Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels

Article abstract of DOI:10.1002/anie.201604155

11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C?C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu₄N][Ph₃SnF₂], which directly constructs the crucial C?C bond at the C11 position in SEA. The Na_VCh-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC₅₀value of (47±12) nm, which is approximately twice as potent as decarbamoyl-STX (dcSTX).

Full text of DOI:10.1002/anie.201604155

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Communications
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International Edition: DOI: 10.1002/anie.201604155
German Edition: DOI: 10.1002/ange.201604155
Natural Product Synthesis
Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its
Inhibitory Activity on Voltage-Gated Sodium Channels
Chao Wang, Mana Oki, Toru Nishikawa, Daisuke Harada, Mari Yotsu-Yamashita, and
Kazuo Nagasawa*
Abstract: 11-Saxitoxinethanoic acid (SEA) is a member of the
saxitoxin (STX) family of paralytic shellfish poisons, and
analogues, only zetekitoxin AB (6; ZTX)[5] and 11-saxitox-
inethanoic acid (7; SEA)[6] contain a C C bond at the C11
À
À
À
contains an unusual C C bond at the C11 position. Reported
position. It is extremely difficult to understand how this C C
herein is a total synthesis of SEA. The key to our synthesis lies
in a Mukaiyama aldol condensation reaction of silyl enol ether
with glyoxylate in the presence of an anhydrous fluoride
reagent, [Bu4N][Ph3SnF2], which directly constructs the cru-
bond arises in terms of proposed biosynthetic pathways for
STXs.[7]
We are interested in developing subtype-selective NaVCh
inhibitors, and in this work we focused on the synthesis of
SEA (7) and its analogues as candidate NaVCh modulators.[8]
SEA was originally isolated from xanthid crab Atergatis
floridus in 1995,[6] and it contains a saxitoxin core with an
acetic acid group at the C11 position. The natural product is
a 9:1 mixture of stereoisomers. The toxicity of 7 was reported
as 830 mouse units per mmol on i.p. injection into mice, and
corresponds to approximately one-third of the toxicity of 1.[3,6]
Herein we describe the synthesis of 7[9] and its derivatives 8
and 9. The NaVCh-inhibitory activity of these new STX
derivatives in a cell-based assay is also reported.
We have recently developed a synthesis of the fully
protected saxitoxinol 11[4g] by utilizing neighboring acyl-
group-assisted construction of the five-membered cyclic
guanidine structure in STXs under mild reaction conditions
(Scheme 1). The compound 11 is a key intermediate for the
synthesis of STX and its derivatives, which have a highly polar
nature because of the two guanidine groups. We have
employed 11 in the syntheses of dcSTX (2), GTX III (4),
and artificial STX derivatives.[4g,8b] Herein, we envisage
À
cial C C bond at the C11 position in SEA. The NaVCh-
inhibitory activities of SEA and its derivatives were evaluated
by means of cell-based assay. SEA showed an IC50 value of
(47 Æ 12) nm, which is approximately twice as potent as
decarbamoyl-STX (dcSTX).
S
axitoxin (1; STX; Figure 1), which was first isolated as
a paralytic shellfish poison,[1] is an inhibitor of voltage-gated
sodium channels (NaVCh).[2] So far, more than 50 analogues
have been discovered[3] and they have attracted considerable
interest from synthetic chemists.[1c,d,4] Among the STX
À
application of 11 to the synthesis of 7 through C C bond
formation at the C11 position.
Scheme 1. Synthesis of the fully protected saxitoxinol 11.[4g] Boc=tert-
butoxycarbonyl, MPM=p-methoxyphenylmethyl.
Figure 1. Structures of saxitoxin (1) and its derivatives 2–5, zetekitoxin
AB (6; ZTX), and 11-saxitoxinethanoic acid (7; SEA) and its derivatives
8 and 9.
