Synthesis of rocaglamide derivatives and evaluation of their Wnt signal inhibitory activities

Article abstract of DOI:10.1039/c5ob02537k

Rocaglamides are bioactive natural compounds which have a cyclopenta[b]benzofuran core structure. The total synthesis of a reported natural product, 3′-hydroxymethylrocaglate (5), was achieved using [3 + 2] cycloaddition between 3-hydroxyflavone and methyl cinnamate. We also describe the synthesis of rocaglamide heterocycle derivatives and evaluate their Wnt signal inhibitory activities. Compounds 4, 5, 22a, 22b, 22c and 23c showed potent Wnt signal inhibitory activity.

Full text of DOI:10.1039/c5ob02537k

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Synthesis of rocaglamide derivatives and
evaluation of their Wnt signal inhibitory activities†
Cite this: DOI: 10.1039/c5ob02537k
Midori A. Arai,* Yuuki Kofuji, Yuuki Tanaka, Natsuki Yanase, Kazuki Yamaku,
Rolly G. Fuentes, Utpal Kumar Karmakar and Masami Ishibashi*
Rocaglamides are bioactive natural compounds which have a cyclopenta[b]benzofuran core structure.
The total synthesis of a reported natural product, 3’-hydroxymethylrocaglate (5), was achieved using
[3 + 2] cycloaddition between 3-hydroxyflavone and methyl cinnamate. We also describe the synthesis of
rocaglamide heterocycle derivatives and evaluate their Wnt signal inhibitory activities. Compounds 4, 5,
22a, 22b, 22c and 23c showed potent Wnt signal inhibitory activity.
Received 11th December 2015,
Accepted 12th February 2016
DOI: 10.1039/c5ob02537k
www.rsc.org/obc
regulating the expression of death receptors DR4 and DR5 and
Introduction
activating caspase-3/7.5 Silvestrol (6)6 was reported to exhibit
Rocaglamides (= flavaglines, 1–6) are naturally occurring potent cytotoxicity towards human prostate carcinoma LNCaP
complex molecules with a cylopenta[b]benzofuran core struc- cells. The rocaglate skeleton comprises five continuous stereo-
ture that have been isolated from the genus Aglaia and they centers and its synthesis has attracted much attention since
possess many potent biological activities (Fig. 1),1 including the first synthesis of rocaglamide (1) by Trost et al.7 Porco and
powerful cytotoxicity against cancer cells,2 anti-inflammatory co-workers reported a oxidopyrylium [3 + 2] cycloaddition
activity3 and neuroprotective activity.4 We have recently approach to the synthesis of rocaglamide derivatives.8
reported that 1-O-formylrocagloic acid (3) and 3′-hydroxy roca- Recently, several “remodeling” natural product approaches
gloic acid (4) at low nanomolar concentrations sensitize tumor have been used to synthesize compounds exhibiting new bio-
necrosis factor (TNF)-related apoptosis-inducing ligand logical activities:9 for example, a synthesized rocaglate-derived
(TRAIL)-resistant human gastric adenocarcinoma cells by up- β-lactone was reported to have serine hydrolase activity.8d The
discovery of rocaglamide derivatives exhibiting novel bioactivi-
ties would provide new biological tools and drug candidates.
We are interested in the role of the heterocyclic structure of
rocaglamide derivatives on their bioactivity. Herein, we
describe the synthesis of 3′-hydroxymethylrocaglate (5) and
rocaglamide heterocycle derivatives and evaluate their Wnt
signal inhibitory activity.
Results and discussion
Synthesis of 3′-hydroxymethylrocaglate (5)
The research was initiated by synthesizing the natural products
(4) and (5) previously isolated from Amoora cucullata. Starting
Fig. 1 Representative examples of flavaglines: rocaglamide (1), roca-
glaol (2), 1-O-formylrocagloic acid (3), 3’-hydroxy rocagloic acid (4), 3’-
hydroxymethylrocaglate (5), and silvestrol (6).
from trihydroxyacetophenone 7, dimethoxy ether
8 was
obtained in 78% yield. Following the preparation of silyl enol
ether, the epoxide was generated by a reaction with mCPBA.
