Crystal engineering construction of caffeic acid derivatives with potential applications in pharmaceuticals and degradable polymeric materials

Article abstract of DOI:10.1039/d0ce01403f

Natural products are precious feedstock in drug discovery and sustainable materials. This work using crystal engineering strategy, visible light, and solvent-free cycloaddition successfully constructed two caffeic acid derivatives, rel-(1R,2R,3S,4S)-2,4-b

Full text of DOI:10.1039/d0ce01403f

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Crystal engineering construction of caffeic acid
derivatives with potential applications in
pharmaceuticals and degradable polymeric
materials†
Cite this: DOI: 10.1039/d0ce01403f
a
a
b
a
Zhihan Wang, * Quinton Flores, Hongye Guo, Raquel Trevizo,
a
c
Xiaochan Zhang and Shihan Wang
Natural products are precious feedstock in drug discovery and sustainable materials. This work using crystal
engineering strategy, visible light, and solvent-free cycloaddition successfully constructed two caffeic acid
derivatives,
rel-(1R,2R,3S,4S)-2,4-bis(3,4-dihydroxyphenyl)cyclobutane-1,3-dicarboxylate
and
rel-(1R,2R,3S,4S)-2,4-bis(3,4-dihydroxyphenyl)cyclobutane-1,3-dicarboxylic acid. Because of the multiple
stereocenters, it is challenging to prepare those compounds using traditional organic synthesis methods.
The crystal engineering Hirshfeld surface analysis and 2D intermolecular interaction fingerprints were
applied to synthetic route design. The light resources used in this work was visible LED or free, clean, and
renewable sunlight. The evidence suggested that pure stereoisomer was obtained demonstrating the
stereospecificity and efficiency of the topochemical cycloaddition reaction. The derivatives exhibited free
radical scavenging and antioxidant biological activities, as well as the potential inhibitory activity of fatty acid
binding proteins. One of the derivatives is the precursor of the natural product shimobashiric acid C which
paves the way for the total synthesis and further study of shimobashiric acid C. In addition, the derivatives
possess photodegradability at a specific wavelength, which is very attractive for “green” degradable
polymeric materials.
Received 24th September 2020,
Accepted 26th October 2020
DOI: 10.1039/d0ce01403f
rsc.li/crystengcomm
3
d,4
hepatocarcinoma.
One of the most studied caffeic acid
Introduction
derivatives is caffeic acid phenethyl ester (CAPE), which can
be extracted from the popular propolis and is considered to
be the main bioactive compound in propolis. According to
Natural products play a crucial role in drug development and
biomass-based materials. Caffeic acid (CA) is a natural
1
5
polyphenol and a key intermediate compound in lignin
previous reports, CAPE has a therapeutic effect on lung
2
biosynthesis. It is ubiquitous in the plant kingdom and can
cancer, liver cancer, cholangiocarcinoma, and prostate cancer,
2
3c,5,6
be extracted from many plants. In vitro and in vivo studies
and has been proven to inhibit colon cancer in vivo.
In
have shown that CA and its derivatives possess variable
biological activities, including antimicrobial, antivirus,
antiinflammation, anticancer, antioxidants, antithrombosis,
addition, caffeic acid, as a secondary metabolite in plants, is
the basis for the production of various plant metabolites. For
example rosmarinic acid was first isolated and characterized
7
3
and antihypertensive activities. Especially, CA exhibited
from the Rosmarinus officinalis and has been found in a
8
encouraging effects against
a
widespread cancer type
number of Lamiaceae plants. It was reported that rosmarinic
acid has antioxidant and anti-inflammatory effects, inhibits
the development of Alzheimer's disease, and is used in the
9
treatment of asthma and allergic diseases. It can be
a
Department of Physical Sciences, Eastern New Mexico University, Portales, NM
8130, USA. E-mail: zhihan.wang@enmu.edu
synthesized by conventional organic synthesis methods using
caffeic acid and salvianic acid A (danshensu) (Fig. 1a).
Shimobashiric acid C, a dimer of rosmarinic acid, is also a
derivative of caffeic acid which can be isolated from Keiskea
japonica and Plectranthus amboinicus. Shimobashiric acid C
contains two moieties, salvianic acid A and rel-(1R,2R,3S,4S)-
8
b
School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021,
China
c
College of Chinese Herbal Medicine, Jilin Agricultural University, Changchun, Jilin
1
30118, China
10
†
Electronic supplementary information (ESI) available: Statistic data and
crystallographic data. CCDC 2021369, 2021371, 2021372 and 2021374. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0ce01403f
2
,4-bis(3,4-dihydroxyphenyl)cyclobutane-1,3-dicarboxylic acid
(CBDA-10) (Fig. 1a). However, due to the existence of multiple
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Fig. 1 a) Two caffeic acid derivatives from plant kingdom: rosmarinic acid (caffeic acid + salvianic acid A) and shimobashiric acid C (salvianic acid
A + CBDA-10). b) The stereoisomers of CBDA-10.
stereocenters, the synthesis of CBDA-10 is exceptionally
engineering include hydrogen bonds, halogen bonds, van der
Waals interactions, dispersion, dipole–dipole interactions,
and ion–dipole interactions. Crystal engineering has been
widely used in pharmaceutical co-crystals, supramolecular
materials, organic polymers, functional materials, etc. In this
work, we employed Hirshfeld surface analysis and
intermolecular interaction 2D fingerprint to guide us in
1
1
arduous using conventional organic synthesis methods.