Regarding synthetic approaches to 7, there are two
[*] C. Wang, M. Oki, T. Nishikawa, D. Harada, Prof. Dr. K. Nagasawa
Department of Biotechnology and Life Science, Faculty of Technology,
Tokyo University of Agriculture and Technology
À
possibilities to construct the C C bond at the C11 position
(Scheme 2), that is, direct alkylation of the enolate 12 with
halides in the presence of base, and Mukaiyama aldol reaction
of the silyl enol ether 13 with glyoxylate. We initially
investigated the alkylation strategy. However, the conversions
were extremely low and only trace amounts of the corre-
sponding alkylation product were obtained.
2-24-16 Nakamachi, Koganei, Tokyo 184–8588 (Japan)
E-mail: knaga@cc.tuat.ac.jp
Prof. Dr. M. Yotsu-Yamashita
Graduate School of Agricultural Science, Tohoku University
1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555 (Japan)
Then, the Mukaiyama aldol reaction was investigated for
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604155.
À
construction of the C C bond at the C11 position. The silyl
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Table 1: Substrate scope of the Mukaiyama aldol condensation reaction
of 14 with aromatic aldehydes.
Scheme 2. Synthetic strategies to SEA (7). TBS=tert-butyldimethylsilyl.
Entry
Ar
t [h]
16
E/Z[b]
Yield [%]
1
2
3
4
4-MeC6H4
C6H5
3-FC6H4
4-ClC6H4
4-NO2C6H4
2-furyl
48
24
24
24
2
16a
16b
16c
16d
16e
16 f
>10:1
>10:1
>10:1
>10:1
6:1
45
60
63
65
80
80
enol ether 14 was synthesized from 11 in three steps:
1) hydrolysis of acetate with potassium carbonate, 2) oxida-
tion of the resulting alcohol by means of Ley oxidation,[10] and
3) silyl enol ether formation from the resulting ketone with
TBSCl in the presence of NaHMDS (Scheme 3). With 14 in
5[a]
6[a]
2
>10:1
[a] Reaction was carried out at 08C. [b] Ratios at C11 were determined by
1H NMR spectroscopy.[14]
Scheme 3. Mukaiyama aldol reaction of 14 with ethyl glyoxylate.
HMDS=hexamethyldisilazide, M.S.=molecular sieves, NMO=N-
methylmorpholine-N-oxide, TPAP=tetrapropylammonium perruthen-
ate.
Scheme 4. Investigation of the reduction at C11 and removal of the
MPM group at C13. THF=tetrahydrofuran.
hand, the Mukaiyama aldol reaction was investigated with
ethyl glyoxylate under various reaction conditions. At first,
Lewis acid promoted conditions with either TiCl4 or BF3·Et2O
were tested,[11] but 14 decomposed to generate mostly Boc-
deprotected compounds, and no aldol reaction products were
obtained. Next, fluoride-anion-promoted reaction conditions
were investigated. In the case of Bu4NF,[12] no reaction
occurred. In contrast, for the case of [Bu4N][Ph3SnF2],[13]
which is an anhydrous fluoride anion reagent, the condensa-
tion the product 15 was obtained in 96% yield as a mixture of
stereoisomers of the double bond (5:1).
that used for 14,[19] and the Mukaiyama aldol condensation
reaction with ethyl glyoxylate was examined in the presence
of [Bu4N][Ph3SnF2] (Scheme 5). Under these reaction con-
ditions, the aldol condensation adduct 20 was obtained in
85% yield. Interestingly, the TBS ether at C13 remained
intact under these reaction conditions. After reduction of the
double bond with l-selectride, removal of the silyl ether in 21
at C13 took place smoothly upon treatment with the HF·Et3N
complex to give 22 in 87% yield.[20] The resulting hydroxy
group was further converted into a carbamoyl group by
Since the Mukaiyama aldol condensation reaction
À
appears to be a powerful tool for constructing the C C
bond at C11 in STXs, the scope of the reaction was
investigated. Thus, various aromatic aldehydes were sub-
jected to reaction with 14, and the corresponding aldol
condensation adducts (16a–f) were obtained in 45–80%
yields (Table 1).