The reaction of the resulting epoxide under acidic conditions
gave alcohol 9 in 69% yield in 3 steps, and coupling between 9
and 10 provided ester 11. The Baker–Venkataraman rearrange-
ment of 11 proceeded to give 12, and under basic conditions a
cyclization–dehydration step afforded flavones 13. Hydrolysis
of 13 followed by hydrogenolysis gave 14 in good yield. The
Department of Natural Product Chemistry, Graduate School of Pharmaceutical
Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan.
E-mail: midori_arai@chiba-u.jp, mish@chiba-u.jp
†Electronic supplementary information (ESI) available. CCDC 1440504, 1440502
and 1440509. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c5ob02537k
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irradiation conditions promoted [3 + 2] cycloaddition between suppress the TRAIL resistance5 and its structure was proposed
methyl cinnamate and the oxidopyrylium from 14 to provide a to be 3′-hydroxy rocagloic acid (4) on the basis of its identical
mixture of the corresponding aglain core products. This spectroscopic data with the reported values.12 However, the
mixture was converted to the natural product 3′-hydroxy- NMR spectra of the synthesized compound 4 were inconsistent
methylrocaglate (5) in two steps: an α-ketol rearrangement and with the literature data for 3′-hydroxy rocagloic acid.12 Further-
1
a hydroxyl-directed reduction.8b The H- and 13C-NMR spectra more, the synthesized compound 4 did not suppress the
of 5 were identical with the reported values.10,11 The hydrolysis TRAIL resistance, indicating that the reported natural product
of 5 gave corresponding acid 4 in good yield. We had pre- has a different structure from 4. Further structure elucidation
viously isolated a natural product exhibiting a strong ability to studies are currently in progress (Scheme 1).
Scheme 1 Synthesis of 3’-hydroxymethylrocaglate (5) and 4. Reagents and conditions: (a) MeOTf (2.8 equiv.), K2CO3 (5.4 equiv.), acetone, reflux,
3 h, 88%; (b) (1) TBSOTf (2.8 equiv.), Et3N (3.0 equiv.), CH2Cl2, 0 °C, 30 min; (2) mCPBA (1.6 equiv.), NaHCO3 (2.5 equiv.), CH2Cl2, rt, 4 h; (3)
TsOH·H2O (0.1 equiv.), THF/H2O (10/1), reflux, 9 h, 69% in 3 steps; (c) 10 (3.0 equiv.), EDC·HCl (4.5 equiv.), DMAP (0.34 equiv.), CH2Cl2, rt, 7 h, 90%;
(d) LHMDS (3.0 equiv.), THF, −20 °C, 3 h; (e) H2SO4 (5.0 equiv.), AcOH, rt, 28 h; (f) aq. NaOH (2.0 equiv.), EtOH, 80 °C, 4 h, 75% in 3 steps; (g) Pd
(OH)2, H2, THF, EtOH, rt, 2 h, quant. (h) methyl cinnamate (13 equiv.), MeCN/MeOH, hv, 0 °C; (i) NaOMe (2.8 equiv.), MeOH, reflux; ( j) NMe4BH(OAc)3
(6.0 equiv.), AcOH (10 equiv.), MeCN, rt, 2 h, 35% in 3 steps; (k) LiOH·H2O (15 equiv.), THF/H2O (5/1), rt, quant.
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Synthesis of heterocyclic rocagloic acid derivatives
mined by X-ray crystallographic analysis13 and revealed that
the endo cycloadducts were the main products14 (Fig. 3).
We next turned our attention to the synthesis of rocaglamide
heterocycle derivatives (Fig. 2). Heterocycles have been incor-
porated into many biologically active compounds. We envi-
sioned that heterocyclic rocaglamides could provide new
biologically active compounds, similar to their natural product
parents. As the heterocycles, we chose furan, thiophen units
and their Br substituted units, which would be useful for
further substitution by a metal catalyzed coupling reaction.
The esterification of 9 with the corresponding carboxylic acids
15a–d provided esters 16a–d (Scheme 2). The Baker–Venkatara-
man rearrangement gave compounds 17a–d. Acidic cyclization
of 17a–d with sulfuric acid, followed by treatment with a base,
afforded the heterocyclic chromones 19a–d. [3 + 2] cyclo-
addition between the methyl cinnamate and oxidopyrylium of
19a–d provided aglain compounds as the major components.
