Antiarrhythmic agents based on diterpenoid alkaloids

Article abstract of DOI:10.1007/s11172-011-0098-7

Diterpenoid alkaloids comprise a large group of natural compounds produced by the plants of the genera Aconitum and Delphinium. Some of these compounds were found to manifest valuable pharmacological properties, including the unique antiarrhythmic activity. Allapinine (derived from the alkaloid lappaconitine) was approved as a drug. The investigation of the structure-activity relationship revealed structural elements responsible for the arrhythmogenic and antiarrhythmic properties.

Full text of DOI:10.1007/s11172-011-0098-7

Russian Chemical Bulletin, International Edition, Vol. 60, No. 4, pp. 633—638, April, 2011
633
Antiarrhythmic agents based on diterpenoid alkaloids*
M. S. Yunusov
Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences,
7
1 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
Fax: +7 (347) 235 6066. Eꢀmail: msyunusov@anrb.ru
Diterpenoid alkaloids comprise a large group of natural compounds produced by the plants
of the genera Aconitum and Delphinium. Some of these compounds were found to manifest
valuable pharmacological properties, including the unique antiarrhythmic activity. Allapinine
(
derived from the alkaloid lappaconitine) was approved as a drug. The investigation of the
structure—activity relationship revealed structural elements responsible for the arrhythmogenic
and antiarrhythmic properties.
Key words: diterpenoid alkaloids, antiarrhythmic agents, arrhythmogenic agents, strucꢀ
ture—activity relationships.
In spite of advances in the development and use of new
antiarrhythmic agents, the pharmacotherapy of cardiac
arrhythmia remains a challenge. The present review sumꢀ
marizes some aspects related to the design of antiarrhythꢀ
mic agents based on diterpenoid alkaloids.
Diterpenoid alkaloids (DTA) comprise one of the most
widespread groups of alkaloids. Plants producing these
substances have long since been used in folk medicine and
have attracted attention of chemists and pharmacologists
for a long time.1
The structures of DTA were for the most part deterꢀ
mined in the 1950s. They can be divided into the following
main types: C ꢀ and C ꢀDTA belonging to the most
Russia, where apparently the largest stocks of these plants
are localizes, are the main sources of DTA.
1
9
20
2
abundant group; C ꢀDTA in which one carbon atom of
1
8
the skeleton is absent; heteratisineꢀtype alkaloids containꢀ
ing the lactone ring (only nine compounds of this group
are currently known). The structures of representatives of
these groups are given below.
Plants of the genera Aconitum and Delphinium, which
are widespread in the Northern hemisphere, including
Plants of the genus Aconitum are highly toxic. Many
C ꢀDTA are arrhythmogenic agents (cause arrhythmia).
1
9
The diterpenoid alkaloid aconitine (1) is used by pharmaꢀ
cologists for the development of a cardiac arrhythmia modꢀ
el (the soꢀcalled aconitine model) and is one of the stronꢀ
1
gest plant toxins (comparable with the cobra venom).
Diterpenoid alkaloids were found to possess various
pharmacological properties, including antiarrhythmic,
arrhythmogenic, local anaesthetic, antiꢀinflammatory,
psychostimulant, antidepressant, spasmolytic, ganglionic
blocking, curareꢀlike, antidote (against aconitine), antiꢀ
1
,3,4
ulcer, and antitumor activities.
Prior to our studies, only one drug based on the diterꢀ
penoid alkaloid methyllycaconitine (2) (methyllycaꢀ
conitine hydroiodide, the trade name Mellictine) belongꢀ
ing to the muscle relaxants (agents with curareꢀlike activꢀ
ity) has been approved in medicine, but it has found little
use. Nevertheless, this drug has attracted attention beꢀ
cause it proved to be relatively effective when adminisꢀ
tered orally.5
*
Based on the materials of the lecture delivered on the Session
of the Presidium of the Russian Academy fo Sciences on Febꢀ
ruary 8, 2011.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 620—624, April, 2011.
066ꢀ5285/11/6004ꢀ633 © 2011 Springer Science+Business Media, Inc.
1

634
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
Yunusov
Collaborative works of botanists, chemists, and pharꢀ
Allapinine (lappaconitine hydrobromide) has passed
clinical trials and was commercially marketed and used
in medical practice since 1987. Cardiologists believe
macologists showed that certain DTA and their derivaꢀ
tives are unique antiarrhythmic agents. The following four
agents were subjected to comprehensive trials: lappacꢀ
onitine (3), Nꢀdeacetyllappaconitine (4), Oꢀbenzoylhetꢀ
eratisine (5), and azopelline (6) (1ꢀbenzoylnapelline (7))
6
that Allapinine can be considered as the firstꢀline drug
for the treatment of certain types of cardiac arrhythmia
4
,7
due to its unique properties. It is constantly included
in the list of vitally important drugs issued by the Ministry
(
Scheme 1). Each agent has its own specificity (Table 1).
Scheme 1