À
After construction of the crucial C C bond at the C11
position of 7, the double bond in 15 had to be reduced with
subsequent removal of the MPM group from the C13 position
(Scheme 4). For the reduction, after extensive investiga-
tion,[15] l-selectride was found to be quite effective, thus
giving 17 in 76% yield as a single diastereomer.[17] Unfortu-
nately, subsequent removal of the MPM group at C13 failed
under all the reaction conditions we investigated, for example,
NBS-Et3B,[4g] DDQ, or CAN.[18] Finally, we decided to change
the protecting group from an MPM to TBS ether at an earlier
stage.
Scheme 5. Synthesis of 7. Reagents and conditions: a) ethyl glyoxylate,
[Bu4N][Ph3SnF2], THF, 08C, 85%; b) l-Selectride, THF, À788C, 76%;
c) HF·Et3N, THF/Et3N (5:1), RT, 87%; d) CCl3C(O)NCO, CH2Cl2, 08C,
then Et3N, MeOH, RT, 68%; e) LiOH, THF/H2O (3:1), 08C; then, TFA,
CH2Cl2, RT, 90%. l-Selectride=lithium tri-sec-butyl(hydrido)borate-
(1À), TFA=trifluoroacetic acid.
Thus, silyl enol ether 19 with a TBS ether at the C13
position was synthesized by following a similar procedure to
2
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Table 2: NaVCh-inhibitory activity of 7 and its derivatives 8, 9, and 25 in
a cell-based assay with Neuro-2a cells.
reaction with trichloroisocyanate followed by hydrolysis with
triethylamine in methanol to give 23 in 68% yield. Finally, 7
was obtained, by further hydrolysis of the ethyl ester with
lithium hydroxide and removal of all four Boc groups with
TFA, in 90% yield.[21] The stereochemistry at C11 of synthetic
7 was found to be a mixture of about a 9:1 ratio, which is
identical with that of the natural product reported by Onoue
and co-workers.[6]
The inhibitory activities towards NaVCh of 7 and its
synthetic derivatives, decarbamoyl-11-saxitoxinethanoic acid
(8; dcSEA) and 11-saxitoxinethanoic ethyl ester (9; SEE),
which were obtained from 21 and 23, respectively (Scheme 6),
were evaluated in a cell-based assay. In addition, 11-benzy-
Compound
IC50 (meanÆSD)
n
SEA (7)
dcSEA (8)
SEE (9)
11-benzylidenSTX (25)
dcSTX (2)[4g]
TTX
47Æ12 nm
5.7Æ3.1 mm
185Æ74 nm
16Æ6.9 nm[24]
89Æ36 nm
3
3
4
5
3
6
5.0Æ1.6 nm
activity than 2. Interestingly, 25 showed the same level of
inhibitory activity as 2, although the hydrated form of the
ketone at C12 in STXs is suggested to be important for their
NaVCh-inhibitory activity.[25] Further structure–activity rela-
tionship studies are under way to examine the inhibitory
À
activity of other STX derivatives having a C C bond at the
C11 position.
In conclusion, a total synthesis of 7 has been achieved
from the silyl enol ether 19 in 35% overall yield. The synthesis
features a Mukaiyama aldol condensation reaction to con-
À
struct the C C bond at the C11 position of STX. The
derivatives (8, 9, and 25) were similarly synthesized. In a cell-
based assay, 7 showed approximately twice more potent
NaVCh-inhibitory activity than 2, but 8 showed about one
hundred times less potent activity, in marked contrast to the
relationship between 1 and 2.[26] Interestingly, the inhibitory
activity of 25 was at a similar level as that of 2, and the mode
of interaction of 25 with NaVCh is quite intriguing.
Acknowledgments
This work was supported in part by JSPS KAKENHI Grant
Number JP16H01134 in Middle Molecular Strategy, and grant
from the Uehara Memorial Foundation. C.W. thanks for the
Otsuka Toshimi Scholarship Foundation for supporting.
