Synthesis of New Lathyrane Diterpenoid Derivatives from Euphorbia lathyris and Evaluation of Their Anti-Inflammatory Activities

Article abstract of DOI:10.1002/cbdv.201900531

Euphorbia factor L₃, a lathyrane diterpenoid extracted from Euphorbia lathyris, was found to display good anti-inflammatory activity with very low cytotoxicity. To find more potent anti-inflammatory drugs, two series of Euphorbia factor L₃ derivatives with fatty and aromatic acids were designed and synthesized. Among them, lathyrane derivative 5n exhibited most potent inhibition on LPS-induced NO production in RAW264.7 cells with no obvious cytotoxicity. To determine the key characteristics of Euphorbia factor L₃ derivatives that contribute to anti-inflammatory activity, we conducted a structure-activity relationship study of these compounds.

Full text of DOI:10.1002/cbdv.201900531

Title: Synthesis of new lathyrane diterpenoid derivatives from
Euphorbia lathyris and evaluation of their anti-inflammatory
activities
Authors: Wang Wang, Yanli Wu, Chen Li, Yueying Yang, Xingzhou Li,
Hua Li, and Lixia Chen
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Biodiversity 10.1002/cbdv.201900531
Link to VoR: http://dx.doi.org/10.1002/cbdv.201900531

10.1002/cbdv.201900531
Chemistry & Biodiversity
Synthesis of new lathyrane diterpenoid derivatives from
Euphorbia lathyris and evaluation of their anti-inflammatory
activities
Wang Wang,a,1 Yanli Wu,a,1 Chen Li,a Yueying Yang,a Xingzhou Li,c,* Hua Li,a,b,*
Lixia Chena,*
aWuya College of Innovation, Key Laboratory of Structure-Based Drug Design &
Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang
110016, China
bHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation,
School of Pharmacy, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430030, China
c National Engineering Research Center for the Emergency Drug, Beijing Institute of
Pharmacology and Toxicology, Beijing 100850, China
1 These two authors contributed equally to this work.
*Corresponding author: Lixia Chen, Hua Li & Xingzhou Li
E-mail: syzyclx@163.com (Lixia Chen)
li_hua@hust.edu.cn (Hua Li)
xingzhouli@aliyun.com (Xingzhou Li)
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10.1002/cbdv.201900531
Chemistry & Biodiversity
ABSTRACT: Euphorbia factor L3, a lathyrane diterpenoid extracted from Euphorbia
lathyris, was found to display good anti-inflammatory activity with very low
cytotoxicity. To find more potent anti-inflammatory drugs, two series of Euphorbia
factor L3 derivatives with fatty and aromatic acids were designed and synthesized.
Among them, compound 5n exhibited most potent inhibition on LPS-induced NO
production in RAW264.7 cells with no obvious cytotoxicity. To determine the key
characteristics of Euphorbia factor L3 derivatives that contribute to anti-inflammatory
activity, we conducted a structure–activity relationship study of these compounds.
Keywords: Euphorbia lathyris, lathyrane diterpenoid, anti-inflammatory activity.
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10.1002/cbdv.201900531
Chemistry & Biodiversity
Introduction
Inflammation is a host generated protective immune response evolved to protect the
host in response to acute trauma or pathogens or their PAMPs by containing the
damage or removing/killing the pathogen responsible for infection.[1] Severe and
systemic acute inflammation may result in pathology, organ failure and death as seen
during sepsis.[2] At present, clinical methods for treating inflammation include
anti-inflammatory steroids, non-selective non-steroidal anti-inflammatory drugs
(NSAID), COX-2 selective inhibitors and biological therapy, all of which have
several unavoidable serious adverse reactions.[3] In this context, it is highly desirable
to find more anti-inflammatory agents with better effect and safety.
Natural products extracted from plants, microbes, and animals have remarkable
structural diversity and biological characteristics, providing researchers with more
possibilities to develop novel drugs for disease therapeutics.[4] In the kingdom of
natural products, terpenoids have emerged as one of the most important families
because of their distinct biological activities and drug-like properties.[5, 6] In China and
other countries, there are many kinds of terpenoids have been found with good
anti-inflammatory activity and some of which were used clinically for treating
inflammation (Fig. 1).[7-12] Finding new anti-inflammatory drugs from terpenoids is
therefore a good strategy.[13]
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10.1002/cbdv.201900531
Chemistry & Biodiversity
Fig.1. Structures of some terpenoids with good anti-inflammatory activity and some lathyrane
diterpenoids.
