An electronic circular dichroism study for the structurechiroptical relationship of chiral proton pump inhibitors

Article abstract of DOI:10.1246/cl.150883

In this paper, we investigated the electronic circular dichroism (ECD) of proton pump inhibitors (PPIs) using a method of combining experimental spectrum and time-dependent density functional theory (TD-DFT) calculations. In our research, an intriguing helicity-like phenomenon was discovered for the relationship between static dipole moment and ECD curves of different conformers in lansoprazole. The scope and validity of the precious phenomenon have been examined by four PPIs using the same method. Hence, it can be used as a reference to determine and verify the absolute configuration of PPIs-type and PPIs-like chiral sulfoxide.

Full text of DOI:10.1246/cl.150883

CL-150883
Received: September 22, 2015 | Accepted: November 9, 2015 | Web Released: November 18, 2015
An Electronic Circular Dichroism Study for the Structure­Chiroptical Relationship
of Chiral Proton Pump Inhibitors
1
1
1
1
2
1
Zhixu Zhou, Linwei Li, Ning Yan, Lei Du, Changshan Sun,* and Tiemin Sun*
1
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University,
Ministry of Education, Shenyang 110016, P. R. China
2
Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
(
E-mail: suntiemin@syphu.edu.cn)
In this paper, we investigated the electronic circular
dichroism (ECD) of proton pump inhibitors (PPIs) using a
method of combining experimental spectrum and time-depend-
ent density functional theory (TD-DFT) calculations. In our
research, an intriguing helicity-like phenomenon was discovered
for the relationship between static dipole moment and ECD
curves of different conformers in lansoprazole. The scope and
validity of the precious phenomenon have been examined by
four PPIs using the same method. Hence, it can be used as a
reference to determine and verify the absolute configuration of
PPIs-type and PPIs-like chiral sulfoxide.
empirical approach is limited to the availability of structural
analogues that exhibit comparable chiroptical property.
11
Another excellent option is to use the exciton chirality method
(ECM) to clarify the AC for compounds having the same or
1
2
similar chromophores. Moreover, quantum chemical calcula-
tions can obtain the correct AC even without a reference
molecule, and have been extensively used to estimate ECD
7
,8
spectrum simulation.
Regarding the absolute configuration of PPIs-type chiral
sulfoxide, the stereochemical assignment of omeprazole (Ome)
enantiomers has been determined by X-ray crystallography of a
1
3
fenchyloxymentyl derivative of (R)-omeprazole; rabeprazole
Rabe) has been determined by X-ray crystallography of an
(
1
4
Proton pump inhibitors (PPIs), as a novel class of efficient
intermediate; pantoprazole (Panto) enantiomers have been
determined by a similar experimental ECD curve to omepra-
+
+
anti-secretory agents, block the H /K -ATPase pump, which is
in charge of gastric acid production, located in the secretory
1
5
zole; notwithstanding, the absolute configuration of lansopra-
zole was determined by a similar measured ECD curve to
1
membranes of the parietal cells selectively. These compounds
1
5,16
have been established for the treatment of peptic ulcers due
to their high top-quality anti-secretory potency, long-lasting
omeprazole and NMR.
Furthermore, the comparison of UV­
vis and ECD spectrum shows that PPIs do not match the demand
of the exciton chirality rule (Figure S1).
2,3
efficacy, and unique pharmacokinetic characteristics. PPIs are
4
