.1039/c0ob00114g
2
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Scheme 1 The acylation reaction pathway of isoniazid (INH) and the chemical structures of INH, cucurbiturils Q[6] and Q[7], acetyl coenzyme A and
acylating agents. The dashed box indicates active thioester groups that are used to convey the acetyl group to INH.
and the host–guest complexes were recorded on an Unico UV-2102
instrument at 25 C at pH = 6.0.
of the proton H2 experiences a downfield shift of 0.20 ppm
when the ratio of CQ[6]/CINH reaches 1 : 1. The above changes in
chemical shift correspond to the interaction model that the INH
molecule is prevented from entering into the cavity and remains
at the portal of Q[6]. With the addition of Q[7], however, the
aromatic resonances are now shifted between 0.38 and 0.45 ppm
upfield when the INH : Q[7] ratio is 1 : 2. The observed upfield
shift resonances for protons H1 and H2 correspond to a different
host–guest interaction model with Q[7]–binding INH, and the
pyridyl moiety of the guest is located in the cavity of Q[7]. On
the other hand, the interactions between INH and Q[6, 7] lead
to broadened resonance signals of the guest to different degrees,
which are related to the formation of loose encapsulations. The
broadness of the resonances indicates a relatively fast exchange on
the NMR time scale.
◦
Theoretical calculations
All calculations have been processed with Gaussian 03 W
12
(
Revision C.02) software package. The initial geometries of
all structures were constructed with the aid of Hyperchem
13
Release 7.52 package. Q[6] and Q[7], and their complexes were
1
constructed based on their H NMR and electronic spectra
titration analysis. Becke’s three-parameter hybrid functional with
14
the correlation functional of Lee, Yang and Parr (B3LYP) was
used for full geometry optimization, solvent effect, and BSSE-
15
corrected (Basis Set Superposition Error corrected) binding
16
17
energy with STO-3G basis set. The Onsager model was
used to calculate the solvent effect, as part of this computing
package.
Absorption spectrophotometric analysis of the interaction between
Q[6, 7] and INH guest
Results and discussion
1
UV-visible spectroscopy was employed to monitor the interaction
between INH and Q[6, 7]. With the electronic absorption spectra
of INH exhibiting a slight blue-shift in the presence of Q[6], the
increase in the peak at 262 nm and the increase in the concentration
of Q[6] fits to a 1 : 1 binding model with a moderate binding
H NMR analysis of the interaction between Q[6, 7] and INH guest
1
Comparison of the H NMR spectra between free and bound INH
suggested that the host–guest interaction models of Q[6, 7] and
INH were largely dependent on the cavity size of the macrocyclic
hosts. Based on the pioneering work of Mock and Shih, the
upshield shifts of the resonances from guest protons represent
insertion of cucurbituril into the cavity, while the downshield shifts
of the resonances from guest protons represent the proximity of
18
5
-1
constant of (2.3 ± 0.4) ¥ 10 L mol (Fig. 2a). The stoichiometry of
this host–guest interaction is affirmed by Job plots (Fig. S2, ESI†).
The UV-visible spectra changes of INH with increasing amounts
of Q[7] are similar to the Q[6]–INH supramolecular system, and
the 1 : 1 inclusion complex of INH and Q[7] is formed with an
1
cucurbituril to the outside of the portal. The H NMR titration
5
-1
spectra of INH guest recorded in the absence, and in the presence of
various equivalents of the hosts Q[6] and Q[7] in aqueous solution
are collected in Fig. 1, respectively. As shown in Fig. 1a, the proton
resonances of the bound INH are observed to undergo downshield
shifts in the presence of Q[6]. The resonance of the proton H1
experiences a downfield shift of 0.27 ppm, while the resonance
binding constant of (1.7 ± 0.6) ¥ 10 L mol , as shown by the
molar ratio plots (Fig. 2b) and Job plots. The binding constants
of Q[6, 7] with INH indicate that there is no obvious difference in
the interaction stability of the two host–guest species despite their
different interaction models, related to the size of the macrocyclic
1
host, as indicated by H NMR.