Diterpenoid alkaloids as antiarrhythmics
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
635
3
Table 1. Comparative efficacy of diterpenoid alkaloids and known
antiarrhythmic agents for aconitineꢀinduced arrhythmia in rats
khangelsk, and other regions. However, the conditions of
harvesting of wolfsbane are quite difficult.
Samples of the plant collected from approximately
100 areals were investigated. The lappaconitine content
varies from 0.3 to 2.5% of the dry root weigh (on the
average, 0.6—0.7%) and depends only slightly on the vegꢀ
etation period. Currently, the raw material is procured
primarily in the Altai territory. The substance is produced
at the Institute of Chemistry of Plant Substances of the
Academy of Sciences of the Republic Uzbekistan (Tashꢀ
kent), and the drug formulation is produced at the Plant of
the AllꢀRussian Institute of Medicinal Plants (Moscow
Region). The production of the substance has increased by
approximately a factor of 30 since 1987 and amounted up
to 250 kg in 2010. However, all attempts to culture northꢀ
ern wolfsbane (Aconitum septentrionale Koelle, Russia) and
Aconitum leucostomum Worosch (Kirgiziya, Kazakhstan),
including the use of bioengineering techniques (cell culꢀ
tures, tissue cultures, clonal reproduction), failed.
Agents
ED50
LD50 Antiarrhythmic
index,
mg kg–1
LD /ED
5
0
50
Allapinine*
0.05
0.24
10.0
12.6
0.035
1.0
20.0
40.0
5.0
4.0
7.0
15.0
5.7
5.9
32.0
87.5
180.0
4.0
38.0
66.9
138.0
33.0
42.0
35.0
39.0
28.0
118.0
133.3
8.7
14.4
114.3
38.0
3.3
3.4
6.6
10.5
5.0
2.6
Azopelline (6)*
Napelline (7)*
Heteratisine (11)*
Benzoylheteratisine (5)*
Dihydroatisine (14)*
Quinidine
Novocainamide
Aimaline
Rytmilen
Mexiletine
Lidocaine
Obsidane
4.9
*
Diterpenoid alkaloids.
The problem of an increase in the availability of antiꢀ
arrhythmic agents based on DTA can be solved in another
way by designing new drug formulations with the aim
of increasing the activity of the agents. For example,
the synthesis of complexes of lappaconitine (3) (the acꢀ
tive substance of the drug Allapinine) with glycyrrhizic
acid showed promise. The new drug is much cheaper,
3—4 times more active, approximately 10 times less toxic,
and, consequently, more available; it is devoid of undesirꢀ
of Healthcare and Social Development of the Russian
Federation.
Allapinine plays an important role in the prevention of
7
,8
attacks of paroxysmal ventricular fibrillation. The antiꢀ
arrhythmic activity of Allapinine is associated with supꢀ
pression of the fast incoming sodium current. An imporꢀ
tant characteristic feature of the interaction of Allapinine
1
1
able adverse side effects. Synthetic aza(diaza)bicycloꢀ
nonane compounds, which can be considered as fragments
7
with sodium channels is the longꢀterm binding.
1
2
The major metabolite of Allapinine, viz., Nꢀdeacetylꢀ
lappaconitine (4), is as efficient as Allapinine on most of
arrhythmia models but it is less toxic, has the wider theraꢀ
peutic index, and is characterized by the more rapid
development of the antiarrhythmic effect compared to
Allapinine. However, the metabolite has a shorterꢀterm
effect compared to Allapinine. Other metabolites (miꢀ
nor) of Allapinine (eight metabolites were characterꢀ
ized)
of diterpenoid alkaloids, also exhibit high activity.
Azopelline (6), benzoylheteratisine (5), and Nꢀdeꢀ
acetyllappaconitine (4) are other antiarrhythmic agents
based on diterpenoid alkaloids, which have been studied
in detail.
Azopelline is particularly efficient against ventricular
fibrillation and is a good antidote for aconitine poisoning.4
Azopelline was designed based on the alkaloid napelꢀ
7
9
,10
13
also have pronounced antiarrhythmic activity and
line (7), it is its 1ꢀOꢀbenzoyl derivative (6). Unfortuꢀ
are similar in the spectrum and strength of pharmacoloꢀ
gical activities to Allapinine. The biotransformation of
Allapinine occurs quite rapidly as evidenced by the apꢀ
pearance of metabolites in urine and blood within 2 h after
its single intragastric administration. The main biotransꢀ
formation pathways of Allapinine are deacetylation, hydrꢀ
oxylation, demethylation, and demethoxylation. The pharꢀ
macological action observed after the administration of
Allapinine into the organism should be considered as the
sum of the effects of Allapinine and its metabolites.
The availability is an important problem for Allapinꢀ
ine, like for other phytoagents. In the Russian Federation,
northern wolfsbane (Aconitum septentrionale Koelle) servꢀ
ing as a source for the preparation of this drug occupies
large areas ranging from the Kola Peninsula to the Mosꢀ
cow, Chelyabinsk, Kemerovo, Magadan, Syktyvkar, Arꢀ
nately, there are no good plant sources of napelline. Meanꢀ
while, azopelline (6) can be synthesized from songorine (8).
We found that Aconitum monticola Steinb is a good
source of songorine (8) (see Scheme 1). The remarkable
feature of this plant is that it does not contain the highly
toxic alkaloids aconitine (2) and mesaconitine (9) (see
Scheme 1), which generally accompany songorine.
Our research group developed a facile method for the
synthesis of azopelline (6) from songorine (8) (see Scheme 1).
The problem was to develop the stereospecific method for
the reduction of the carbonyl group of songorine to the
αꢀhydroxy group (napelline). The direct reduction of sonꢀ
1
4
gorine with NaBH in ethanol afforded a mixture of napelꢀ
4
line and isonapelline (C(12)—βꢀOH) in a ratio of 1 : 1. It
was difficult to isolate napelline from this mixture, and the
yield of napelline was low. The reduction of the dibenzoyl