Therefore, there are few studies on the biological activities of
1
0b,12
shimobashiric acid C.
The challenge in the synthesis of CBDA-10 is to construct
the stereospecific cyclobutane, which is the key motif of the
CBDA-10. Photon excitation can be used to construct a
cyclobutane ring through a 2π–2π cycloaddition reaction, but
the excited olefin-containing molecules in the solution may
lead to cis-trans isomerization and produce a mixture of
designing
proper
molecules
for
topochemical
photocycloaddition to construct the desired caffeic acid
1
6
derivatives.
1
1b,c,13
stereo products.
In particular, CBDA-10 has five
With aid of crystal engineering strategies, especially the
intermolecular interaction information provided by Hirshfeld
surface analysis and 2D fingerprints, we designed the molecule
stereoisomers (Fig. 1b), which brings great obstacles to the
preparation of it using the reported methods. This work
demonstrates the stereospecific preparation of CBDA-10
using topochemical photocycloaddition reaction. In
topochemical reactions, the atoms only proceed with
minimal movement, which can avoid side reactions and
produce stereospecific products. Topochemical reactions
have the advantage of realizing sophisticated structures that
are difficult to achieve in conventional organic synthesis.
However, the most difficult aspect of topochemical
photocycloaddition is to construct the required atomic
orientations. The ideal orientation of atoms and the 2π–2π
system is that the distance must be in the range of 3.5–4.2 Å,
and the reactive double bonds must also be arranged in
with
ideal
atomic
orientation
for
topochemical
photocycloaddition and successfully constructed the desired
caffeic acid derivatives, dimethyl rel-(1R,2R,3S,4S)-2,4-bis(3,4-
dihydroxyphenyl)cyclobutane-1,3-dicarboxylate (CBDE-10) and
CBDA-10. The designed molecule has absorption below 420 nm,
while 43% of solar energy is visible light (400 nm to 700 nm).
According to the report of the National Renewable Energy
Laboratory, the annual average daily solar radiation in the
−2
17
school area is 5.50 to 5.75 kW h m per day. This free, clean
and renewable energy provides a sustainable way to construct
18
our research. Therefore, sunlight was implemented to trigger
the topochemical cycloaddition. The sunlight-induced
topochemical cycloaddition in this work is solvent-free, metal-
free, byproduct-free, high efficiency, and low consumption of
external energy. The CBDE-10 demonstrated free radical
scavenging and antioxidant activities in vitro the biological
activity studies. In silico study suggested the CBDE-10 is a
potential inhibitor of the fatty acid binding proteins.
Interestingly, the newly synthesized CBDE-10 exhibited
1
4
parallel.
Applying crystal engineering strategies to
topochemical reactions has the merit of arranging atoms in
the desired orientations. Crystal engineering is based on the
understanding and use of the weak intermolecular
interactions to design and synthesize molecular structures
1
5
with desired physical and chemical properties. Those weak
intermolecular interactions that can be used in crystal
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photodegradable property at 254 nm radiation. The
photodegradation properties and thermal stability of CBDE-10
provide possibilities for its application in the field of
move away from each other, thereby not forming a new single
bond. This offset may be caused by the hydrogen bonds of
1
4
carboxylic groups, which may weaken the π–π stacking of the
19
26
environmentally friendly degradable polymeric materials. The
monomer caffeic acid methyl ester exists in a variety of plants,
and existing studies have shown that it can inhibit the growth
and development of harmful insects and is an environmentally
friendly plant insecticide. In addition, cyclobutane-containing
polymers (CBPs) have demonstrated various applications such
double bonds.
To further understand the interactions
between CA molecules, we performed Hirshfeld surface
analysis and 2D fingerprint of intermolecular interaction
contribution.
Intermolecular interactions are very important in
molecular stacking. Hirshfeld surfaces with different
properties (for example, dnorm, electrostatic potential, shape
index, and curvature) are very useful tools for visualizing the
interactions between molecules and their contribution to
1
9c
20
as UV-shielding materials,
sustainable materials,
19a,21
19b,22
degradable materials,
self-healing materials,
and
23
photoresponsive materials. The use of CBDE-10 and CBDA-10
as the building blocks of polymeric materials greatly fulfils the
call for environmental protection and zero pollution, which is
taken from nature and attributed to nature. Moreover, the
construction of CBDA-10 paved the way for the total synthesis
and further study of the natural product shimobashiric acid C.
2
7
molecular crystal packing behavior. On the dnorm mapped
Hirshfeld surface, the red-blue-white colour scheme is used
to distinguish intermolecular interactions in the crystal
structure (Fig. 3a). The white surface represents contacts
whose distance is equal to the sum of the van der Waals
radii. The red region represents shorter distance than sum of
van der Waals radii, while blue region represent indicates a
Results and discussion
CA is an analogue of cinnamic acid, an example of classical
2
4
topochemical photocycloaddition.
We initially tried to
perform topochemical photocycloaddition on CA, but even if
CA has an absorption of 300 to 385 nm (Fig. S6†), it still
showed photostability with ultraviolet radiation (Fig. S5†).
When we noticed the photoactivity of CA, we recrystallized
CA in a mixed solvent of methanol and water. The single
crystal X-ray diffraction structure shows that the double
bonds are parallel with each other, and the distance between
them is 3.903 Å with 80.16° inner angle (Fig. 2a and b).
Despite those conditions falling into the solid-state postulate
of photoreaction, the CA single crystal is not photoreactive
2
4,25
under 365 nm UV lamp.