The seeds of Euphorbia lathyris are utilized as traditional Chinese medicine for
treating terminal schistosomiasis, ascities, hydropsy, and snakebites.[14-16] It is an
abundant source of special diterpenoids with various macrocyclic and polycyclic
skeletons including jatrophane, ningenane, daphnane, tigliane, and lathyrane.[17, 18]
Some of these diterpenoids possess various biological activities, such as anticancer,[19,
20]
multidrug resistance (MDR) reversal,[21, 22] antiviral,[23] and antifungal effects.[24]
It’s reported that the esterified and Michael addition derivatives of Euphorbia factor
L3,[25] Epoxyboetirane A,[26] and Jolkinol D exhibited more potent MDR-modulating
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10.1002/cbdv.201900531
Chemistry & Biodiversity
effects through inhibiting P-glycoprotein.[27, 28]
In our group’s previous work,[29] Euphorbia factors L1, L3 and some new lathyrane
diterpenoids were found to display good inhibition on NO production induced by LPS
in RAW264.7 macrophage cells with very low cytotoxicity. The mechanism of these
compounds was related to decreasing the production of inflammatory factors and also
reducing the expression of iNOS and NF-κB and the phosphorylation of IκBα. It is
the first time to report the anti-inflammatory activity and mechanism of lathyranes. In
order to investigate the influence of the kind of acids on the anti-inflammatory
efficacy of Euphorbia factor L3 derivatives, and to find more potent anti-inflammatory
drugs with low toxicity, herein, we design and synthesize two series of Euphorbia
factor L3 derivatives with fatty and aromatic acids. The inhibitory activity on
LPS-induced NO production in RAW264.7 macrophage of these derivatives was
investigated as well.
Results and discussion
Chemistry
In our previous work,[29] we have found that Euphorbia factor L3 displayed good
inhibition on NO production induced by LPS in RAW264.7 macrophage cells. When
a hydroxyl was added to C-7 position (compound 2 in Scheme 1), the inhibition
activity could be improved. Meanwhile, the inhibition activity of compounds could be
changed when the hydroxyl group was esterified with different acids. To investigate
the influence of the kind of acids on anti-inflammatory efficacy of compound 2, we
designed and synthesized series 1 (Scheme 1). Since there is difficult to get enough
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10.1002/cbdv.201900531
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compound 2 from plants, at first, Euphorbia factor L3 was oxidized by Selenium
dioxide (SeO2) and tert-butyl hydroperoxide (TBHP) to yield compound 2. As
described in some previous work,[30-33] this reaction could achieve stereo-selectivity.
In our study, this reaction is stereo-selectivity, but the yield is relatively low (15%),
which might be related to steric hindrance of compound 1. The stereostructure of C-7
hydroxyl was determined by NOESY experiment. Then we use fatty acids, substituted
benzoic acids, cinnamic acid and heterocyclic acids for its esterification. Our previous
study has shown that the inhibition activity of compound 2 could be improved
significantly when the hydroxyl group was esterified with nicotinic acid,[29] so we also
used isonicotinic acid and substituted nicotinic acid for esterification. In addition,
α-ipoic acid and N-Boc-glycine are also used for esterification.
Scheme 1. Synthetic route of series 1. Reagents and conditions: (a) SeO2, TBHP, AcOH/DCM,
30 °C , 48 h; (b) EDCI, DMAP, DIPEA, DCM, rt, 8-10 h.
To investigate the influence of the kind of acids on anti-inflammatory efficacy of
Euphorbia factor L3, we designed and synthesized series 2 (Scheme 2). It has been
reported that C-5 hydroxyl can be esterified, but C-3 and C-15 hydroxyls can’t under
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10.1002/cbdv.201900531
Chemistry & Biodiversity
the condition of EDCI and DMAP. But C-3 hydroxyl could be acylated by
corresponding acid chloride.[25] Alkaline hydrolysis of Euphorbia factor L3 afforded
lathyrol 4 with three free hydroxyl groups, followed by the esterification of C-5
hydroxyl with fatty acids, substituted benzoic acids, cinnamic acid and heterocyclic
acids to yield the final products 5a-m. We also synthesized compounds 5n-o and 5p-q
to investigate the influence of C-3 hydroxyl and its etherification on
anti-inflammatory efficacy.
