Semi-synthesis and Structure–Activity Relationship of Neuritogenic Oleanene Derivatives

Article abstract of DOI:10.1002/cmdc.201800352

(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl (2E)-3-(3,4-dihydroxyphenyl)acrylate (1 a), which possesses significant neuritogenic activity, was isolated from the traditional Chinese medicine (TCM) plant, Desmodium sambuense. To confirm the structure and to assess biological activity, we semi-synthesized 1 a from commercially available oleanolic acid. A series of novel 1 a derivatives was then designed and synthesized for a structure–activity relationship (SAR) study. All synthetic derivatives were characterized by analysis of spectral data, and their neuritogenic activities were evaluated in assays with PC12 cells. The SAR results indicate that the number and position of the hydroxy groups on the phenyl ring and the triterpene moiety, as well as the length of the (saturated or unsaturated) alkyl chain that links the phenyl ring with the triterpene critically influence neuritogenic activity. Among all the tested compounds, 1 e [(3S,4R)-23,28-dihydroxyolean-12-en-3-yl (2E)-3-(3,4,5-trihydroxyphenyl)acrylate] was found to be the most potent, inducing significant neurite outgrowth at 1 μm.

Full text of DOI:10.1002/cmdc.201800352

Accepted Article
Title: Semi-synthesis and Structure-Activity Relationship of
Neuritogenic Oleanene Derivatives
Authors: Linglin Bian, Shining Cao, Lihong Cheng, Atsuo Nakazaki,
Toshio Nishikawa, and Jianhua Qi
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10.1002/cmdc.201800352
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Table of Contents
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Semi-synthesis and Structure-Activity Relationship of Neuritogenic
Oleanene Derivatives
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Linglin Bian, Shining Cao, Lihong Cheng, Dr. Atsuo Nakazaki, Prof. Toshio
Nishikawa and Prof. Jianhua Qi
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(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl (2E)-3-(3,4-dihydroxyphenyl)acrylate (1a) was
isolated from Desmodium sambuense. Firstly, compound 1a was semi-synthesised. Then
a series of 1a derivatives was designed, synthesised for structure-activity relationship
study. Amongst all tested compounds, 1e was the most active, inducing a significant
neurite outgrowth at 1 μM.
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(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl
(2E)-3-(3,4-dihydroxyphenyl)acrylate (1a), which possess significant
neuritogenic activity, was isolated from the traditional Chinese medicine (TCM)
Desmodium sambuense. To confirm the structure and biological activity, we
semi-synthesised 1a from commercially available oleanolic acid. Then, a
series of novel 1a derivatives was designed and synthesised for
structure-activity relationship (SAR) study. All synthetic derivatives were
characterised by analysing the spectral data, and their neuritogenic activities
were evaluated in PC12 cells. The SAR results indicated that the number and
position of the hydroxy groups on the benzene ring and the triterpene moiety,
as well as the length of the (saturated or unsaturated) alkyl chain linking the
benzene ring and the triterpene critically influence the neuritogenic activity.
Amongst all the tested compounds, 1e was the most potent, inducing
significant neurite outgrowth at 1 μM.
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Semi-synthesis and Structure-Activity Relationship of
Neuritogenic Oleanene Derivatives
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Linglin Bian,[a] Shining Cao,[a] Lihong Cheng,[a] Dr. Atsuo Nakazaki,[b] Prof.
Toshio Nishikawa,*[b] and Prof. Jianhua Qi*[a]
[a] College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang
Road 388, Hangzhou 310058, China
[b] Laboratory of Organic Chemistry, Graduate School of Bioagricultural
Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
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* To whom correspondence should be addressed:
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Prof. Jianhua Qi
College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road
866, Hangzhou 310058, China.
Tel/Fax: +86-571-88208627
E-mail: qijianhua@zju.edu.cn
Prof. Toshio Nishikawa
Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences,
Nagoya University, Chikusa, Nagoya 464-8601, Japan.