After further analysis, we noticed
that although the double bonds are parallel to each other,
there is a 59.32° interfacial angle between the planes α (α′)
and plane β, which results in 1.991 Å offset between the
double bonds on the CA molecules (Fig. 2c and d). This offset
causes the p orbitals on the corresponding double bonds to
Fig. 3 Hirshfeld surface analysis of CA. a) Hirshfeld surface mapped
with
dnorm visualize the intermolecular interactions. b) Hirshfeld
surfaces mapped with electrostatic potential using the 6-311G(d,p)
basis set at B3LYP level theory. c) Hirshfeld surfaces mapped over the
shape-index of CA. d) Shape-index indicates the π–π interaction
between the adjacent CA molecule. e) Hirshfeld surfaces mapped over
curvedness of CA. f) Curvedness map indicate the π–π interaction
between the adjacent CA molecule. g) H⋯O/O⋯H interaction
contribution. h) C⋯C interaction contribution. Note: the green dots
lines represent the prominent hydrogen bonds. The pattern of orange
and blue triangles in the shape-index represents the π–π interaction.
The flat regions on the curvedness indicate the π–π interaction as well.
Fig. 2 Single crystal X-ray diffraction of CA. a) & b) The view of closest
distance of the two double bonds on CA. c) The interfacial angle
between molecular planes α (α′) and two double bonds plane β. d) The
corresponding p orbitals offset on horizontal line. Oak ridge thermal
ellipsoid plot (ORTEP) diagram displayed at 50% probability level.
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longer distance than the van der Waals radii. On the
electrostatic potential Hirshfeld surface, it is shown as blue
and red areas, corresponding to the positive and negative
potentials, respectively (Fig. 3b). The blue area (e.g. O1–
flexible the alkoxy chain, the shorter chain is preferred in crystal
engineering to maintain the original molecular pattern.
Methoxy, ethoxy and propoxy are the idea candidates. To verify
our hypothesis, we started from methoxy group. The synthesis
was started from Steglich esterification of caffeic acid using N,
H1⋯O2) represents
a
positive electrostatic potential
(
hydrogen bond donor), and the red area (e.g. O2⋯H6–O3)
N′-dicyclohexylcarbodiimide
(DCC)
and
represents a negative electrostatic potential (hydrogen bond
acceptor). From Fig. 3a and b, we can clearly see that a CA
molecule interacts with five adjacent molecules mainly
through hydrogen bonds. The 2D intermolecular interaction
fingerprint provides information about intermolecular
interactions and their relative contribution to the Hirshfeld
surface. The 2D fingerprint obviously shows that the
contribution of hydrogen bonds to the interaction between
CA molecules is 41.4% (Fig. 3g). The shape index of the
Hirshfeld surface is a tool to visualize the π–π interaction
through the presence of adjacent orange and blue triangles
4-dimethylaminopyridine (DMAP) (Scheme 1). The synthesized
methyl caffeate (MC) is also a natural product that can be
extracted from Solanum torvum fruits and is reported to have
28
anticancer activity. Additionally, methyl caffeate showed anti-
29
inflammatory activity. Once MC was prepared, its single
crystal was obtained from ethyl acetate and hexane. The single
crystal X-ray diffraction results showed the double bounds are
parallel and the distance is 3.654 Å with inner angle 70.39°
(Fig. 4a and b). Planes α (α′) and plane β have an 86.63°
interfacial angle which induced 0.214 Å offset between p
orbitals on each double bound (Fig. 4c and d). Now, the
orientations of the reactive double bonds fall within the ideal
conditions of topochemical photocycloaddition.
(Fig. 3c). The blue triangle is the convex region representing
the atoms of the molecules inside the surface, while the
orange triangle is the concave region associated with the π–π
interacting atoms above it. Fig. 3c shows the pattern of
alternating orange and blue triangles with appropriate
symmetry, indicating an offset π–π interaction with the
molecules above it. The π–π interaction can also be observed
on the curvedness mapped Hirshfeld surface, which is a flat
area on the surface (Fig. 3e). However, the π–π interaction is
very weak between C2–C3 and C3–C2 (Fig. 3d and f). This
analysis is consistent with the 2D fingerprint which shows
the contribution of the C⋯C interaction is 4.7%. It is shown
In order to elucidate the pattern change along with the
influence of methoxy group, a close examination with
Hirshfeld surface on MC was performed. Both dnorm mapped
Hirshfeld surface and electrostatic potential mapped
Hirshfeld surface indicate the reduced hydrogens bonds
(Fig. 5a and b). One CA molecule has hydrogen bonds with
five surrounding CA molecules, while one MC molecule has
hydrogen bonds with three surrounding MC molecules
(Fig. 5a and b). The 2D fingerprint shows that the
contribution of hydrogen bonds to molecular interactions of
MC molecules is decreased to 33.1% (Fig. 5g), which is 18.8%
lower than that of CA molecules (Fig. 3g). On the other hand,
it is easy to observe the π–π interaction related to the
adjacent orange and blue triangles in the Hirshfeld surface
mapped by the shape index (Fig. 5c). In particular, the π–π
interaction between reactive double bonds (C2–C3⋯C3–C2)
is enhanced (Fig. 5d). The curvedness surface shows more
flat areas confirming the same observation (Fig. 5e and f).