Scheme 2. Synthetic route of series 2. Reagents and conditions: (c) KOH, MeOH, rt, 6 h; (d)
corresponding acid chloride, TEA, DCM, rt/40 °C , 10 h; (e) (CH3)2SO4/BnBr, NaH, DMF, 0 °C ,
0.5 h.
Inhibitory effect on LPS-induced nitric oxide (NO) production and SAR
study
As an important inflammatory mediator, NO is over produced and secreted out of
mouse macrophages in response to bacterial lipopolysaccharide (LPS).[34] The
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Chemistry & Biodiversity
anti-inflammatory activity of these synthesized compounds was evaluated by
detecting the secretion level of NO in the medium of RAW264.7 cells after LPS
stimulated, using dexamethasone as positive control. Among the tested compounds,
series 2 displayed a better inhibitory activity than series 1. Compounds 5n and 5o
showed the most remarkable inhibition against NO production (IC50 values: 3.93 ±
1.04 and 3.70 ± 1.01 μM, respectively), being about twofold more potent than
dexamethasone (Table 1).
In series 1, when C-7-hydroxyl was esterified, many derivatives exhibited weaker NO
production inhibitory activity than compound 2. So the preliminary SARs showed that
the C-7-hydroxyl is important for maintaining the anti-inflammatory activity of
compound 2. Curiously, when C-7-hydroxyl was esterified with nicotinic acid,
isonicotinic acid and glycine, the derivatives exhibited comparable or even better
inhibitory activity than compound 2 (i.e. compounds 3p, q, u). But when
C-7-hydroxyl was esterified with substituted nicotinic acid, the derivatives exhibited
poor inhibitory activity (i.e. compounds 3r-s). So the above results suggested that the
anti-inflammatory activity of compound 2 couldn’t be enhanced by esterification.
In series 2, lathyrol 4 didn't exhibit NO production inhibitory activity. When the
C-5-hydroxyl was esterified, many derivatives exhibited better inhibitory activity than
4. The preliminary SARs showed that the esterification of C-5-hydroxyl is important
for improving the anti-inflammatory activity of 4. It could be concluded that the
compounds with aromatic groups were more potent than compounds with aliphatic
substituents. Meanwhile, the substituents of the benzene ring or changing benzene
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10.1002/cbdv.201900531
Chemistry & Biodiversity
ring into heterocyclic ring could weaken the inhibitory activity of these compounds
(i.e. compounds 5f-m). And the electron donating group of the benzene ring could
weaken the inhibitory activity more than the electron withdrawing group (i.e.
compounds 5f-g and 5h-i). When C-3 and C-5 hydroxyl groups are simultaneously
esterified, the activity of these compounds could be further enhanced (i.e. compounds
5n-o), and the anti-inflammatory activity of etherification derivatives are weaker than
esterification derivatives (i.e. compounds 5p-q). It could be concluded that
esterification is an effective way to improve the anti-inflammatory activity of 4.
Therefore, the above results would provide helpful information for the further
structure modification of Euphorbia factor L3.
Table 1. The IC50 values of the inhibition against NO production of all compounds.[a]
NO
IC50 (μM)
11.24±1.12
7.93±1.03
>50
NO
Compounds
Compounds
IC50 (μM)
>100
1 (Euphorbia factor L3)
3t
3u
3v
4
2
3a
3b
3c
3d
3e
3f
7.05±1.04
>100
11.74±1.08
>50
>100
5a
5b
5c
5d
5e
5f
>50
>50
>50
>50
5.88±1.01
6.57±1.07
9.50±1.01
7.89±1.04
14.50±1.22
21.55±1.72
19.35±1.65
8.86±1.22
23.51±2.42
30.53±2.65
16.59±1.47
3.93±1.04
3.70±1.01
42.26±3.52
13.78±1.52
>100
3g
3h
3i
>100
21.37±2.42
23.69±2.37
>50
5g
5h
5i
3j
3k
3l
>100
>100
5j
3m
3n
3o
3p
3q
3r
3s
>100
5k
5l
>50
>100
5m
5n
5o
5p
5q
5.72±1.04
5.03±1.13
>100
>100
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Dexamethasone[b]
8.36±1.32
[a] The results were showed as means ± SD of at least three independent experiments.