The rearrangement and hydroxyl-directed reduction gave the
rocaglamide heterocycle derivatives 22a–d and the rocagloic
acid derivatives 23a–d were obtained by hydrolysis (Scheme 3).
The relative stereochemistries of 22a, 23c and 23d were deter-
Evaluation of the Wnt signal inhibitory activity of synthetic
rocaglamide derivatives
Novel bioactive rocaglamide derivatives were identified using a
previously described cell-based assay for Wnt signal inhibi-
tors.15 The Wnt signal plays crucial roles in the differentiation
and proliferation of many types of cells.16 In normal cells, the
β-catenin levels are controlled by a degradation system that
involves the action of a destruction complex consisting of
glycogen synthase kinase 3β (GSK-3β), adenomatous polyposis
coli (APC), and casein kinase 1α. Inactivation of this system
due to mutation of the components causes aberrant activation
of the Wnt signal associated with many cancers and dis-
eases.17 Therefore, inhibitors of this signal could be drug
candidates or useful biological tools. Several Wnt signal inhibitors
have been reported,18a,b including windorphen,18c XAV939,18d
IWP-2,18e and ICG-001,18f but more potent inhibitors with
novel structures are required. We have recently reported several
Wnt signal inhibitors.15,18b,19 Even though the synthesized
rocaglamide derivatives are racemates, it would be useful to
evaluate the Wnt signal inhibitory activities of these unique
complex structures.
We have investigated Wnt signal inhibition using the TOP-
Flash assay, a cell-based reporter luciferase assay for TCF/
β-catenin transcription in the STF/293 cell line,15 and pre-
viously constructed a cell assay using LiCl as a GSK-3β inhibi-
tor for inducing β-catenin accumulation. Interestingly, as
shown in Fig. 4, several synthetic rocaglamide derivatives
showed potent inhibition of TCF/β-catenin transcription
activity and low toxicity. To the best of our knowledge, this is
Fig. 2 Design of the rocaglate with heterocycles.
Scheme 2 Reagents and conditions: (a) carboxylic acids R1COOH (15a–d) (3.0 equiv.), EDC·HCl (4.5 equiv.), DMAP (0.34 equiv.), CH2Cl2, reflux,
91%-quant.; (b) LHMDS (3.0 equiv.), THF, −20 °C, 65–85% in 2 steps; (c) H2SO4 (5.0 equiv.), AcOH, 55–85%; (d) 1 N NaOH (2.0 equiv.), EtOH, 80 °C,
55–92%.
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Scheme 3 Synthesis of rocaglamide derivatives.
the first report of the Wnt signal inhibitory activity of rocagla-
mide derivatives. For example, 4, 5, 22a, 22b, 22c and 23c
exhibited inhibition activity with IC50 values of 9.3 μM, 32 nM,
9.4 μM, 9.4 μM, 0.19 μM and 1.0 μM, respectively. To determine
if these inhibitions are selective for the Wnt signal pathway, we
next examined their potency for β-catenin/TCF transcriptional
inhibition using the FOP-Flash assay. The FOP-Flash plasmid
has mutated TCF binding sites. The compounds that are Wnt
signal inhibitors affect only the TOP-Flash activity, which has
the native TCF binding sites. As shown in Fig. 5, 4, 5, 22a, 22b,
22c and 23c showed potent inhibition of TOP-Flash activity
whereas FOP-Flash activities were unaffected, indicating that
these inhibitors are potent Wnt signal inhibitors.
Because there is a report showing that Wnt expressing cells
suppress TRAIL-induced apoptosis,20 Wnt signal inhibitors
might show TRAIL resistance overcoming activity. As we
expected, compounds 5, 22c and 23c showed good TRAIL
resistance overcoming activity (see the ESI†).
Fig. 3 X-ray structure of (A) 22a, (B) 23c and (C) 23d. Solvent molecules
are omitted for clarity.
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Fig. 4 Inhibition of TCF/β-catenin transcriptional activity by the synthesized compounds. The results of the Super TOP-Flash (blue bars) assay and
cell viability (red) are shown.