Tel: +81-52-789-4115
Fax: +81-52-789-4111
E-mail: nisikawa@agr.nagoya-u.ac.jp
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Introduction
Nerve growth factor (NGF), a neurotrophic factor (NTF), plays important
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roles in the development, survival and functional maintenance of neurons.[1-3]
In recent decades, significant progress has been attained about this protein
and its roles in diseases.[4] NGF is regarded as a potential therapeutic drug for
treating various neurodegenerative diseases, such as Alzheimer’s disease
(AD).[5] However, NGF, due to its high molecular weight and hydrophilicity,
cannot pass through the blood-brain barrier (BBB)[6] and thus its medicinal
applications are limited. Therefore, low-molecular-weight compounds that
display NGF-mimicking activity have been considered potential drugs for the
treatment of neurodegenerative diseases.[7] The PC12 cell lines,[8] derived
from rat pheochromocytoma, exhibit sympathetic neuron-like phenotypes
under NGF stimulation. In our study, we used a PC12 cell bioassay system to
screen active samples and guide the isolation of neuritogenic small
molecules.[9-11]
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To date, we have isolated or synthesised dozens of neuritogenic
substances.[12-16] To identify new highly effective substances that exhibit low
toxicity and novel mechanisms, we have steadily pursued the extraction and
separation of traditional Chinese medicines (TCMs) and synthesised
derivatives for structure-activity relationship (SAR) study. Desmodium
sambuense, which belongs to the Leguminosae family, is an important TCM. In
a recent study, a compound with neuritogenic activity, that is,
(3S,4R)-23,28-dihydroxyolean-12-en-3-yl
(2E)-3-(3,4-dihydroxyphenyl)acrylate (1a) (Figure 1) was isolated by
separating the ethanol extract of D. sambuense. Its chemical structure was
elucidated by analysing its spectral data and comparing the spectroscopic data
with those reported in the literature.[17]
Herein, we report the semi-synthesis, design and synthesis of a series of 1a
derivatives, perform SAR study, and discover a lead compound in drug
development.
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Figure 1. The structure of 1a isolated from Desmodium sambuense
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Results and discussion
Synthesis of oleane derivatives
The natural product 1a is an important substance with significant
neuritogenic activities. However, the content of 1a in D. sambuense is
extremely low. We synthesised 1a and its analogues from oleanolic acid (2),
which is a commercially available compound, for SAR studies to find a lead
compound for future drug development.
The synthetic route of 1a is shown in Schemes 1 and 2. Oleanolic acid (2)
was esterized with methyl iodide in the presence of anhydrous K2CO3 in dry
DMF at room temperature to obtain methyl ester 3 with 98% yield.[18] One of
the germinal dimethyl groups of 3 was selectively hydroxylated for the
acquisition of 6 (78% overall yield) in three steps according to Hartwig’s
procedure. Briefly, methyl oleanate 3 was converted into diethyl(hydrido)silyl
ether 4 with diethylsilane in the presence of [Ir(cod)OMe]2. Then, we catalyzed
the C-H silylation with [Ir(cod)OMe]2/Me4phen to obtain 5, which was oxidized
under the conditions of Tamao-Fleming oxidation, giving methyl hederagenate
6 as a colourless solid.[19] The reduction of 6 with LiAlH4 in THF at reflux
afforded triol 7 with 97% yield. Then, we selectively protected the two primary
hydroxy groups of triol 7 with TBS to obtain the intermediate 8 with 92%
yield.[20] Compound 10a was synthesised by the esterification of the
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O-TBS-protected caffeic acid 9a with 8 in dry CH2Cl2 by using
N,N’-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) at
room temperature overnight (56% yield). Then, the selective deprotection of
the TBS groups of 10a was investigated. For the removal of all TBS groups,
numerous reaction conditions, such as TBAF, Et3N-3HF, p-TsOH and PPTS,
were performed. Finally, deprotection was achieved by using camphor sulfonic
acid (CSA) in MeOH at room temperature (88% yield). The NMR spectra of the
synthesised 1a was agreed well with the natural spectra. The neuritogenic
activity of the synthesised 1a tested in PC12 cells was comparable to that of
the natural one.
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Scheme 1. Synthesis of key intermediate 8
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Scheme 2. Synthesis of oleanene derivatives 1a-1q
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To analyse the SAR of 1a, a series of oleanene derivatives 1b to 1q was
synthesised. Most derivatives (1b-1i, 1l-1q) were synthesised from 8 and
acids by the same procedure as for that of 1a. Caffeic acid derivatives 9a and
its analogues 9c-9i were prepared according to the method described in the
literature.[20, 21]
Derivatives
1j
(3-nitro-4-hydroxycinnamic
ester)
and
1k
(3-amino-4-hydroxycinnamic ester) were synthesised from the common
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intermediate 8 in a slightly different manner (Scheme 2). The O-TBS-protected
8 was converted into 10j (or 10k) by treating of 9j (or 9k), DCC and DMAP in
dry toluene overnight under a reflux temperature. Afterwards, the TBS groups
were removed by using CSA in MeOH at room temperature to afford
compound 1i (or 1j).
For further SAR study, compounds 1r and 1s (the corresponding diacetate
of 1a), 1t and 1u (23-deoxyanalogues of 1a), were synthesised through
Scheme 3. The acetylation of 1a with acetic anhydride, DMAP and pyridine in
CH2Cl2 produced tetraacetate 1r with 96% yield. When 1r was treated with
MeONa in MeOH, the selective deacetylation of phenol provided 1s with
71% yield.
