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Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against NaV
Matthew M. Logan, Tatsuya Toma, Rhiannon Thomas-Tran and J. Du Bois
Science, 2016, 354, 865-869 1
OOH
H
MeOH
O
HN
O
O
NHMe
MeMe
(-)-Batrachotoxin (BTX)LD50 = 2 µg/kg
Steph McCabe@ Wipf Group Page 1 of 16 12/25/2016
EXPERIENTIA Vol. X I X - Fasc. 7 Pag. 329-376 15. VII. 1963
The Venom of the Colombian Arrow Poison Frog Pbyllobates bicolor By F. MXRKI* and B. WITKOP**
I. Introduction. The use of arrow poisons--once the most sophisticated weapon in the arsenal of man--is becoming obsolete. I t is only in inaccessible jungle areas which have not yet been touched by civilization, that the use of these poisons and the often" secret art of their preparation are still practiced. One of the little-known arrow poisons is the kokoi, a substance of unusually high toxicity which is used by the Indians of the Choc6 in Colombia (South America). This article summarizes the present knowledge of the kokoi venom and describes recent chemical and pharmacological studies carried out by the authors and their colleagues.
II. Geographical and Ethnological Background. The jungle area of the Choc6 is situated in the northwest of Colombia, between the Pacific coast and the Cordillera Occidental and stretches from about 4 to 8 ° north of the equator (Figure 1). I t is isolated from the rest of the country by the western chains of the Andes, the highest peaks of which, like the Cerro Tatam~, tower to an altitude of over 4000 m. I t is a very rare event when, between the frequent thunderstorms, their forest-clad
ATLANTI C ~ , ~ ~
% mEzuEa
+ Y . +.+'+"
.j
ECUADOR " - . , --~
PERU +--, Fig. l . G e o g r a p h i c loca t ion of the Co lombian Choe6 J u n g l e Region.
tops can be seen through a break in the heavy cloud cover. An annual precipitation of 11 m and high tem- peratures all year around are favorable to the growth of an almost impenetrable jungle. The only practical routes of transportation are the rivers, which often flood wide areas.
The life of the native population of Choc6 Indians has barely changed since the time of the conquista- dores. Although a penetration of Negroes--former slaves of the Spaniards--has advanced during the cen- turies along the lower parts of the big rivers, the moun- tain areas are still the undisputed property of the In- dians. They live in many different tribes which speak the Noanamd language as do the Cholos on the upper Rio San Juan or the somewhat related language of EmperA as do the Cunas on the Rio Atr~ito. We are fairly well informed about their life and culture by several ethnological studies, for instance the one by WASS~N 1 on the Southern group of Choc6 Indians (on the lower Rio San Juan, Figure 2).
P l a y a ~ o~
! < ]. I
/ C . T a t a m i I"] \ ' - . co
/ J/\~. I.'lamana
10 miles I !
Fig. 2. The frog material was collected in the upper rcgion of the Rio San J u a n wi th P l a y a de Oro as a d w m e e d base a n d the c a m p at
A n d a g o y a l a b o r a t o r y at td w o r k i n g base .
* Associa te in the Visi t ing lJrogranl of the U.S. Publ ic t t ea l th Ser- vice.
** Na t iona l I n s t i t u t e of Ar thr i tb ; a n d Metabol ic Disease~, Na t iona l Ins t i t u t e s of t t e a l t h , B e t h e s d a (Mary land , U.S.A.) .
1 H. VV'ASSL,'N, Etnologiska Studier (G6 teborg Museum, 1935), p. 35.
2
the golden poison dart frog, Phyllobates terribilis
• Isolated in 1963 in the Chocó jungle region of Colombia from the skin extracts of the Colombian poison dart frog.
• Phyllobates terribilis (~1-2 mg BTX/frog), Phyllobates aurotaenia & Phyllobates bicolor (~10 fold less BTX)
• Subsequently identified in birds (genus Pitohui and Ifrita) and beetles
(genus Choresine); ~1.8 µg of (−)-BTX per beetle.
• Levels of BTX tend to be reduced when frogs are maintained in captivity, possessing on average ~ 35% of the BTX contained in freshly captured frogs. In addition BTX was not detected in phyllobates frogs bred in captivity, suggesting that wild frogs possibly sequester the toxin from a dietary source.