1
042 | Org. Biomol. Chem., 2011, 9, 1041–1046
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1
Fig. 1 Variation in the H NMR spectra of (a) Q[6]–INH system and (b) Q[7]–INH system with increasing concentration of hosts.
(
pH = 6–8), and the pH of a solution can influence on the
16
interaction in a host–guest system. In Fig. 3, the curves A, B
and C show the absorbance vs. pH for INH and its host–guest
complexes with Q[6] and Q[7] at a ratio of 1 : 1, respectively. The
plots exhibit a significant absorbance difference between the guest
and its interaction complex with Q[7] in both acidic (2 < pH <
3
) and neutral aqueous solution (5 < pH < 9), but the different
absorption between INH and Q[6]–INH arises only at neutrality.
The curves become slightly different in the pH range from 4 to
5
9
, while the curves B and C incline to be above curve A (pH >
), which indicates that we can not use UV-visible spectroscopy to
study the interaction of Q[6, 7]–INH systems at these pH ranges.
-5
-1
Fig. 2 UV-visible spectra with a fixed concentration (2.5 ¥ 10 mol L )
of INH and a variable concentration (from 0 to 7.5 ¥ 10 mol L along
the arrow direction) of (a) Q[6] and (b) Q[7].
-5
-1
Fig. 3 Maximum absorbance (lmax = 262 nm) change at different pH of
INH (curve A) and its interaction complexes with Q[6] (curve B) and Q[7]
(
curve C).
Acidity effect on interaction of Q[6, 7] with INH guest
To take into account protonation of the guest and evaluation of
the binding constant (and binding geometry) changes, the same H
1
Generally, INH as a sort of weak basic drug can be absorbed
in the intestine where the pH value is kept in neutrality
NMR titrations and UV-vis titration of Q[6]–INH and Q[7]–INH
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systems at pH = 2 have also been performed (Fig. S2–S4 in ESI†).
The titration experiments of the Q[7]–INH system shows that the
interaction model of Q[7] with INH is still an encapsulation model,
to form hydrogen bonds with the carbonyl oxygen on one portal
of the hosts. The optimized structure of the complex of Q[6]–
INH has four hydrogen bonds, N1–H ◊ ◊ ◊ Ocarbonyl (1.41 and 1.42
6
-1
˚ ˚ ˚
A), N2–H . . . Ocarbonyl (1.47 A) and CPyridyl–H . . . Ocarbonyl (1.79 A),
and a higher binding constant of 1.0 ¥ 10 L mol is obtained
with the competition of INH with glutamic acid (Glu), which can
be encapsulated in the cavity of Q[7] with a binding constant of
˚
respectively, while only two hydrogen bonds of 1.41 A (N1–
˚
H . . . Ocarbonyl) and 1.32 A (N2–H . . . Ocarbonyl), respectively, are
2
-1 19
1
0 L mol . However, the titration experiments of the Q[6]–INH
found for the complex of Q[7]–INH. Consequently, the multi-
site interactions account for the extra stability in the ‘excluded’
supramolecule of the Q[6]–INH system.
system show that almost no chemical shift and absorption band
changes of INH are observed, and it suggests that no obvious
interaction occurs between Q[6] and the guest INH under more
acidic conditions. Moreover, the absorption band of the guest INH
exhibits a progressively lower absorbance as the ratio of Q[7] : INH
is increased at pH = 2.0, consistent with the results shown in the
Fig. 3.