The C⋯C interaction contribution of MC molecules
increased to 7.4%, which also reflects the enhanced π–π
interaction (Fig. 5h).
as an obvious triangle near d
the characteristic of π–π interaction (Fig. 3h).
e
= d
i
≈ 1.8 Å, which refers to
According the intermolecular interaction information
provided by Hirshfeld surface and 2D fingerprints of CA, we
hypothesize that if an electron-donating group is introduced to
the carboxyl group of CA, the hydrogen bond interaction will
decrease, and the π–π interaction will be relatively increased,
which may result in the ideal atomic orientations for
topochemical photocycloaddition. Alkoxy group is a good
electron-donating group which have the chance to break the
hydrogen bonds. Since the longer the alkoxy chain, the more
Scheme 1 The designed synthetic route of CBDE-10 and CBDA-10 using crystal engineering guidance. Oak ridge thermal ellipsoid plot (ORTEP)
diagram displayed at 50% probability level.
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Once we determined that MC was in the ideal atomic
orientation for topochemical photocycloaddition, we started
to proceed the photocycloaddition of MC. The electron-
donating group not only brings the atoms to ideal
orientations, but also makes the bathochromic shift of MC.
The solid-state MC has absorption below 420 nm (Fig. S6†),
which makes it possible to perform topochemical
photocycloaddition under visible light. Most of the solar
radiation that reaches the earth is visible light that provides
clean and renewable free energy for photocycloaddition.
Therefore, the solid MC was placed into sunlight (outside the
laboratory, 18 h) or underneath a 400 nm light-emitting
diode (LED) bulb (in the laboratory, 24 h) for cycloaddition.
FT-IR confirmed the completion of the cycloaddition.
Infrared spectra showed that the characteristic absorption
Fig. 4 Single crystal X-ray diffraction of MC. a) & b) The view of
closest distance of the two double bonds on MC. c) The interfacial
angle between molecular planes α (α′) and two double bonds plane β
on MC. d) The corresponding p orbitals offset on horizontal line of MC.
Oak ridge thermal ellipsoid plot (ORTEP) diagram displayed at 50%
probability level.
−
1
peak of CO at 1669 cm under sunlight shifted to 1705
−
1
cm due to the deconjugation of the carbonyl group. After
−
1
the reaction, the stretching of CC (1624 cm ) disappeared
as well as the out-of-plane distortion of the hydrocarbon
−
1
single bonds in the trans-CHCH (970 cm ). The solvent-
free photocycloaddition showed high efficiency with a yield
of 95%. The remaining 5% may be attributable to the
sublimation of MC, because when molecules absorb photons,
they may generate heat. The structure of CBDE-10 was
1
13
1
confirmed by H-, COSY-, C-, and DEPT90-NMR. H-NMR
spectra showed that the double bond peaks at 7.49 (d) and
6
.27 (d) ppm faded in the sunlight. The peaks at 3.70 (dd)
3
and 4.07 (dd) ppm corresponding to the sp -hybridized
carbons in the newly formed cyclobutane ring indicate that
CBDE-10 possesses an α-stereoisomer structure. The 46.83
and 40.89 ppm peaks in DEPT90-NMR also provide evidence
of newly formed cyclobutane rings. The stereocenters were
further confirmed by the single crystal analysis which was
3
0
obtained
from
methanol
and
dimethylformamide
(
Scheme 1). The results proved the stereospecific preparation
of the α-isomer. Besides, no side reactions and by-products
were observed which also proved the efficiency of the
topochemical photocycloaddition. The cyclobutane moiety
possesses a coplanar conformation with 88.68° inner angle
and 0.00° torsion. The precursor of shimobashiric acid C was
successfully prepared by the hydrolysis of CBDE-10 and the
single crystal analysis of CBDA-10 showed the same
cylclobutane moiety as CBDE-10 (Scheme 1). Both results
suggested that the stereocenters on the CBDE-10 and CBDA-
10 are rel-(1α,2α,3β,4β) proving the stereospecific synthesis
strategy in topochemical photocycloaddition. After refining
the method of synthesis, we studied bioactivities including
radical scavenging, antioxidant and in silico protein binding.
Free radicals are atoms or molecules with highly reactive
unpaired electrons. They can be produced naturally in the
body during normal cellular metabolism, or they can be
Fig. 5 Hirshfeld surface analysis of MC. a) Hirshfeld surface mapped
with
dnorm visualize the intermolecular interactions. b) Hirshfeld
surfaces mapped with electrostatic potential using the 6-311G(d,p)
basis set at B3LYP level theory. c) Hirshfeld surfaces mapped over the
shape-index of MC. d) Shape-index indicates the π–π interaction
between the adjacent MC molecule. e) Hirshfeld surfaces mapped over
curvedness of MC. f) Curvedness map indicate the π–π interaction
between the adjacent MC molecule. g) H⋯O/O⋯H interaction
contribution. h) C⋯C interaction contribution. Note: the green dots
lines represent the prominent hydrogen bonds. The pattern of orange
and blue triangles in the shape-index represents the π–π interaction.
The flat regions on the curvedness indicate the π–π interaction as well.
3
1
introduced from the environment.
However, the
uncontrolled generation of free radicals can damage the
main components of cells, such as DNA, proteins, lipid
3
1
membranes, and carbohydrates. Those damages may cause
various adverse reactions such as cancer, atherosclerosis,
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central nervous system diseases, autoimmune diseases, heart
3
1
diseases, diabetes, and cardiovascular disease. Studies have
shown that the anticancer activities of CA and its derivatives
are linked to their antioxidant properties. This can be
attributed to the prevention of cellular damage induced by
2
8b,32
free radicals.