Natural Source
OOH
H
MeOH
O
HN
O
O
NHMe
MeMe
(-)-Batrachotoxin (BTX)
Experientia, 1963, 19, 329 Science, 1980, 208, 1383
Steph McCabe@ Wipf Group Page 2 of 16 12/25/2016
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• Extremely potent cardio- and neurotoxin • Traditionally used by Native Chocó Indians who poison the tip of their arrows and blow-darts with the skin secretion
of the frogs, which they call “kokoi.” • Selective and irreversible activation of voltage-gated sodium channels (Navs) in nerve and muscle cell membranes.
Locking the ion channel in an ‘open’ state and causing membrane depolarization.
• This ultimately results in the inability of the muscle and nerve cells to generate and respond to electrical signals ultimately resulting in death through heart failure and/or respiratory failure.
Biological Activity/ Uses
Journal of Natural Products, 2010, 73, 299
Steph McCabe@ Wipf Group Page 3 of 16 12/25/2016
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The structure and pharmacology of BTX was determined by John Daly’s group (NIH) between 1962-1973 § involved 7 more expeditions to the Choco jungle region and the collection/sacrifice of >10 000
frogs
Scientists (from l) Bernhard Witkop, John Daly and Takashi Tokuyama study the structure of batrachotoxins
Steph McCabe@ Wipf Group Page 4 of 16 12/25/2016
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Isolation/ structural determination
• Structural elucidation was challenging due to the minute
quantities of alkaloid obtained e.g. in the early isolation/purification process ~5000 frog skins yielded ~11 mg of BTX. Structure eventually solved by mass spectrometry & NMR analysis of BTX and X-ray analysis of the 20-p-bromobenzoate derivative of BTX A.
• Pregnane-type steroidal core functionalized with a
homomorpholine ring, tertiary hemiketal & pyrrole ester
Science, 1971, 172, 995-1002
7
Figure 1: Confusion over the configuration of the C20 stereocenter in batrachotoxinin A. A.
Original crystal structure.15,10 B. Original stereodiagram with an incorrect Fischer projection
representation of the C20 stereocenter.15,10 C. Revised stereodiagram by Gillardi.16 D. Crystal
structure of 7,8-dihydrobatrachotoxinin A from the Wehrli synthesis with incorrect C20
stereochemistry.17
The crystal structure of 20-p-bromobenzoate derivative of batrachotoxinin A also helped to
shed light on the structure of batrachotoxin itself and another Ehrlich-positive batrachotoxin-
like alkaloid named homobatrachotoxin (hBTX).12 Close analysis of the 1H NMR spectra of
these two substances in CDCl3 and CD3CO2D suggested that both compounds were derived
from the same steroidal skeleton as batrachotoxinin A. The C20 hydrogen of batrachotoxinin A
(! 4.57, q) was not present in the spectra of either BTX or hBTX, and additional peaks were
present in the 5-7 ppm region that were absent in the batrachotoxinin A spectrum. In particular,
it was speculated that a new multiplet (~5.8 ppm in both spectra) in this region could be the C20
proton, which was downfield-shifted as a result of esterification of the C20 alcohol. Further, an
aromatic proton (~6.35 ppm in both spectra) might correspond to a pyrrole–H of a
dialkylpyrrolecarboxylate moiety. The presence of both a tertiary amine and a trisubstituted
pyrrole linked to BTX through a hydrolytically labile ester at C20 would explain the previously
confusing IR, HRMS, and chemical test data. The carbonyl and NH stretches in the IR could
stem from the pyrrole carboxylate residue, which was labile under HRMS conditions. Thus, the
399 m/z ion corresponding to the originally-assigned empirical formula C24H33NO4 was in fact a
A. B.
C. D.
H
Me
H
H
H
pregnane
• The crude alkaloid extract contained 3 major constituents:
OOH
H
MeOH
O
HN
O
Me O
NH
Me
Me OOH
H
MeOH
O
HN
O
Me O
NH
Me
Et OOH
H
MeOH
O
HN
OH
Me
+ +
batrachotoxin(BTX)
LD50 = 2 µg/kg
* most potent non-peptidic naturally occurring toxin currently known
homobatrachotoxin (hBTX)
LD50 = 3 µg/kg
batrachotoxinin A (BTX A)
LD50 = >1000 µg/kg
Steph McCabe@ Wipf Group Page 5 of 16 12/25/2016
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the handle of our “Tiger Calculator” to assist his work. His ‘built-in compass’ allowed him to learn
exactly these complicated operations during this less computer-equipped age.