Compounds 1t and 1u were synthesised from oleanolic acid (2). 2 was
esterified with the O-TBS-protected caffeic acid (9a), followed by the
deprotection of the TBS group with CSA in MeOH, to produce 1t. The
reduction of the carboxy group of 2 with LiAlH4 at reflux in THF afforded
substance 11. Then, the primary hydroxyl group of 11 was protected by the
TBS group to obtain 12. 14 was synthesised through the esterification of the
O-TBS-protected caffeic acid (9a) with 12 in dry CH2Cl2 by using DCC and
DMAP at room temperature overnight. The deprotection of the TBS group
provided 1u. Compounds 1a-1u were purified by semi-preparative HPLC.
Their structures were confirmed by NMR and high-resolution ESI-TOF-MS.
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Scheme 3. Synthesis of oleanene derivatives 1r-1u
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Neuritogenic activity
The neuritogenic activities of the obtained oleanene derivatives were
evaluated by using PC12 cells and compared with the negative (0.5% DMSO)
and positive control (NGF at an optimum concentration of 40 ng/mL). The
dose-dependent response of the NGF-mimicking activity of each compound
was evaluated.
Figure 2 shows the maximum neuritogenic activities of natural 1a, synthetic
1a, triol 7, caffeic acid and oleanolic acid 2 at optimum concentrations. Natural
1a and synthetic 1a showed comparable neuritogenic activities, reaching
maximum activities of 76% (1 M) and 78% (1 M), respectively. Triol 7, caffeic
acid and oleanolic acid 2 showed neuritogenic activities of 26% (1 M), 31%
(10 M) and 22% (3 M), respectively. The results revealed that the
neuritogenic activities of triol 7 and caffeic acid were significantly lower than
that of 1a.
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Figure 2. Maximum NGF-mimicking activity of 1a, synthetic 1a, triol 7, caffeic
acid and oleanolic acid (2) at the optimum concentration. Value means the
average percentage of neurite outgrowth ± SD (n=3). C: control (0.5% DMSO);
positive control: NGF (40 ng/mL); (NGF, 1a, synthetic 1a, triol 7, caffeic acid
and oleanolic acid: ***P < 0.001)
The neuritogenic activities of synthetic 1a-1f are depicted in Figure 3a,
which show the SAR of the position and number of phenolic hydroxyl groups.
Oleanene derivatives 1a, 1b, 1c, 1d, 1e and 1f exhibited maximum activities of
76% (1 μM), 35% (3 μM), 42% (3 μM), 49% (3 μM), 85% (1 μM) and 41% (3
μM), respectively, suggesting that at least two ortho-hydroxy groups in
cinnamic acid were critical for neuritogenic activity and that the three o-OH
groups on the cinnamic moiety of 1e exhibited better activity than that of the
natural compound 1a.
The length of (saturated or unsaturated) alkyl chains linking the benzene
ring and triterpene was investigated. 3-(3,4-Dihydroxyphenyl) propanoic acid
derivative 1g, 2-(3,4-dihydroxyphenyl) acetic acid derivative 1h and
3,4-dihydroxybenzoic acid derivative 1i induced maximum activities of 58% (3
μM), 46% (3 μM) and 37% (3 μM), respectively (Figure 3b). These results
implied that a shorter length of the (saturated or unsaturated) alkyl chain
linking the benzene ring and triterpene corresponded to a worse neuritogenic
activity (1a, 1h and 1i). In addition, the double bond of caffeic acid is also
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important for neuritogenic activity (1g vs. 1a).
As shown in Figure 3c, the introduction of a nitro or amino group into a
hydroxy group substituent at the 3ʹ-position of 1a weakened the potency (1j vs.
1a; 1k vs. 1a) with 1j and 1k displaying neurite outgrowths of 49% (1 μM) and
48% (1 μM), respectively. These results suggested that the phenolic hydroxyl
group was better than the nitro or amino group in these cases. The
heterocyclic rings that were introduced at position 3 obtained moderate to low
neuritogenic activity compounds. 1l-1o induced maximum activities of 55% (1
μM), 42% (1 μM), 32% (3 μM) and 31% (3 μM), respectively (Figure 3c). Finally,
we used butyric acid or hexanoic acid instead of caffeic acid and yielded 1p
(29%, 3 μM) and 1q (33%, 3 μM). These results demonstrated that the
introduction of an alkyl chain is harmful to neuritogenic activity.