Herein, we investigated the in vitro radical
scavenging and antioxidative activities of compounds CA,
MC, and CBDE-10. Their free-radical-scavenging activities
were assessed by their activity against a stable free radical
3
3
2,2-diphenyl-1-picrylhydrazyl (DPPH).
DPPH is a stable
organic radical with a purple colour and a strong absorption
at 517 nm. Their antioxidant activities were investigated
using lipid peroxidation of linoleic acid emulsion system and
Fig. 7 The in silico study of CBDE-10 binding with FABP5 and FABP7.
a) & c) The interactions between CBDE-10 and FABP5/FABP7. b) & d)
The surface model of the docking site which shows the CBDE-10 fit
the pockets of FABP5 and FABP7.
3
2a,33
ferric thiocyanate assay.
The free radical scavenging
activities of compound CA, MC, and CBDE-10 were studied
by measuring the absorbance decrease at 517 nm within 30
min. The results showed that the scavenging rate of free
radicals for CA, MC, and CBDE-10 is about 90% at 50 μg
−
1
mL (Fig. 6a). As the concentration increased, the efficiency
of free radicals scavenging increased. The inset of Fig. 6a
shows the colour change of the inhibitions in different
concentrations of CBDE-10. Meanwhile, we studied the
kinetics of the free radical scavenging, and the results
showed the radical scavenging reached the highest rate in 5
min (Fig. S8†). Fig. 6b showed the results of antioxidative
activity. In the process of linoleic acid peroxidation, the
FABP5-releated-signalling transduction pathway involves in
3
6
the prostate tumour promotion. FABP7, also known as
brain FABP, plays a pivotal role in HER2+ breast cancer brain
3
7
metastasis. Hence, we studied the binding affinity of CBDE-
10 and FABP5(PDB: 4LKT)/FABP7(PDB: 1FE3). The in silico
study was carried out using Autodock Vina program using
the crystalline data of CBDE-10 as the docking ligand
3
8
(Fig. 7). The results showed that the maximum docking
2
+
3+
3+
−1
produced peroxide can oxidize Fe to Fe , and then Fe ion
score of CBDE-10 in FABP5 was −8.1 kcal mol and the
2
+
forms a red complex [Fe(SCN)] , which has a maximum
absorption at 500 nm. Therefore, high absorbance indicates
high oxidation. The results showed that all samples had a
decent inhibitory effect on the oxidation of the lipid,
especially MC, which was better than CA and CBDE-10 in
antioxidant study. The above studies indicated that the
caffeic acid derivatives are promising radical scavenging
agents and antioxidants.
maximum docking score of CBDE-10 in FABP7 was −7.6 kcal
−
1
mol . Fig. 7 visualized the docking results which showed the
interactions between CBDE-10 and the amino acids on FABP5
3
9
and FABP7.
CBDE-10 has the potential to be a lead
compound or an inhibitor of FABP5 and FABP7.
An additional finding, compound CBDE-10 can be steadily
degraded under 254 nm radiation. In 30 min of radiation,
96% of compound CBDE-10 was degraded (Fig. 8a). This
special property makes CBDE-10 a degradable building block
for polymeric materials. Polymeric plastics not only bring
great benefits to society, but also threaten the environment
due to the plastic pollutions. Compound CBDE-10 has the
potential to build photodegradable plastics. In addition,
thermogravimetric analysis demonstrated the thermostability
of CBDE-10, which showed the maximum decomposition
occurred at 328 °C (Fig. 8b). The T5% and T10% occurred at
Fatty acid-binding protein (FABP) is composed of a group
of proteins that coordinate lipid transport and responses,
which can be found in the brain, liver, heart, intestine, testis,
adipocyte, epidermis, and myelin. FABPs play an important
role in metabolic pathways, regulating gene expression and
3
4
cell growth. It is believed that FABPs are related to the
3
5
proliferation and apoptosis of cancer cells. For example,
Fig. 6 a) Scavenging effect of CA, MC, and CBDE-10 on the stable
−
1
DPPH˙ at different concentrations (10–50 μg mL ). Inset: The radical
scavenging results of 3 after 30 min. b) Antioxidant study of CA, MC,
Fig. 8 a) The degradation of CBDE-10 at 254 nm in 30 min. b)
Thermogravimetric analysis of CBDE-10 from 50 °C to 700 °C at 20 °C
−1
−1
and CBDE-10 (20 μg mL ) in 10 h using lipid peroxidation assay.
min heating rate under N
2
atmosphere.
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3
1
00 °C and 310 °C, respectively, which also indicated CBDE-
0 is suitable to be a backbone in thermoplastics.
for the topochemical photocycloaddition and degradation were
sunlight, an 11 W hocinderal LED bulb (wavelength: 400 nm)
and a Philips G15T8 Germicidal lamp (wavelength: 254 nm).
Sonication was carried out in a BRANSON 2800 digitally heated
timer-adjustable ultrasonic cleaner or Fisher Scientific FS-14
Solid State/Ultrasonic Cleaner. Centrifuge used in this study was
Fisher Scientific Centrific Model 228.