A turning point came when another look was taken at the mass spectrum of Batrachotoxinin A
p-bromobenzoate, where twin molecular ions were observed as a weak but definite pair of signals (m/z
599 and 601) on a noisy baseline. New attention was paid to these molecular ions, which looked to yield
two noteworthy peaks by fragmentation. Those were the ion p-bromobenzoic acid (m/z 200 and 202) and
the ion m/z 399, the latter which had been observed as the likely molecular ions of the batrachotoxins as
cited above. This fragmentation suggested that Batrachotoxin was possibly an ester of Batrachotoxinin A
and some acid, and should show a higher molecule ion than m/z 399. In practice, a mass-measured-peak
m/z 139, C7H9NO2, was picked up from the spectrum as the likely acid part of Batrachotoxin and
consequently the real molecular weight was estimated as 538. After various trials of EI ionization of
Batrachotoxin with John, we finally observed the real molecular ion, m/z 538, coming up from a noisy
background but just for a moment. This was on a Saturday afternoon, June 22, 1968. We were very much
pleased by this observation and shook hands with each other and then we patted the cool titan instrument
AEI MS-9 all over. Especially for John, who had worked so hard to master its operation, this had to be
one of the most impressive moments for him. Afterward John concentrated most of his attention on
structural analysis by expanding his mass spectrometry studies, and these eventually led to the discovery
of more than 800 alkaloids from other poison frogs.
6 HETEROCYCLES, Vol. 79, 2009
8
fragmentation ion formed from ester hydrolysis and eliminination of water from batrachotoxin.
Moreover, previously unidentified fragmentation peaks of m/z 139 in BTX and 153 in hBTX
might correspond to the dimethyl pyrrole carboxylate and ethylmethylpyrrolecarboxylate
moieties, respectively. By comparing UV spectra of pyrrolecarboxylic acids and their esters to
the spectra of BTX and hBTX, it was hypothesized that BTX is a C20 batrachotoxinin A ester
of 2,4-dimethylpyrrole-3-carboxylic acid, and hBTX is the ester derived from 2-ethyl-4-methyl-
3-pyrrole carboxylic acid (Figure 3). This hypothesis was further substantiated by comparing
the 1H NMR resonances of BTX, hBTX, and pyrrolecarboxylates in CDCl3 and C6H6.
The structure of BTX was finally confirmed by partial synthesis (Figure 2).12 The sterically-
hindered ester of BTX was hydrolyzed with difficulty under basic conditions (2.0 N aqueous
NaOH, 60 ˚C, 16 h) to batrachotoxinin A. Batrachotoxinin A was then converted to
batrachotoxin through treatment with 9.2 equivalents of the anhydride of 2,4-dimethylpyrrole-3-
carboxylic acid and 0.2 N aqueous KOH in chloroform for 5 h. Although esterification was
incomplete, batrachotoxin was isolated in 35% yield following purification on silica gel, and its
identity was confirmed through TLC, mass spectrometry, NMR, and toxicity analyses.
Figure 2: Semi-synthesis of batrachotoxin through esterification of batrachotoxinin A.
Following extensive fieldwork and chemical analysis, the structures of batrachotoxinin A,
batrachotoxin, and homobatrachotoxin had been successfully elucidated (Figure 3). In addition
to the unique structural features contained in batrachotoxinin, the pyrrole esters of BTX and
hBTX are unknown in other steroidal structures.12 The importance of the pyrrole ester for the
biological activity of BTX will be discussed later in this chapter. In addition to the three
aforementioned compounds, an additional substance known as pseudobatrachotoxin was also
purified. However, this alkaloid, isolated as the smallest component from frog skin extracts,
was extremely labile and hydrolyzed upon standing to batrachotoxinin A. As a result, its
structure could not be determined. Finally, two additional compounds were later isolated from
the skins of Phyllobates terribilis and identified from mass spectral and NMR analysis as 4!-
hydroxybatrachotoxin and 4!-hydroxyhomobatrachotoxin (Figure 3).19
19 Tokuyama, T.; Daly, J. W. Tetrahedron 1983, 39, 41-47.
N Me O
ONH
Me
MeO
HOMe
HO H
Me
O2.0 N NaOH (aq)
60 ˚C, 16 h
N Me OH
O
HOMe
HO H
Me
ONH
OEtO
OO Me
Me
0.2 N KOH (aq), CHCl35h
N Me O
ONH
Me
MeO
HOMe
HO H
Me
O
batrachotoxinin Abatrachotoxin batrachotoxin35%
• The structure was confirmed by semi-synthesis of BTX and analysis by TLC, MS, NMR and toxicity studies on the synthetic material.