The neuritogenic activities were obviously decreased when all hydroxyls (1r)
or primary hydroxyls (1s) of 1a were replaced by OCOCH3 or when triol 7 was
replaced with oleanolic acid 2 (1t) or oleanolic-acid-reducing substance 11 (1u)
(Figure 3d). This finding implied that triol 7 is important for neuritogenic activity
and that the acetylation of the hydroxyl groups of 1a reduced the neuritogenic
activity.
The dose-dependent responses of the NGF-mimicking activity of
compounds 1a, 1d, 1g, 1h, 1j, 1k, 1l and 1t which exhibited neuritogenic
activity higher than 45% were showed in supporting information, Figures 1-8,
respectively.
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a)
b)
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***
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DMSO
NGF
1g (3)
1h (3)
1i (3)
(µM)
DMSO
NGF
1a (1) 1b (3) 1c (3) 1d (3) 1e (1)
1f (3)
(µM)
c)
d)
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***
DMSO NGF 1j (1) 1k (1) 1l (1) 1m (1) 1n (3) 1o (3) 1p (3) 1q (3)
DMSO
NGF
1r (10)
1s (10)
1t (3)
1u (3)
(µM)
(µM)
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Figure 3. Maximum NGF-mimicking activity of triterpenoid derivatives 1a-1f,
1g-1i, 1j-1q, 1r-1u at the optimum concentration. Value means the average
percentage of neurite outgrowth ± SD (n=3). C: control (0.5% DMSO); positive
control: NGF (40 ng/mL); (NGF, 1a-1f, 1g-1i, 1j-1q, 1r-1u: ***P < 0.001)
On the basis of these results, 1e was selected as the lead compound.
Compound 1e exhibited a dose-dependent increase in neuritogenic activity at
the concentration range of 0.03-3 M, as shown in Figure 4a. The 1e showed a
neuritogenic activity of 35% even at 0.03 M and a significant neuritogenic
activity of 85% at 1 M. Figure 4b showed dose-response curve of 1e in PC12
cells indicating EC50 was 0.3 M. Figure 5 shows the morphological changes
of PC12 cells after treatment with 1e at 1 M in comparison with the solvent
control (0.5% DMSO) and positive control (NGF 40 ng/mL). The control cells
displayed a few short neurite outgrowths (Figure 5a). By contrast, the cells
exhibited long multipolar neurite outgrowths at 48 h after treatment of 1e at
1M (Figure 5c), and these outgrowths were similar to those produced
following treatment with NGF at 40 ng/mL (Figure 5b). Photomicrographs of
PC12 cells after treatment of 1e at concentrations ranged from 0.03-1 M were
showed in supporting information Figure 9.
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Figure 4. a. Dose-dependent response of the NGF-mimicking activity of 1e 48
h after treatment. C: control (0.5% DMSO); positive control: NGF (40 ng/mL),
1e at 0.03, 0.1, 0.3, 1, 3 M: ***P < 0.001. b. Dose-response curve of 1e in
PC12 cells. Independent experiments and the numbers of replicates in each
experiment were repeated three times. Each value represents the mean ±
SEM of three replicates.
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Figure 5. Photomicrographs of PC12 cells under a phase-contrast microscope
48 h after treatment: (a) solvent control 0.5 % DMSO; (b) NGF 40 ng/mL; (c)
1e (1 M).
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Conclusions
(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl
(2E)-3-(3,4-dihydroxyphenyl)acrylate (1a) was isolated as a potent
neuritogenic compound from TCM D. sambuense and was efficiently
synthesised from a commercially available material. Then, a series of 1a
derivatives was prepared for SAR studies. Most of the tested compounds
demonstrated significant neuritogenic activity in the PC12 cells. The
neuritogenic activities of these derivatives were affected by the number and
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position of phenolic hydroxy and other hydroxy groups of terpene moiety, by
the type and length of the linker between the benzene ring and triol 7 and by
the heterocycles. Compound 1e possessing triol 7 and cinnamic acid with
three close hydroxy groups exhibited the best neuritogenic activity and was
therefore selected as the lead compound. Investigations on the action
mechanism and animal experiments involving the lead compound are currently
underway in our lab.
Experimental Section
The experimental details of compound syntheses and characterization data
are available in the Supporting Information.
Acknowledgements
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This work was financially supported by the National Natural Science
Foundation of China [Grant No. 21661140001 and 21572204]. This work was
also supported by the international and interdisciplinary environments of the
JSPS Core-to-Core Program, “Asian Chemical Biology Initiative,” and JSPS
A3 Foresight Program.
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Conflict of interest
The authors declare no conflict of interest.
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Keywords: Oleanene derivatives
activity · NGF · PC12 cells · Structure-activity relationship (SAR)
·
Semi-synthesis
·
Neuritogenic
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