Conclusion
In conclusion, we demonstrated how to apply crystal
engineering strategies into molecular stacking as well as how
to use free, clean, and renewable solar energy into solvent-
free cycloaddition to construct caffeic acid derivatives. Based
on the intermolecular interaction information provided by
Hirshfeld surface and 2D fingerprints, we designed the
photoreactive monomer. In the synthesis process, sunlight or
Synthesis of MC
Caffeic acid (2.0 g, 11 mmol), N,N′-dicyclohexylcarbodiimide
(
0
DCC, 2.7 g, 13 mmol), and 4-dimethylaminopyridine (DMAP,
.1 g, 1 mmol) were added to 15 mL of methanol in a 50 mL
4
00 nm LED was employed as the light source, which
round bottom flask. The mixture was kept stirring and
refluxed for 16 h. After reaction, the mixture was cooled down
to room temperature. The side product dicyclohexylurea
indicates the application of clean renewable energy to drug
discovery and polymeric materials. One of the five
stereoisomers of CBDA-10 was successfully prepared. No by-
products or other stereoisomers were observed, proving the
high efficiency of topochemical cycloaddition reaction.
Meanwhile, solar energy was harvested and stored into
chemical bonds. The synthesized caffeic acid derivatives
possess biological activities of scavenging free radicals and
antioxidants. In particular, CBDE-10 showed the potential
inhibitory activity of fatty acid binding proteins in molecular
simulations, which offered a new lead compound for the
development of FABPs inhibitors. The photodegradable
(
DCU) was filtered through filter paper and the solid was
washed with ethyl acetate 50 mL for twice. Then the filtrate
was washed with 1 M HCl 50 mL and then with brine 50 mL
in a 125 mL separatory funnel. The organic layer was
concentrated to give a yellow crude product. The crude
product was dissolved into 30 mL ethyl acetate and charged
with 90 mL of hexane. The suspension was filtered through a
10 cm silica gel column. The column was eluted twice using
mixed 30 mL ethyl acetate and 60 mL hexane. TLC showed
all samples were collected. The combined collections were
properties CBDE-10 may provide
a new way for the
concentrated by roller evaporator to give a white product 2
degradable polymeric materials. On the other hand, the
CBDA-10 affords the core scaffold of the natural product
shimobashiric acid C, paving the way of the total synthesis.
Using CBDA-10 or CBDE-10 as the lead compound or
building block achieves the goal of “nature-to-nature” in
green chemistry.
1
(
2.0 g, 93%). H NMR (400 MHz, DMSO-d
6
) δ 9.36 (s, 2H),
7
6
.49 (d, J = 15.9 Hz, 1H), 7.06 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H),
.77 (d, J = 7.9 Hz, 1H), 6.27 (d, J = 15.9 Hz, 1H), 3.69 (s, 3H)
1
3
ppm. C NMR (126 MHz, DMSO-d
6
) δ 167.47, 148.87, 146.02,
1
45.63, 125.93, 121.88, 116.17, 115.23, 114.12, 51.67 ppm. MS
+
+
(
m/z): [M + Na] calcd. for C10
H
10
O
4
Na , 217.047; found
2
1
17.046. IR: ν = 3473, 3086, 3033, 2953, 2918, 1669, 1624,
604, 1535, 1435, 1305, 1293, 1240, 1179, 1159, 1111 cm .
−
1
Experimental section
Materials
Visible light topochemical cycloaddition of CBDE-10
All chemicals and solvents were purchased from Alfa-Aesar
(
caffeic acid 98+%, N,N′-dicyclohexylcarbodiimide 99%, ethyl
acetate environmental grade 99.5+%), TCI Chemicals
4-dimethylaminopyridine >99%, 1,1-diphenyl-2-picrylhydrazyl
radical 97+%, 2,2′-azobis(2-methylpropionamidine)
dihydrochloride 98%, linoleic acid 99%), MilliporeSigma
acetonitrile HPLC grade, methanol HPLC grade), VWR
500 mg powder of MC was scattered on a 5″ × 5″ glass slide
and placed in sunlight or underneath 400 nm LED with 1 cm
distance for radiation (18–24 h). The powder was flipped over
every 3 h until FT-IR showed the completion of the reaction.
Another alternative method can be used as well. 1.0 g of MC
was suspended into 15 mL deionized water in a 20 mL vial.
The suspension was put in front a LED with 1 cm distance.
The mixture was stirred and irradiated at room temperature
for 18 h. FT-IR was used to monitor the photoreaction. Once
FT-IR showed the completion of the photoreaction, the
(
(
Chemicals BDH (sodium hydroxide ACS grade), VWR (Tween 20
polysorbate proteomics grade), Acros Organics (ammonium
thiocyanate 99+% extra pure, iron(II) chloride tetrahydrate
9
9+%), Innovating Science (sodium chloride reagent grade,
sodium sulfate anhydrous lab grade, phosphate buffered saline
lab grade, PBS buffer pH 7.0 lab grade, 1.0 M hydrochloric acid
solution lab grade), Beantown Chemical Corporation (ethyl
acetate ACS 99.5% min), Thermo Fisher Scientific (hexanes ACS
grade), Best Value Vacs (hexanes high purity lab grade), Decon
Labs, Inc. (ethanol 190 proof), or Cambridge Isotope
Laboratories, Inc. (deuterium solvents) and used without further
purification. Borosilicate glass vial used in the photoreaction
were purchased from VWR (66022-106). The light source used
mixture was filtered through a filter paper to give CBDE (0.95
1
g, 95%) as a white powder. H NMR (500 MHz, DMSO-d ) δ
6
8.81 (d, J = 23.8 Hz, 4H), 6.65 (d, J = 8.3 Hz, 4H), 6.52 (dd, J =
8.2, 2.2 Hz, 2H), 4.07 (dd, J = 10.4, 7.2 Hz, 2H), 3.70 (dd, J =
1
3
10.4, 7.2 Hz, 2H), 3.29 (s, 6H) ppm. C NMR (126 MHz,
DMSO-d ) δ 172.42, 145.37, 144.56, 130.00, 118.58, 115.77,
6
+
115.27, 51.63, 46.83, 40.89 ppm. MS (m/z): [M + Na] calcd.