also used to the treatment of acid-related diseases. The basic
Taking these aspects into account, we investigated the
absolute configuration of lansoprazole by experimental and
calculated ECD. In our research, we discovered a helicity-like
phenomenon for the structure­chiroptical relationship of differ-
ent conformers in ECD curves. Then, in order to investigate the
scope and validity of the precious phenomenon, another three
PPIs (Figure S2) were studied by a similar procedure. In the
following context, lansoprazole was chosen from the four pairs
of isomeric compounds under investigation as the example to
state the computational process.
structural units of PPIs include a substituted aromatic ring, a
substituted benzimidazole ring, and a methyl sulfoxide group.
In terms of defining the structure­activity relationship (SAR) of
PPIs, a flexible chiral sulfur atom is the indispensable structural
unit for PPIs. The pharmacological, pharmacokinetic, and
toxicological differences between the two enantiomers have
been investigated. The chiral switches of PPIs demonstrate
therapeutic advantages, such as reducing metabolic load on the
body, simplifying pharmacokinetics, and providing benefit to the
nonresponders to the standard dose of the racemate. Esomepra-
zole, the (S)-form of omeprazole, was marketed in 2001 as the
first single-optical-isomer PPI; dexlansoprazole, the (R)-enan-
tiomer of lansoprazole, has been approved by the US Food and
Drug Administration (FDA) in January 2009. Other chiral PPIs
such as (S)-pantoprazole and (R)-rabeprazole are either under
development or have been approved.3 Thus, it is urgent to
determine the absolute configuration (AC) of target PPIs. In this
study, we further investigate the role of structure (static dipole
moments of chromophores) in the absolute configuration of PPIs.
Nowadays, many techniques are available to determine
the absolute configuration of chiral molecules. X-ray crystallog-
raphy defines the ACs unambiguously if a single crystal is
available for the molecule.7 As not every molecule can be
crystallized successfully, electronic circular dichroism (ECD)
is an ideal alternative for determining the AC of a molecule
that has chromophores near the chiral center.9 In general,
the AC of a chiral molecule can be deduced directly from its
ECD spectrum using semiempirical correlations. However, the
In principle, the physical and chemical properties of a
1
7
compound are critically influenced by its conformers. Thus,
reliable conformational analysis has a fundamentally important
effect for the computational results close to the experimental
ones. Several researches have shown that even minor changes
in a molecule conformer could lead to significant changes in
theoretical CD. It is particularly true for simple nonpolar
,5,6
1
8,19
compounds.
A crucial issue to be addressed is that the
rotatable single bonds around a chiral center have a predominant
role in the chiroptical properties of flexible molecules. Thus, we
launched a conformational searching for PPIs-type compounds
as follows: Firstly, a conformational searching was performed
2
0
using the Spartan 14 program with MMFF
molecular
,8
mechanics force field for the target compound. Secondly, the
most stable conformer resulting from the molecular mechanics
calculations was subjected to potential energy surface (PES)
,10
21
22
scans. PES scans were carried out by PM3 scanning the
dihedral angles O2S1C3N4 and O2S1C5H6 ensemble while
other geometrical parameters were relaxed to arrive at better
110 | Chem. Lett. 2016, 45, 110–112 | doi:10.1246/cl.150883
© 2016 The Chemical Society of Japan