[b] Positive control.
Cell survival of RAW264.7
The cytotoxicity of compounds 5n and 5o were measured by MTT to eliminate its
influence on the detection of NO production. The result showed that compound 5n
had no obvious effect on the cell survival at the concentration up to 100 μM (Fig. 2),
revealing that the anti-inflammatory activity of compound 5n is not produced by
cytotoxicity. As the result, compound 5n could be selected for further
pharmacological study.
Fig. 2. The RAW264.7 cell viability after exposure to different concentrations of compounds 5n
and 5o for 24 h.
Conclusion
Two series of Euphorbia factors L3 derivatives with fatty and aromatic acids were
designed and synthesized. About half of tested compounds showed obvious inhibitory
effect on LPS-induced NO production in RAW264.7 macrophage. Among them,
compound 5n exhibited the most potent inhibition with IC50 of 3.38 ± 1.03 μM with
no obvious cytotoxicity. The preliminary SARs showed that a hydroxyl at C-7
position is helpful to maintain the anti-inflammatory activity of Euphorbia factors L3.
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10.1002/cbdv.201900531
Chemistry & Biodiversity
And the esterification of C-5-hydroxyl with aromatic acids is important for improving
the anti-inflammatory activity of lathyrol scaffold. Therefore, these results are
expected to be useful in the development of lathyrane diterpenoid derivatives or
structurally related compounds as clinical trial candidates.
Experimental Section
Chemistry
All commercially available starting materials and solvents were reagent grade and
used without further purification. Reactions were monitored by thin-layer
chromatography (TLC) on 0.25 mm silica gel plates (GF254) and visualized under UV
light or by heating after spraying with anisaldehyde-H2SO4 reagent. 1H NMR and 13C
NMR spectra were recorded on a Bruker AV-400 spectrometer (Bruker Biospin,
Fallanden, Switzerland). Chemical shifts are stated relative to TMS and expressed in δ
values (ppm), with coupling constants reported in Hz. High resolution mass spectra
(HRMS) of all derivatives were recorded on a Bruker micrOTOF focusII mass
spectrometry by electrospray ionization (ESI). Optical rotations were recorded on a
Autopol IV-T polarimeter (Rudolph Research Analytical). The physical
1
characteristics, H NMR, 13C NMR, MS and specific optical rotation data for all
intermediates and target compounds, were reported in Supporting Information.
Synthetic methods of all compounds
Synthesis of compound 2
Euphorbia factor L3 (compound 1, 1.0 g, 1.9 mmol) was dissolved in DCM (50 mL).
Then acetic acid (5 mL), TBHP (733 mL, 5.7 mmol), and SeO2 (107 mg, 0.96 mmol)
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10.1002/cbdv.201900531
Chemistry & Biodiversity
were added to the solution. The mixture was stirred for 48 h at 30 °C . Upon
completion, the organic layers was washed with brine, and saturated sodium
bicarbonate solution, respectively, dried over anhydrous Na2SO4, and then filtered,
evaporated, and purified by silica gel CC to obtain compound 2 as white solid (15%
yield).
Synthesis of compounds 3a-v
EDCI (44 mg, 0.23 mmol) and acid molecules (0.23 mmol) were dissolved in DCM
(3 mL). After 20 minutes, compound 2 (80 mg, 0.15 mmol), DMAP (catalytic amount)
and DIPEA (49 μL, 0.3mmol) were added to the mixture. The mixture was stirred for
about 8-10 h at room temprature. Upon completion, the organic layer was washed
with 20% citric acid solution and brine, respectively, dried over anhydrous Na2SO4,
filtered, evaporated, and purified by CC to afford compounds 3a-v.
Synthesis of compound 4
Compound 1 (5 g, 9.6 mmol) in 5% KOH/MeOH (100 mL) was stirred at room
temperature for 6 h. Upon completion, the solvent was removed under reduced
pressure, and the residue was extracted with DCM, washed with brine, dried with
anhydrous Na2SO4, filtered, evaporated and purified by CC to afford compound 4 as
white solid (82% yield).