+
for C H O Na , 411.105; found 411.105. IR: ν = 3384, 3320,
2
0
20 8
−
1
1705, 1616, 1537, 1446, 1359, 1258, 1237, 1196, 1178 cm .
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1
13
1
Synthesis of CBDA-10
at 500 MHz ( H) and 126 MHz ( C). H NMR data were
reported as follows: chemical shift (ppm), s = singlet, d =
doublet, t = triplet, q = quartet, dd = doublet of doublets, m =
multiplet, coupling constant (Hz), and integration.
Deuterated solvents were used: dimethyl sulfoxide (DMSO)-
The 0.2 g of CBDE-10 was added to 5 mL of water. A 1 M
solution of NaOH 0.2 g in 5 mL water was added dropwise to
the sample mixture. The mixture was stirred at room
temperature for 8 h. Then the mixture was poured into 10
mL 1 M HCl. The precipitate was filtered. The filtrate was
extracted with 20 mL ethyl acetate for twice. The combined
organic layers were dried over sodium sulfate and filtered
through a 10 cm silica gel column. The collections were
6
d . Fourier transform infrared (FT-IR) spectra were acquired
−
1
with a wavenumber range of 400–4000 cm on a Thermo
Scientific Nicolet iS10 FT-IR spectrometer. High-resolution
mass spectrometry (HRMS) was performed on a Waters
SYNAPT G2Si with electrospray ionization (ESI) source.
Thermogravimetric analysis (TGA) was performed on a TA
concentrated to give CBDA-10 (0.15 g, 81%) as a white solid.
1
6
H NMR (500 MHz, DMSO-d ) δ 11.98 (s, 2H), 8.77 (d, J = 37.6
−
1
Instruments SDT Q5000 at a ramp rate of 20 °C min from
0 °C to 700 °C in nitrogen constant flow of 100 mL min .
Hz, 4H), 6.67 (d, J = 2.1 Hz, 2H), 6.64 (d, J = 8.1 Hz, 2H), 6.54
−
1
5
(dd, J = 8.2, 2.1 Hz, 2H), 4.00 (dd, J = 10.4, 7.2 Hz, 2H), 3.58–
1
3
Single-crystal X-ray data were collected on a Rigaku XtaLAB
Synergy-i Kappa diffractometer equipped with a PhotonJet-i
X-ray source operated at 50 W (50 kV, 1 mA) to generate Cu
Kα radiation (λ = 1.54178 Å) and a HyPix-6000HE HPC
detector or a Bruker Apex or Bruker Kappa Apex II Duo X-ray
diffractometer with Mo Kα (λ = 0.71073 Å) or Cu Kα (λ =
3
6
.51 (dd, J = 10.4, 7.2 Hz, 2H). C NMR (126 MHz, DMSO-d )
δ 173.54, 145.28, 144.48, 130.78, 118.83, 115.70, 115.46,
+
+
4
3
1
7.19, 40.95. MS (m/z): [M + Na] calcd. for C18
83.073, found 383.073. IR: ν = 3253, 1689, 1608, 1513, 1440,
349, 1283, 1203, 1112 cm .
16 8
H O Na ,
−
1
1
.54178 Å). The structures were solved by direct methods and
Crystallization of CA, MC, CBDE-10, and CBDA-10
refined by the full-matrix least-squares technique using the
SHELXL-2014 package.
CA (200 mg) was dissolved in 5 mL of methanol and 1 mL of
water. The mixture was sonicated for 30 min and filtered into
a 20 mL glass vial. The vial was placed uncovered into a fume
hood. High-quality single crystals were obtained in about
three days.
1,1-Diphenyl-2-picrylhydrazyl (DPPH) scavenging assay
−1
A 0.2 mg mL DPPH˙ ethanol solution was prepared, and 1
MC (100 mg) was mixed with 15 mL of hexane and 5 ml of
ethyl acetate, sonicated for 30 minutes, and then filtered into
a 20 mL glass vial. The vial was exposed in a fume hood
without cover. Cubic shape crystals were obtained in about
two days.
ml of this solution was added to 1 mL of sample solutions
with different ethanol concentrations (10–50 μg mL ). After
−1
30 minutes, the absorbance was measured at 517 nm. The
scavenge efficiency of the DPPH˙ radical was calculated using
the following equation: DPPH˙ scavenging effect (%) =
CBDE-10 (35 mg) was mixed with 10 mL of methanol and
(
AControl − ASample)/AControl × 100. AControl is the absorbance of
1
ml of dimethylformamide, sonicated for 30 minutes, and
the control reaction and ASample is the absorbance in the
then filtered into a 20 mL glass vial. The vial was exposed in
a fume hood without cover. High-quality single crystals were
obtained in about seven days.
presence of samples. All tests were repeated three times.