Structural Determination
8
fragmentation ion formed from ester hydrolysis and eliminination of water from batrachotoxin.
Moreover, previously unidentified fragmentation peaks of m/z 139 in BTX and 153 in hBTX
might correspond to the dimethyl pyrrole carboxylate and ethylmethylpyrrolecarboxylate
moieties, respectively. By comparing UV spectra of pyrrolecarboxylic acids and their esters to
the spectra of BTX and hBTX, it was hypothesized that BTX is a C20 batrachotoxinin A ester
of 2,4-dimethylpyrrole-3-carboxylic acid, and hBTX is the ester derived from 2-ethyl-4-methyl-
3-pyrrole carboxylic acid (Figure 3). This hypothesis was further substantiated by comparing
the 1H NMR resonances of BTX, hBTX, and pyrrolecarboxylates in CDCl3 and C6H6.
The structure of BTX was finally confirmed by partial synthesis (Figure 2).12 The sterically-
hindered ester of BTX was hydrolyzed with difficulty under basic conditions (2.0 N aqueous
NaOH, 60 ˚C, 16 h) to batrachotoxinin A. Batrachotoxinin A was then converted to
batrachotoxin through treatment with 9.2 equivalents of the anhydride of 2,4-dimethylpyrrole-3-
carboxylic acid and 0.2 N aqueous KOH in chloroform for 5 h. Although esterification was
incomplete, batrachotoxin was isolated in 35% yield following purification on silica gel, and its
identity was confirmed through TLC, mass spectrometry, NMR, and toxicity analyses.
Figure 2: Semi-synthesis of batrachotoxin through esterification of batrachotoxinin A.
Following extensive fieldwork and chemical analysis, the structures of batrachotoxinin A,
batrachotoxin, and homobatrachotoxin had been successfully elucidated (Figure 3). In addition
to the unique structural features contained in batrachotoxinin, the pyrrole esters of BTX and
hBTX are unknown in other steroidal structures.12 The importance of the pyrrole ester for the
biological activity of BTX will be discussed later in this chapter. In addition to the three
aforementioned compounds, an additional substance known as pseudobatrachotoxin was also
purified. However, this alkaloid, isolated as the smallest component from frog skin extracts,
was extremely labile and hydrolyzed upon standing to batrachotoxinin A. As a result, its
structure could not be determined. Finally, two additional compounds were later isolated from
the skins of Phyllobates terribilis and identified from mass spectral and NMR analysis as 4!-
hydroxybatrachotoxin and 4!-hydroxyhomobatrachotoxin (Figure 3).19
19 Tokuyama, T.; Daly, J. W. Tetrahedron 1983, 39, 41-47.
N Me O
ONH
Me
MeO
HOMe
HO H
Me
O2.0 N NaOH (aq)
60 ˚C, 16 h
N Me OH
O
HOMe
HO H
Me
ONH
OEtO
OO Me
Me
0.2 N KOH (aq), CHCl35h
N Me O
ONH
Me
MeO
HOMe
HO H
Me
O
batrachotoxinin Abatrachotoxin batrachotoxin35%
Synthetic BTX LD50 = 2 µg/kg
Steph McCabe@ Wipf Group Page 6 of 16 12/25/2016
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§ Wehrli group (1972) Total synthesis of 20S-batrachotoxinin A, 43 linear steps
§ Kishi group (1998)
Total synth. of (±)-batrachotoxinin A 48 linear steps
Formal synth. of (±)-batrachotoxinin § Several approaches to the A/B/C framework
by Keana, Magnus, Parsons, Deslongchamps, Schow and Lacrouts
§ Approach to the C/D/E ring by Du Bois
O
HO
S
S
OTBSTBSO
Me
H
1. MnO2, 2. CH2Cl2, rt, 12 h
OTBSTBSO
Me
H
O
HO
S
SC D
13
Kishi’s Group - IMDAF/ oxy-Michael addition
J. Am. Chem. Soc., 1998, 120, 6627-6628OTBS
TBSO
Me
H
AcN
OTBS
MOMO
O
O
O
TASF; PhNTf2, TEA; 95%
OTBSTBSO
Me
H
MOMO
O
OTf
O
O
AcN
14
NSN
N
SiFF
Synthetic Efforts Towards Batrachotoxin
Synthetic studies are of continued importance: § Use of (−)-BTX as a Nav activator has led to
depletion in the world supply from >1 g to 170 mg
§ The Phyllobates species have been placed
on the endangered species list, thus, collection of (−)-BTX from the natural source is restricted.