Synthesis of compounds 5a-m
EDCI (44 mg, 0.23 mmol) and acid molecules (0.23 mmol) were dissolved in DCM
(3 mL). After 20 minutes, compound 4 (40 mg, 0.15 mmol), DMAP (catalytic amount)
and DIPEA (49 μL, 0.3mmol) were added to the mixture. The mixture was stirred for
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10.1002/cbdv.201900531
Chemistry & Biodiversity
about 8-10 h at room temprature. Upon completion, the organic layer was washed
with 20% citric acid solution and brine, respectively, dried over anhydrous Na2SO4,
filtered, evaporated, and purified by CC to afford compounds 5a-m.
Synthesis of compounds 5n-o
To a 0 °C solution of 4 (120 mg, 0.36 mmol) and corresponding acid chloride (1.44
mmol) in dry DCM (4 mL) was added dropwise TEA (181 μL, 1.47 mmol) under
argon atmosphere. The resulting mixture was stirred for 10 h at 0 °C to room
temperature. Upon completion, the organic layer was washed with NaHCO3 solution
and brine, respectively, dried over anhydrous Na2SO4, filtered, evaporated, and
purified by CC to afford compounds 5n-o.
Synthesis of compounds 5p-q
To a 0 °C solution of 4 (120 mg, 0.36 mmol) and NaH (1.44 mmol) in dry DMF (2.5
mL) was added dropwise (CH3)2SO4 (or BnBr) (1.47 mmol) under argon atmosphere.
The resulting mixture was stirred for 0.5 h at 0 °C. Upon completion, the organic
layer was washed with NH4Cl solution and brine, respectively, dried over anhydrous
Na2SO4, filtered, evaporated, and purified by CC to afford compounds 5p-q.
Biology
Cell cultures
RAW264.7 mouse macrophage cells were obtained from the American Type Culture
Collection (ATCC, USA). The cells were cultured in high Glucose Dulbecco's
modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS),
100 U/mL penicillin and 100 μg/mL streptomycin. Cell cultures were incubated in a
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10.1002/cbdv.201900531
Chemistry & Biodiversity
humidified tissue incubator containing 5% CO2 at 37 °C according to standard tissue
procedures.
Detection of NO production
Measurement of NO production in RAW264.7 mouse macrophages for all compounds
was refered to our recent article.[35] The RAW264.7 cells seeded in 96-well plates
were incubated with synthesized compounds for 3 h and then 1 μg/mL LPS was added
for 24 h. NO content was measured using Griess reagent at 540 nm and the IC50
values of compounds were determined based on the inhibition rate (%) compared to
vehicle control and model control. DMSO plus LPS or not was set as a model control
or vehicle control.
Cytotoxicity test
RAW264.7 cells were incubated in serum-free medium with compound 5n and 5o.
After incubation for 24 h, MTT (20 μL, 5 mg/mL) was added to each well and
incubated with cells for 4 h. Then the culture medium was carefully removed and 150
μL dimethyl sulfoxide (DMSO) was added to dissolve the crystals by shaking for 10
min. The absorbance was determined at 490 nm. DMSO was also treated as a vehicle
control. All of the experiments were performed in triplicate.
Author Contributions Statement
Xingzhou Li, Hua Li, and Lixia Chen designed the experiments. Wang Wang
contributed to the synthesis and characterization of all compounds. Yanli Wu, Chen Li
and Yueying Yang conducted the biological assays. Wang Wang and Lixia Chen
prepared the manuscript. All the authors revised the final manuscript.
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10.1002/cbdv.201900531
Chemistry & Biodiversity
Acknowledgements
This work was financially supported by National Natural Science Foundation of
China (NSFC) [NOs. 81773594, U1703111, U1803122, and 81773637], Program for
Liaoning Innovation Talents in University (NO. LR2016002), Liaoning Province
Natural Science Foundation (NO. 2019-MS-299), Liaoning Revitalization Talents
Program (NO. XLYC1807182), and Shenyang Planning Project of Science and
Technology (NO. 18-013-0-46).
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10.1002/cbdv.201900531
Chemistry & Biodiversity
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