Fig. 5 Inhibition of TCF/β-catenin transcriptional activity by 4, 22a, 22c and 23c. The results of the TOP-Flash (blue bars) and FOP-Flash (green
bars) assays are shown. The FOP-Flash assay was carried out as a transient luciferase reporter assay by using Super FOP-Flash reporter and control
pRL-CMV vectors, and HEK293 cells. The control (DMSO) luciferase activity was normalized to 100%. N = 3. Error bars represent SD.
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resulting residue and the mixture was stirred for several hours
under reflux. The reaction mixture was concentrated and the
Conclusions
In conclusion, we synthesized a natural product, 3′-hydroxy- resulting crude product 18a (307 mg) was used for the next
methylrocaglate (5), and eight rocaglamide heterocycle deriva- reaction without further purification. To a solution of crude
tives and investigated their Wnt signal inhibitory activities. We product 18a (307 mg) in EtOH (3.7 mL) was added 1 N NaOH
found that 4, 5, 22a, 22b, 22c and 23c are potent Wnt signal (890 µL). The reaction mixture was heated at 80 °C and stirred
inhibitors. To the best of our knowledge, this is the first report for 5 h. The reaction was quenched with 1 N HCl and filtered
of the Wnt signal inhibitory activity of rocaglamide derivatives. through a Kiriyama funnel. The residue was washed with cool
The synthesis of more complex derivatives exhibiting more EtOH and the solvent was evaporated in vacuo to afford 19a
effective Wnt signal inhibition is in progress.
(149 mg, 0.5 mmol, 66% from 17a).
General procedure for compounds 5, 22a–d
To a solution of 3-hydroxychromone (19a; 91 mg, 0.30 mmol)
in dry acetonitrile (4.7 mL) and dry MeOH (3.2 mL) was added
methyl cinnamate (610 µL, 3.9 mmol). The reaction mixture
was irradiated (400 W mercury lamp) at 0 °C for 2 h. The
solvent was removed in vacuo and the resulting residue was
purified by silica gel column chromatography (hexane : AcOEt
= 10 : 1 → 2 : 1 → 1 : 1) to afford a mixture containing 20a
(95.7 mg). To a mixture containing 20a (95.7 mg) in dry MeOH
(7 mL) was added NaOMe (31 mg, 0.57 mmol). The reaction
mixture was stirred for 2 h under reflux, quenched with sat.
aq. NH4Cl and then extracted with EtOAc. The combined
organic layer was washed with brine and dried over Na2SO4.
After filtration and concentration, the resulting residue was
purified by silica gel column chromatography (hexane : AcOEt
= 2 : 1) to afford the inseparable keto–enol isomers of 21a
(55.9 mg, 0.12 mmol, 53% in 2 steps from 19a). A mixture of
tetramethylammonium triacetoxyborohydride (189 mg,
0.72 mmol) and acetic acid (70 µL, 1.2 mmol) in dry aceto-
nitrile (3.1 mL) was stirred at rt for 5 min, added to a solution
of keto–enol tautomers 21a (55.9 mg, 0.12 mmol) in dry aceto-
nitrile (2.1 mL) and stirred at rt for 2 h. The reaction was
quenched with sat. aq. NH4Cl and the mixture was extracted
with CH2Cl2. The combined organic layer was washed with
brine and dried over Na2SO4. After filtration and concen-
tration, the resulting residue was purified by silica gel column
chromatography (hexane : AcOEt = 3 : 2) to afford 22a (45.9 mg,
0.098 mmol, 82%).
Experimental section
General experimental procedure
NMR spectra were recorded on JEOL ECP400 and ECP600 spectro-
meters in a deuterated solvent whose chemical shift was used
as an internal standard. Mass spectra were obtained on an
AccuTOF LC-plus JMS-T100LP (JEOL). ATR-IR spectra were
measured on a JASCO FT-IR 230 spectrophotometer. Column
chromatography was performed using silica gel PSQ100B (Fuji
Silysia Chemical Ltd, Kasugai, Japan) and silica gel 60N (Kanto
Chemical Co., Inc., Tokyo, Japan). Photochemical reactions
were carried out using HL-400B-8 (400 W, 33 A; mercury lamp)
and HB400P-1 (400 W) (SEN Light Co., Osaka, Japan) lamps
and the cooling system consisted of TRL-117ST and TC-107E
(THOMAS, KAGAKU Co., Ltd, Tokyo, Japan) units. The mercury
lamp was cooled using a glass container (Pyrex) (USHIO Inc.,
Tokyo, Japan) filled with water.