§ The biosynthesis of (−)-BTX is unknown.
O
O
H
H
H
11α-acetoxy progesterone
AcO
HO H
Me
O
O
NMe
(S)
MeOH
HO*
Helv. Chim. Acta., 1972, 55, 1151
Wehrli group
CD
E
A B
Steph McCabe@ Wipf Group Page 7 of 16 12/25/2016
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Retrosynthesis Analysis of (−)-Batrachotoxin
HO H
Me
O
O
NMe
MeO
HO
ONH
Me
Me
(-)-Batrachotoxin (BTX)LD50 = 2 µg/kg
regioselectiveesterification
HO H
Me
O
O
NMe
MeOH
HO
(-)-Batrachotoxinin (BTX) A (BTX-A)LD50 = >1000 µg/kg
HO H
Me
O OH
OTBSTMS
HO H
Me
O O
OTBS
SiEt2
TMSBr
HO H
Me
O
OTBS
TMS
O
+
reductive amination/ring closure
tandemradical
cyclization
C=O 1,2-addition
Steph McCabe@ Wipf Group Page 8 of 16 12/25/2016
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Asymmetric Total Synthesis of (−)-Batrachotoxin
OTBS
OBr
MeO H
Me
O
TMS1. t-BuLi, THF, -90 °C, then
2.
65%
MeO H
Me
O OH
OTBS
MeO H
Me
O O
OTBS
SiEt2
TMS
3. K2CO3, MeOH, 94%
TMS
SiEt2Climidazole, CH2Cl2
93%
O
O(S)-(+)-Hajos-Parrish
ketone
literatureprotocol
* LiBr generated in situ during t-BuLi transmetallation was critical for obtaining yields >30% in the 1,2-addition
* α-deprotonation was competitive with 1,2-addition (D2O quench)
radical cyclization precursor8.8 g scale
Steph McCabe@ Wipf Group Page 9 of 16 12/25/2016
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Key Radical Cyclization
MeO H
Me
O O
OTBS
SiEt2
TMS
OOMe
H
Me O OTBSSiEt2
SiMe3Bu3Sn
H
Bu3SnH
Bu3SnH, O2, Et3B, Ph2O, 150 °C, 75%
MeO H
Me
O
O
OTBSBu3Sn
SiEt2
Me3Si
OOMe
H
Me O OTBSSiEt2Bu3Sn
TMS
OOMe
H
Me O OTBSSiEt2Bu3Sn
TMS
OOMe
H
Me O OTBSSiEt2
TMS
SnBu3
6-endo-trig 5-exo-dig
1,4-HAT
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Asymmetric Total Synthesis of (−)-Batrachotoxin
MeO H
Me
O
O
OTBSBu3Sn
Et2Si
Me3Si
TBAF, THF 60 °C, 94%
MeO H
Me
O OH
OHC OBu3Sn
1. MeNH2, CH2Cl22. NaB(O2CCF3)3H CH2Cl2, -78 °C
3. ClCH2COCl 2,6-lutidine -78 to 0 °C, 52%
MeO H
Me
O OH
OHBu3Sn
IBX, t-BuOH, 65 °C thenOsO4 (7 mol%), NaIO4 pyridine/ H2O, 57%
SiMe3
MeO H
Me
O OH
OBu3Sn
NMe
OCl
1.6 g scale
Steph McCabe@ Wipf Group Page 11 of 16 12/25/2016
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Asymmetric Total Synthesis of (−)-Batrachotoxin
MeO H
Me
O
O
NMe
OTfO1. NaOEt, EtOH
1:1 THF/C6H6, 92%
2. KHMDS, PhNTf2 THF, -78 to 0 °C 94%
O H
Me
O
O
NMe
OOTf
O1. NaClO2, NaH2PO4 DMSO/ H2O2. SOCl2, pyridine
3. NaN3, acetone/H2O4. AcOH (aq), 1,4-dioxane 90 °C, 15 h, 57% (4 steps)5. p-TsOH, 4 A MS PMBCH2OH, 89%
Bu3Sn
CuCl2 (3.3 equiv.),O2,1,4-dioxane 73 °C, 85%
MeO H
Me
O
O
NMe
OHCOTf
O
PMB
MeO H
Me
O OH
OBu3Sn
NMe
OCl
Steph McCabe@ Wipf Group Page 12 of 16 12/25/2016
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Asymmetric Total Synthesis of (−)-Batrachotoxin
O H
Me
O
O