Figure 1. PES scans of conformer (R)-Lan at PM3 level.
Figure 3. The relative stable conformers of (R)-Lan, and their
calculated ECDs.
Figure 2. Experimental and calculated ECD of Lan.
Figure 4. The chromane helicity-like rule for P/M-helicity.
geometric structures (Figure 1). Thirdly, so as to give a more
accurate description about this, the above conformations
obtained by PES were re-optimized by DFT using the
(R)-Lan is based on Conf.1. The contribution of the individual
transition to the band having strength larger than 0.1 is shown in
Figure S6, and the electron density between the ground state and
excited states is presented in Figure S5. As shown in Figure S6
and Figure S7, the experimental absorption peak at 267 nm
corresponds to the electronic transition from S to S , involving
transitions between the pyridine ring itself and from the chiral
center to benzimidazole ring. The experimental negative CE at
228 nm is ascribed to π­π* transitions from the chiral center to
the benzene ring and CT in the pyridine ring itself.
23
B3LYP/6-311++G(d,p) method under the PCM model in the
Gaussian 09 package.24 Finally, the redistributed energy values
according to the Boltzmann distribution,25 regardless of the
conformers that possess inappreciable contribution for confor-
mational equilibrium, permitting define the stable conformers
for further investigation. ECD was simulated by TDDFT/
B3LYP/6-311++G**. Furthermore, in order to set forth the
relationship between the stereostructures and Cotton effects
0
1
(
CE), the static dipole moments of chromophore units have been
In our studies on the relationship between the stereo-
structures and CE, an interesting phenomenon was observed and
valuable results were summarized for the CE of PPIs-type chiral
sulfoxides. As previously represented, the Boltzmann-averaged
theoretical ECD of R/S-isomers represents a perfect mirror
image. However, the simulated ECDs of individual conformers
vary greatly due to conformational changes due to the rotation of
single bonds (Figure 3). Figure 3 presents the stereostructures of
stable conformers and their calculated ECD curves. By viewing
the stable conformers along the C5-S1 axis, (R)-Lan could be
divided into two types of P (plus, clockwise) and M (minus,
anticlockwise) according to the static dipole moment of the
chromophores around the chiral center. In detail, that is to say,
the sign of the CE curve and the type of molecule depends on
the summed vector of the static dipole moment of the two
chromophores in Lan. If the summed vector in the plane
perpendicular to the C5-S1 axis is positive, the angle of the
vectors less than 180 degree, the molecular type is P, versus M
(Figure 4). A remarkable positive relevance exists between
the positive CE at 267 nm and conformer P, and the negative
relevance for negative CE at 228 nm. Conf.1 and Conf.3 are in
type P; thus, the theoretical ECD demonstrates a positive CE at
267 nm. On the contrary, the summed dipole moment in the (R)-
Lan-2 structure is counterclockwise; therefore, negative CE is
detected. The difference in magnitude between 1 and 3 may be
due to the relative position between the chiral center and the
archived by DFT/B3LYP/6-31+G(d), and are presented in
Figure S3 and Figure S4.
The simulated ECD spectrum for (R)-Lan and (S)-Lan,
which were re-plotted with population weighting along with the
experimental spectrum, are shown in Figure 2. The theoretical
spectra have been corrected based on the UV correction
(Figure S5). In the so-called UV correction, one looks for a
match between measured and calculated UV­vis spectra and
then applies the same shift to ECD.26 Figure 2 showed that
calculated ECD provides a sign, trend, and order of magnitude
similar to the measured in spite of the blue shift, which stems
from the system error in theoretical calculations.
The calculated ECD of (R)-Lan showed a strong positive
CE at 267 nm and a negative CE at 228 nm, which is similar
to the curve of the R-isomer in the experimental spectrum. As
expected, the computed ECD of (S)-Lan mirrored that of (R)-
Lan, as displayed in Figure 2. The high conformity between
the experimental and theoretical ECD curves, noting that the
conformational searching approach we used is reasonable for
flexible chiral molecules.
The origin of the CEs in the ECD spectrum can be explained
by charge transition (CT) analysis in the ground and excited
states at the same level of ECD calculation. The conformer 1 is
the most populated conformer of (R)-Lan with a Boltzmann
proportion of 79.8%; hence, the charge transition analysis of
Chem. Lett. 2016, 45, 110–112 | doi:10.1246/cl.150883
© 2016 The Chemical Society of Japan | 111

Liaoning Innovative Research Team in University. The theo-
retical calculations were conducted on the ScGrid and
Deepcomp7000 the Supercomputing Center, Computer Network
Information Center of Chinese Academy of Sciences.
Supporting Information is available on http://dx.doi.org/
1
0.1246/cl.150883.
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Figure 5. The most stable conformer of R configuration and
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This work was supported by the Program for Innovative
Research Team of the Ministry of Education, Program for
112 | Chem. Lett. 2016, 45, 110–112 | doi:10.1246/cl.150883
© 2016 The Chemical Society of Japan