Scheme 6. Synthesis of dcSEA (8), SEE (9), and (25).
liden-saxitoxin (25; 11-benzylidenSTX), synthesized from 19
via 24 (Scheme 6), was also tested.[22] Specifically, the NaVCh-
inhibitory activity of ligands was evaluated in terms of
cytotoxicity to mouse neuroblastoma Neuro-2a cells, which
express NaVCh.[23] In this cell-based assay, Neuro-2a is treated
with a sodium channel activator, veratridine, in the presence
of ouabain, an inhibitor of Na+/K+ ATPase. This treatment
blocks sodium ion efflux, and decreases the cell viability.
NaVCh inhibition by tetrodotoxin (TTX), STX, and related
compounds antagonizes this effect and rescues the cells in
a dose-dependent manner.[23e,8] The inhibitory activities of 7,
8, 9, and 25 were calculated from the cell viability in the above
assay, and the results are summarized in Table 2. SEA (7),
dcSEA (8), SEE (9), and 11-benzylidenSTX (25) showed
a concentration-dependent NaVCh-inhibitory effect, and their
IC50 values were determined to be (47 Æ 12) nm, (5.7 Æ
3.1) mm, (185 Æ 74) nm, and (16 Æ 6.9) nm,[24] respectively [the
IC50 values of synthetic dcSTX (2)[4g] and TTX, used as
controls, were (89 Æ 36) nm and (5.0 Æ 1.6) nm, respectively].
Thus, 7 was twice as potent as 2 on its NaVCh-inhibitory
activity. In the case of 8, the inhibitory activity was markedly
decreased, and it was approximately one hundred times less
potent than 2. SEE (9) showed about half weaker inhibitory
Keywords: aldol reaction · heterocylces · natural products ·
saxitoxin · total synthesis
[1] a) E. J. Schantz, V. E. Ghazarossian, H. K. Schnoes, F. M. Strong,
J. P. Springer, J. O. Pezzanite, J. Clardy, J. Am. Chem. Soc. 1975,
97, 1238 – 1239; b) J. Bordner, W. E. Thiessen, H. A. Bates, H.
Rapoport, J. Am. Chem. Soc. 1975, 97, 6008 – 6012; for recent
review of STXs, see: c) A. P. Thottumkara, W. H. Parsons, J.
Du Bois, Angew. Chem. Int. Ed. 2014, 53, 5760 – 5784; Angew.
Chem. 2014, 126, 5868 – 5894; d) Y. Ma, S. De, C. Chen,
Tetrahedron 2015, 71, 1145 – 1173.
[2] a) V. L. Salgado, J. Z. Yeh, T. Narahashi, Ann. N. Y. Acad. Sci.
1986, 479, 84 – 95; b) L. E. Llewellyn, Nat. Prod. Rep. 2006, 23,
200 – 222.
[3] M. Wiese, P. M. DꢀAgostino, T. K. Mihali, M. C. Moffitt, B. A.
Neilan, Mar. Drugs 2010, 8, 2185 – 2211.
[4] For total synthesis of STXs, see: a) H. Tanino, T. Nakada, Y.
Kaneko, Y. Kishi, J. Am. Chem. Soc. 1977, 99, 2818 – 2819;
b) P. A. Jacobi, M. J. Martineli, S. Polanc, J. Am. Chem. Soc.
1984, 106, 5594 – 5598; c) J. J. Fleming, J. Du Bois, J. Am. Chem.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

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Communications
Chemie
Soc. 2006, 128, 3926 – 3927; d) O. Iwamoto, H. Koshino, D.
Hashizume, K. Nagasawa, Angew. Chem. Int. Ed. 2007, 46,
8625 – 8628; Angew. Chem. 2007, 119, 8779 – 8782; e) J. V.
Mulcahy, J. Du Bois, J. Am. Chem. Soc. 2008, 130, 12630 –
12631; f) O. Iwamoto, R. Shinohara, K. Nagasawa, Chem.
Asian J. 2009, 4, 277 – 285; g) O. Iwamoto, K. Nagasawa, Org.
Lett. 2010, 12, 2150 – 2153; h) Y. Sawayama, T. Nishikawa,
Angew. Chem. Int. Ed. 2011, 50, 7176 – 7178; Angew. Chem.