General procedure for compounds 11, 16a–d
To a solution of 9 (300 mg, 1.4 mmol) in CH2Cl2 (14 mL) was
added 15a (538 mg, 4.2 mmol), DMAP (59 mg, 0.48 mmol) and
EDC·HCl (1.2 g, 6.3 mmol). The reaction mixture was stirred at
rt for 8 h and then diluted with water. The mixture was
extracted with CH2Cl2 and the organic layer was dried over
Na2SO4. After filtration and concentration, the resulting
residue was purified by silica gel chromatography (hexane :
AcOEt = 3 : 1) to afford 16a (605 mg, 1.4 mmol, quant.).
General procedure for compounds 12, 17a–d
General procedure for compounds 4, 23a–d
To a solution of 16a (578 mg, 1.3 mmol) in THF (38 mL),
LHMDS (1.3 M, 3.1 mL, 4.0 mmol) was added dropwise at
−20 °C. The reaction mixture was stirred for 2 h and the reac-
tion was quenched using sat. aq. NaHCO3. The resulting
mixture was extracted using EtOAc. The combined organic
layer was washed with brine, dried over Na2SO4 and filtered.
The solvent was evaporated in vacuo and the resulting residue
was purified by silica gel chromatography (hexane : AcOEt =
3 : 1) to afford 17a (432 mg, 1.0 mmol, 75%).
Rocaglamide derivative 22a (10.3 mg, 0.022 mmol) was dis-
solved in 4.7 μL of a 5 : 1 mixture of dry THF and distilled
water. Lithium hydroxide monohydrate (13.8 mg, 0.33 mmol)
was added and the reaction mixture was stirred at rt for 23 h.
The mixture was diluted with CH2Cl2 and washed with 1 N
HCl and the organic layer was extracted with CH2Cl2. The com-
bined organic layer was dried over Na2SO4 and filtered. Con-
centration in vacuo gave rocagloic acid 23a (9.7 mg,
0.021 mmol, 97%).
General procedure for compounds 13, 19a–d
Reporter gene assay and transfection for the Wnt signal
inhibitory activity
To a solution of 17a (404 mg, 0.93 mmol) in 12 mL of glacial
acetic acid was added 246 µL of sulfuric acid. The resulting A previously described cell-based assay method15 was used to
mixture was stirred at rt for 22 h. The reaction was quenched evaluate the TCF/β-catenin transcriptional activity. Assay cells
with cool water and filtered, then EtOH was added to the (STF/293 cells) were seeded into 96-well plates (3 × 104 cells per
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well). After 24 h, the cells were treated for 24 h with the syn-
thesized compounds mixed with 15 mM LiCl. The cells were
then lysed, and the luciferase activity was measured using the
Luciferase Assay System (Promega) on a Luminoskan Ascent
Microplate Luminometer (Thermo). The FOP activity was also
evaluated to eliminate nonspecific inhibition of TOP activity.
HEK293 cells were plated on 24-well plates (1 × 105 cells per
well) and incubated for 24 h. Using Lipofectamine 2000, the
cells were transiently transfected with 500 ng per well of a
luciferase reporter construct (SuperFOPflash), and 25 ng per
well of pRL-CMV (Promega) for normalization. The
compounds mixed with 15 mM LiCl were added to the cells
12 h post-transfection. After incubation for 24 h with the
compounds, the cells were lysed and the luciferase activity
was measured using the PICAGENE Dual Sea Pansy assay
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Acknowledgements
This study was supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science
(JSPS), a Grant-in-Aid for Scientific Research on Innovative
Areas “Chemical Biology of Natural Products” from The Minis-
try of Education, Culture, Sports, Science and Technology,
Japan (MEXT), the Naito Foundation, the Tokyo Biochemical
Research Foundation, and by a Workshop on Chirality at
Chiba University (WCCU). This work was inspired by the inter-
national and interdisciplinary environment of the Asian Core
Program (JSPS), “Asian Chemical Biology Initiative”.
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