On the other hand, the negative differences of the energy minima
between the free host, free guest, and the host–guest inclusion
complex (stabilization energy, DE < 0) reveal that the hosts Q[6,
7] favor inclusion of the guest via supramolecular interactions
in either gas phase or aqueous solution. The BSSE-corrected
-
1
The host–guest interaction could lead to a change of pK
a
binding energies are -277.1 kJ mol for the encapsulation of INH
20
-1
value of guest, and the drug guest has three sites which can
be protonated, the nitrogen on the pyridine moiety, the hydrazine
with Q[6] host and -236.4 kJ mol for the encapsulation of INH
with Q[7] host in gas phase, and in liquid phase they are -362.6
21
-1
–
NH group and the hydrazine –NH
Fig. 3 that DpK values of about -0.3 units for hydrazine –NH
group, and 0.6 units for hydrazine –NH group are found in the
presence of Q[6, 7], respectively. At pH ª 6.0, INH is considered
protonated at the hydrazine –NH group.
2
group One can see from the
and -316.9 kJ mol , respectively. Accordingly, the approximate
a
stabilization energies indicate that the different interaction models
of exclusion for the Q[6]–INH system and inclusion for the Q[7]–
INH are thermodynamically stable in either the gas and liquid
phrase.
2
2
Molecular geometry simulation of Q[6, 7] and their interaction
complexes
Acylation kinetics of INH and its interaction with Q[6, 7]
Based on the investigation of host–guest interactions described
above, the acylation kinetics of INH with some classic acylating
agents 1–4 (Scheme 1) in the presence and absence of macrocyclic
compounds were used to estimate the acylation resistance of INH
with supramolecular formation at a ratio Q[6, 7] : INH of 0.8 : 1
and 1 : 1. A fixed concentration of INH and acylation agents
Generally, cucurbit[n]urils form stable inclusion complexes with
guests through a combination of dipole–ion, hydrogen bonding,
hydrophobic interactions, and size effect of cavity. To understand
what the static structures of the interaction of ionogenic INH
with Q[6, 7] look like and their thermodynamic stability, quan-
tum chemistry calculations were performed and the simulated
supramolecular structures (Fig. 4) are consistent with the above
-
5
-1
(
4
2.5 ¥ 10 mol L , respectively) and a reaction temperature of
◦
0 C were adopted from the kinetic data (Table S1, ESI†). As
1
experimental results of H NMR analysis, spectrometric titrations
expected, the host–guest interaction hindered the acylation of
INH. The stoichiometric addition of Q[6] or Q[7] made INH
almost unavailable for acylation, whereas the presence of host in a
and deterministic searching (potential energy curves shown in Fig
S5, ESI†). It is seen that the interaction models of INH with Q[6, 7]
depend on the size of host’s cavity strongly as the experimental and
calculated results unambiguously demonstrate different binding
for Q[6] and Q[7]. Thus the pyridyl moiety of the INH guest lies
outside Q[6] when they interact with each other but it is included
inside the bigger cavity of Q[7]. Therefore, a portal interaction
involving hydrogen bonding could be the reason leading to stable
formation of the two host–guest inclusion complexes. Principally,
the protons of the hydrazide on the guest offer an opportunity
0
.8 : 1 ratio to INH caused the initial rate of the acylation reaction
to be decreased about 10–100 times and the INH resistance was
found to be independent of the nature of the acylating agents. The
cavity size of the cucurbiturils and the relevant observed initial
rates (denoted by pkobs, see ESI†) are collected in Fig. 5.
Fig. 4 Energy minimized structures of INH and host–guest complexes of
10
INH with Q[6, 7] optimized at the B3LYP/STO-3G level, Color codes:
Fig. 5 Initial rates of INH with acylating agents 1–4 in the absence and
carbon, gray; nitrogen, blue; oxygen, red; white: hydrogen.
presence of Q[6, 7].
1
044 | Org. Biomol. Chem., 2011, 9, 1041–1046
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Scheme 2 Possible mechanism of supramolecular prevention of INH from acylation reaction with cucurbiturils (taking benzyl chloride as an example).