2011, 123, 7314 – 7316; i) V. R. Bhonde, R. E. Looper, J. Am.
Chem. Soc. 2011, 133, 20172 – 20174; j) J. V. Mulcahy, J. R.
Walker, J. E. Merit, A. Whitehead, J. Du Bois, J. Am. Chem. Soc.
2016, 138, 5994 – 6001; for synthetic studies of STXs, see: k) S. M.
Hannick, Y. Kishi, J. Org. Chem. 1983, 48, 3833 – 3835; l) T.
Nishikawa, D. Urabe, M. Isobe, Heterocycles 2009, 79, 379 – 385;
m) T. Nishikawa, C. Wang, T. Akimoto, H. Koshino, K.
Nagasawa, Asian J. Org. Chem. 2014, 3, 1308 – 1311; n) A. D.
Pearson, R. M. Williams, Tetrahedron 2014, 70, 7942 – 7949;
o) S. R. Paladugu, R. E. Looper, Tetrahedron Lett. 2015, 56,
6332 – 6334.
recovered quantitatively. Raney Ni in MeOH under hydro-
genation conditions gave the desired 17 in 70% yield, but
reproducibility was poor in large-scale reaction. In the case of
single-electron reduction using activated Mg in dry MeOH,[16] 17
was obtained in 30% yield.
[16] G. H. Lee, I. K. Youn, E. B. Chio, H. K. Lee, G. H. Yon, H. C.
Yang, C. S. Pak, Curr. Org. Chem. 2004, 8, 1263 – 1287.
[17] The 1H NMR spectrum indicated the presence of only one
diastereoisomer, but the stereochemistry at C11 in 17 was
difficult to determine.
[18] Standard reaction conditions (DDQ and CAN) did not give 18
and caused removal of the Boc groups in 17.
[19] For the synthesis of silyl enol ether 19, see the Supporting
Information.
[20] In the case of Bu4NF, the substrate 21 decomposed immediately.
When HF·Py was tried, the reaction proceeded extremely slowly.
[21] Intermediates 20, 21, 22, and 23 were quite unstable under
regular silica gel column purification conditions. After extensive
investigation, we found that rapid purification on neutral silica
gel gave acceptable results. Since C11 in 22 and 23 epimerized
easily, the products were obtained as diastereomeric mixtures.
Data for the major diastereomers are presented in Supporting
Information (for the data collection process, 22 and 23 were
purified by preparative thin layer chromatography. During this
process, the minor diastereomer decomposed, and we collected
only the major diastereomer).
[5] M. Yotsu-Yamashita, Y.-H. Kim, S. C. Dudley, Jr., G. Choudh-
ary, A. Pfahnl, Y. Oshima, J. W. Daly, Proc. Natl. Acad. Sci. USA
2004, 101, 4346 – 4351.
[6] O. Arakawa, S. Nishio, T. Noguchi, Y. Shida, Y. Onoue, Toxicon
1995, 12, 1577 – 1584.
[7] a) Y. Shimizu, Chem. Rev. 1993, 93, 1685 – 1698; b) T. K. Mihali,
R. Kellmann, B. A. Neilan, BMC Biochem. 2009, 10, 8; c) S.
Tsuchiya, Y. Cho, K. Konoki, K. Nagasawa, Y. Oshima, M.
Yotsu-Yamashita, Sci. Rep. 2016, 6, 20340.
[8] For our previous work on synthesis of STX derivatives as
candidate NaVCh modulators, see: a) R. Shinohara, T. Akimoto,
O. Iwamoto, T. Hirokawa, M. Yotsu-Yamashita, K. Yamaoka, K.
Nagasawa, Chem. Eur. J. 2011, 17, 12144 – 12152; b) T. Akimoto,
A. Masuda, M. Yotsu-Yamashita, T. Hirokawa, K. Nagasawa,
Org. Biomol. Chem. 2013, 11, 6642 – 6649.