NMe
OOTf
O
PMB O H
Me
O
O
NMe
O
O
PMB
LiCl, CuCl, Pd(PPh3)4tributyl(1-ethoxyvinyl)tinTHF, 60 °C, then1M oxalic acid, 0 °C, 77%
O1. AlH3, THF, -78 °C to 0 °C, 33%2. pTsOH, 3:2 acetone/ H2O, 83%
HO H
Me
O
O
NMe
HOOH
Me
(-)-BTX A
NEt3, benzene, 45 °C, 79%
HO H
Me
O
O
NMe
MeO
HO
ONH
Me
Me
O
O
NHMe
MeO
EtO
(-)-BTX
2 mg synthesized24 steps
0.25% overall yield
35 mg scale
Steph McCabe@ Wipf Group Page 13 of 16 12/25/2016
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Asymmetric Total Synthesis of (−)-Batrachotoxin B & (+)-Batrachotoxin B
Electrophysiological characterization of synthetic alkaloids against Nav subtypes showed:
§ (−)-BTX & BTX-B act as irreversible agonists of channel function. (−)-BTX-B showed similar potency to the natural product (−)-BTX
§ The unnatural enantiomer (+)-BTX and derivative ent-BTX-B act as
reversible antagonists of channel function by blocking the sodium channel.
HO H
Me
O
O
NMe
HOOH
Me
(-)-BTX A
HO H
Me
O
O
NMe
HOO
Me
BTX B
OPh
OHH
Me
O
O
NMe
OHO
MeO
Ph
NEt3, benzene45 °C, 70% Br
OMeH
Me
O
TMS
ent-BTX B
O
O
PhEtO
O
OHH
Me
O
O
NMe
MeO
OH
OHN
Me
Me
(+)-BTX
ent-starting material
Steph McCabe@ Wipf Group Page 14 of 16 12/25/2016
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Percent current inhibition of rNaV1.4 mutants by 5 µM ent-BTX-B
§ ent-BTX-B was tested against five rNaV1.4 single-
point mutants that were previously shown to destabilize BTX binding.
§ Mutation of N434, L1280, F1579, and N1584 to lysine resulted in a ~3- to 30-fold decrease in current block by 5 mM ent-BTX-B.
§ However, against F1236K, ent-BTX-B retained significant activity (~34% current inhibition).
§ Indicates an over-lapping, but nonidentical, binding
region for ent-BTX-B and BTX-B within the inner pore cavity
homology model highlighting residues that have previously been shown to abolish (–)-BTX activity
Biological Activity of Synthetic Materials
Steph McCabe@ Wipf Group Page 15 of 16 12/25/2016
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• First asymmetric synthesis of steroidal neurotoxin (-)-batrachotoxin and it’s unnatural enantiomer (+)-batrachotoxin
• Completed in 24 steps it is a significant improvement in terms of efficiency compared to
prior racemic syntheses (>40 steps) • Demonstrated that the unnatural enantiomer (+)-batrachotoxin has a different
mechanism of action acting as a reversible antagonist of Nav ion channels.
• Synthesis and biological evaluation of derivative BTX-B & ent-BTX-B which possess enhanced chemical stability and similar activity and potency to the natural/ unnatural enantiomers.
Conculsions
OOH
H
MeOH
O
HN
O
O
NHMe
MeMe
(-)-Batrachotoxin (BTX)LD50 = 2 µg/kg
Steph McCabe@ Wipf Group Page 16 of 16 12/25/2016