CBDA-10 (20 mg) was mixed with 10 mL of ethyl acetate
and filtered into a 20 mL glass vial. The vial was exposed in a
fume hood without cover. Cubic shape crystals were obtained
Determination of antioxidant activity in a linoleic acid
system
A linoleic acid emulsion was prepared by mixing 0.28 g of
linoleic acid, 0.28 g of Tween 20 as an emulsifier, and 50 mL
of phosphate buffer (0.2 M, pH 7.0). A 0.5 mL ethanol
1
in about two days. CBDA10-co-EA H NMR (500 MHz, DMSO-
d
6
) δ 11.98 (s, 2H), 8.77 (d, J = 37.7 Hz, 4H), 6.67 (d, J = 2.1
Hz, 2H), 6.64 (d, J = 8.1 Hz, 2H), 6.54 (dd, J = 8.2, 2.1 Hz, 2H),
−1
solution of different samples (20 μg mL ) was mixed with
4
1
1
6
.05–3.96 (m, 5H), 3.55 (dd, J = 10.4, 7.2 Hz, 2H), 1.98 (s, 4H),
.16 (t, J = 7.1 Hz, 4H) ppm. C NMR (126 MHz, DMSO-d ) δ
6
73.54, 170.82, 145.28, 144.48, 130.78, 118.82, 115.70, 115.45,
0.23, 47.18, 40.95, 21.52, 21.23, 14.54.
linoleic acid emulsion (1 mL, 0.2 M, pH 7.0) and phosphate
buffer (0.5 mL, 0.2 M, pH 7.0). The samples were placed into
1
3
15 mL centrifuge tubes separately. The control sample
contained 1 mL of emulsion, 0.5 mL of PBS buffer, and 0.5
mL of ethanol. The peroxidation was initiated by adding
AAPH solution (0.1 M, 50 μL). All samples were vortexed for 1
min. The reaction mixture was incubated in the dark at 37 °C
to accelerate peroxidation. The absorbance at 500 nm was
measured every hour. According to the thiocyanate method,
the levels of peroxidation were determined by sequentially
adding ethanol (2 mL, 75%), ammonium thiocyanate (0.1
Characterization
Ultraviolet-visible (UV-vis) spectra were recorded on a Thermo
Scientific™ GENESYS™ 50 UV-visible spectrophotometer
with a 3.5 mL quartz cuvette. Melting points were measured
on
a Stanford Research Systems (SRS) melting point
apparatus MPA100 automated melting point system without
correction. Nuclear magnetic resonance (NMR) spectra were
recorded on a JEOL ECS 400 MHz NMR spectrometer at 400
−
1
mL, 30%), sample solution (0.1 mL, 20 μg mL ), and ferrous
chloride (0.1 mL, 20 mM in 3.5% HCl). After 3 min, the
peroxide value was determined by reading the absorbance at
1
MHz ( H) or Varian Unity Inova 500 spectrometer operating
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00 nm on a UV-vis spectrometer. All tests were repeated
Paper
5
scale of −0.0910 au (red)–0.2539 au (blue). Shape index plots
were mapped in the colour range −1.000 au (concave) to 1.000
au (convex), and the curvedness in the range of – 4.0000 au
three times.
(flat)–.4000 au (singular). The three-dimensional dnorm surfaces
Statistical analysis
of MC were plotted over a fixed colour scale of −0.7436 au (red)–
All experiments were performed in triplicate. The data were
recorded as expressed as the mean of three replicate
1
.2760 au (blue). Electrostatic potential was plotted in scale of
−
0.0843 au (red)–0.2618 au (blue). Shape index plots were
mapped in the colour range −1.000 au (concave) to 1.000 au
determinations
comparisons were performed by one-way analysis of variance
ANOVA), followed by least significant difference procedure.
p-Values < 0.05 were considered as significant and p-values
0.01 were regarded as very significant.
and
standard
deviation.
Multiple
(convex), and the curvedness in the range of −4.0000 au (flat)–
(
0.4000 au (singular).
<
Conflicts of interest
Photodegradation of CBDE-10
There are no conflicts to declare.
−
1
3
mL of CBDE-10 (40 μg mL in acetonitrile) was transferred
Acknowledgements
into a quartz cuvette. The cuvette was placed 10 cm away
from the UV lamp (254 nm). The absorbance was measured
by UV-vis spectrometer in 30 min. The degradation level was
calculated via the calibration curve determined by linear
This work was supported by an Institutional Development
Award from the National Institute of General Medical
Sciences of the National Institutes of Health (P20GM103451)
and Faculty Research and Instructional Development (FRID)
grant from the Eastern New Mexico University. The authors
acknowledge Dr. Angel Ugrinov at North Dakota State
University and Dr. Daniel Unruh at Texas Tech University for
the single crystal X-ray diffraction assistance, and Dr. Piotr
Dobrowolski at Texas Tech University for the NMR assistance.
2
regression (R = 0.997).
Molecular docking
Macromolecule target structures, FABP-5 (4LKT, 2.57 Å Res.
crystal structure of human epidermal fatty acid binding
protein) and FABP-7 (1FE3, 2.80 Å Res. crystal structure of
human brain fatty acid binding protein oleic acid), were
obtained using the RCSB Protein Data Banks and the ligand
PDB structure of interest was obtained from XRD
characterization. After restricting the proteins of interest to
strictly A chains, standard processing was then used to
obtain the respective PDBQT files for analysis via Autodock
Vina. Parameters used moderate exhaustiveness (>8),
keeping all others in default states. Each was only found to
contain the binding site of the previously bound active site
for each respective protein; thus, the grid coordinates were
centered around these active sites while encompassing the
entire protein section due to its relatively small size.
Validation of poses was achieved by ensuring the database
ligands could be redocked to their corresponding protein
under the established parameters.
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