[22] 11-BenzylidenSTX (25) exists as a keto-form at C12 (from
13C NMR in D2O), and is different from the other member of
STX derivatives.
[23] a) K. Kogure, M. L. Tamplin, U. Simidu, R. R. Colwell, Toxin
1988, 26, 191 – 197; b) R. L. Manger, L. S. Leja, S. Y. Lee, J. M.
Hungerford, M. M. Wekell, Anal. Biochem. 1993, 214, 190 – 194;
c) R. L. Manger, L. S. Leja, S. Y. Lee, J. M. Hungerford, Y.
Hokama, R. W. Dickey, H. R. Granade, R. Lewis, T. Yasumoto,
M. M. Wekell, J. AOAC Int. 1995, 78, 521 – 527; d) T. Yasumoto,
M. Fukui, K. Sasaki, K. Sugiyama, J. AOAC Int. 1995, 78, 574 –
582; e) M. Yotsu-Yamashita, D. Urabe, M. Asai, T. Nishikawa,
M. Isobe, Toxicon 2003, 42, 557 – 560.
[9] Synthesis of 7 was reported by the group of Du Bois, see: J. R.
Walker, Ph.D. Dissertation, Stanford University, 2014.
[10] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
1994, 639 – 666.
[11] a) T. Mukaiyama, K. Narasaka, K. Banno, Chem. Lett. 1973,
1011 – 1014; b) T. Mukaiyama, K. Banno, K. Narasaka, J. Am.
Chem. Soc. 1974, 96, 7503 – 7509.
[24] In the case of 25, the IC50 values of 2 and TTX, which were used
as controls, were (18 Æ 2.1) nm (n = 3) and (5.0 Æ 2.8) nm (n = 4),
respectively.
[12] R. Noyori, K. Yokoyama, J. Sakata, I. Kuwajima, E. Nakamura,
M. Shimizu, J. Am. Chem. Soc. 1977, 99, 1265 – 1267.
[13] M. Gingras, Y. M. Chabre, J.-M. Raimundo, Synthesis 2006, 182 –
185.
[14] The stereochemistry of olefin in 16a was determined by NOESY
(see the Supporting Information), and according to 16a, the
stereochemistry for 16b–f was determined.
[25] D. B. Tikhonov, B. S. Zhorov, Biophys. J. 2005, 88, 184 – 197.
[26] The NaVCh inhibitory activity of 2 has been reported to be two-
to tenfold less potent than that of STX.[27]
[27] a) C. Y. Kao, S. E. Walker, J. Physiol. 1982, 323, 619 – 637; b) J.
Mahar, G. L. Lukacs, Y. Li, S. Hall, W. Moczydlowski, Toxicon
1991, 29, 53 – 71; c) G. Usup, C. P. Leaw, M. Y. Cheah, A. Ahmas,
B. K. Ng, Toxicon 2004, 44, 37 – 43.
[15] Metal catalysts (Pd/C, Pd(OH)2/C, PtO2, [RhCl(PPh3)3], [Ir-
(cod)py(PCy3)]PF6, and Raney Ni) were tried first under hydro-
genation conditions. In the case of Pd/C and Pd(OH)2/C, the
desired product was not obtained and Boc-deprotected products
were generated. In the case of the next three catalysts, the
reaction did not proceed at all, and the starting material 15 was
Received: April 28, 2016
Revised: June 17, 2016
Published online: && &&, &&&&
4
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Natural Product Synthesis
At sea: 11-Saxitoxinethanoic acid (SEA) is
a member of the saxitoxin family of
C. Wang, M. Oki, T. Nishikawa,
D. Harada, M. Yotsu-Yamashita,
paralytic shellfish poisons, and contains
À
an unusual C C bond at the C11 position.
À
K. Nagasawa*
&&&& — &&&&
Direct construction the C C bond at the
C11 position of the saxitoxin skeleton
involved a Mukaiyama condensation
reaction an efficient synthesis of SEA.
Total Synthesis of 11-Saxitoxinethanoic
Acid and Evaluation of its Inhibitory
Activity on Voltage-Gated Sodium
Channels
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