In the biochemical reaction, INH is generally acetylated by
acetyl coenzyme A (Scheme 1). Acetyl coenzyme A is a thioester
that comprises a cysteine residue as a thiol and an acetyl moiety
that is the main active group in acetylation of INH and can be
transferred to INH. Analogues of the active moiety in Acetyl
Coenzyme A, compounds 5 and 6 (Scheme 1), which comprise
cysteine and acetyl chlorine, were used to investigate the influence
of the amount and cavity size of cucurbiturils on the rate of
transfer of the acetyl moieties from the thioesters to INH. Fig. 6
shows the obvious dependence of INH resistance of acetylation
in the experimental time of about 300 min. The kinetic evidence
suggests that only free INH can be attacked by acetylating agents
and the formation of loose encapsulation of INH with Q[6] or
Q[7] is unfavorable for the acetylation reaction, and the so the
effectiveness of resistance depends on the ratio of Q[6, 7] to INH.
Supramolecular protection mechanism of INH with Q[6, 7]
According to the above experimental evidences and results of
calculation chemistry, a possible mechanism of supramolecular
resistance of INH to acylation reaction in the presence of Q[6, 7]
has been established. In general the acylation reaction of the amino
◦
on the amount of cucurbiturils at 40 C, as observed with a
-
5
-1
fixed concentration of INH and thioesters (2.5 ¥ 10 mol L ,
respectively). The initial reaction rates are sharply decreased by
increasing the amount of Q[6] or Q[7], and are decreased by a
factor of 10- in the presence of 0.8 equivalent of supramolecular
hosts. The controllable acetylation resistance of INH is unrelated
to the models of host–guest interactions, the cavity size of
macrocyclic compounds and the thioester species. The addition
of Q[6] or Q[7] in 1 : stoichiometry causes the INH acetylation
to be so slowed that no obvious kinetic behavior can be observed
22
group shows the Schotten–Baumann mechanism, which involves
a two-step pathway of nucleophilic addition, then elimination
(Scheme 2). In the first step, the lone-pair electron of the hydrazide
group attacks the carbonyl group of acylating agents, and then,
in the second step, the activity of the hydrazine group is crucial in
2
the elimination reaction. The increased pK values of the Q[6,
a
7]-bound INH predicate the protons on the hydrazine can be
stabilized and the reactivity of hydrazine is decreased, that is,
the binding INH by cucurbiturils and the formation of hydrogen
bonding between the amino protons and portal carbonyls of the
Q[6, 7] could protect the amino proton from the elimination
reaction.
Conclusion
In summary, we propose that the resistance of INH to acylation
is due to the host–guest interaction with cucurbit[6, 7]urils. The
amount of host available is crucial to the prevention of INH
acylation, whereas the site of guest INH moieties relative to the
cucurbit[6, 7]urils, and the size of the host, had little effect. The
chemical results provide evidence that cucurbiturils can be used as
potential drug-carriers of INH, and that by altering the amount
of cucurbiturils added, the acylation rate of INH can be modified.
This will potentially enable the acylation rate to be slowed down in
fast acetylators. These findings may have important implications
for a patient’s response to anti-TB therapy.
Fig. 6 Relationship between the acetylation rates of INH, the amount of
Q[6, 7] and thioester species at 40 C.
◦
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Acknowledgements
10 G.-L. Zhang, Z.-Q. Xu, S.-F. Xue, Q.-J. Zhu and Z. Tao, Chin. J. Inorg.
Chem., 2003, 19, 655–659.
1
1 H. Watzig, C. Dette, A. Aigner and L. Wilschowitz, Pharmazie, 1994,
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This work was supported by the National Natural Science
Foundation of China (No. 20972034), the “Chun Hui” Project
of the Chinese Ministry of Education (No. Z2008-1-5501), the
Natural Science Foundation of Guizhou Province (No. [2008]75,
4
1
2 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, J. A. Montgomery Jr., T. Vreven, K. N. Kudin, J. C.
Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
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