636
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
Yunusov
derivative of songorine (10) appeared to be a good idea. In
this case, dibenzoylnapelline and dibenzoylisonapelline
formed in a ratio of 4 : 1, and the former was easily sepaꢀ
Scheme 3
1
3
rated in the pure form by recrystallization.
Earlier, our research group has shown that saponificaꢀ
tion of the acetyl group in the position C(1) of C ꢀDTA
1
9
occurs with difficulty due to which 1ꢀOꢀacetyl derivatives
can be synthesized in good yields.15
This observation was used for the preparation of the
1
ꢀOꢀbenzoylnapelline, viz., azopelline. It appeared that
the benzoyl group in the position C(1) is more difficult to
remove than the 1ꢀOꢀacetyl group, which made it possible
to perform saponification of dibenzoylnapelline and obꢀ
tain 1ꢀOꢀbenzoylnapelline in quantitative yield.16
Heteratisine (11), atisine (12), and isoatisine (13)
(
Schemes 2 and 3) are components of the plant Aconitum
1
7
zeravshanicum Steinb. endemic to Tajikistan. It is diffiꢀ
cult to separate atisine and isoatisine from heteratisine;
besides, atisine is easily transformed into isoatisine.
The effect of benzoylheteratisine (5) is achieved very
Scheme 2
rapidly, at the moment of the administration, but the duꢀ
ration of its action is 1.5—2 h.
1
4,19,20
It should be noted that all antiarrhythmic agents based on
DTA are good antidotes for poisoning with lethal doses of
aconitine and related alkaloids. This is an important problem
because the poisoning in humans and animals with plants
containing aconitine and related alkaloids still happens.
Figure 1 schematically presents the relative efficiency
of the known antiarrhythmic agents. Is can be seen that
agents based on the diterpenoid alkaloids, particularly
azopelline (6) and benzoylheteratisine (5), and much more
efficient than other antidotes in the case of administration
of the 1/10 dose of LD .
5
0
1
00% Lethality after the administration
of the fatal dose of aconitine (AC)
Aimaline + AC
Napelline (7) + AC
Novocainꢀ
amide + AC
Allapinine + AC
Our research group developed a facile method for the
quantitative separation of heteratisine from atisine and
isoatisine (see Scheme 2). The lactone ring opening in
heteratisine upon heating in ethane alkali easily afforded
the salt of the corresponding hydroxy acid. Other alkaꢀ
loids were extracted with chloroform and precipitated as a
mixture of hydrochlorides. The reduction of a mixture of
Heteratisine (11) +
Quinidine + AC
Lidocaine + AC
+
AC
Benzoylheterꢀ
atisine (5) + AC
atisine and isoatisine (with NaBH in EtOH) gave the
4
only product, viz., dihydroatisine (14) (see Scheme 3),
which proved to be an efficient antiarrhythmic agent.
1
8
Obsidane + AC
Azopelline (6) + AC
The alkaline solution was neutralized. The pure heteraꢀ
tisine was extracted with chloroform and was used for the
synthesis of benzoylheteratisine (5).
Fig. 1. Antidote action of agents in a dose equal to 1/10 of LD50
for aconitine poisoning.

Diterpenoid alkaloids as antiarrhythmics
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 4, April, 2011
637
Table 2. Compounds having antiarrhythmic and arrhythmogenic properties
Compound
R1
R2
R3
R4
R5
R6
R7
Antiarrhythmic agents
2
1
1
1
6
6
4ꢀBenzoyltalatisamine
Me
Bz
Me
Me
CH OMe
H
H
Bz
Bz
H
H
OH
OH
H
H
OH
H
Bz
H
Me
Me
2
2
2
ꢀBenzoylkaracoline
Me
Me
2
3
ꢀBenzoyleldelidine
—OCH O—
—OCH O—
2
2
4
ꢀBenzoyldelcorine
CH OMe
2
Arrhythmogenic agents
Aconitine (2)
Mesaconitine (9)
Bikaconitine
Pseudoaconitine
Aconifine
Et
Me
Et
Et
Et
OH
OH
H
OH
OH
OH
H
H
H
H
OH
H
Bz
Bz
OH
OH
H
H
OH
OH
COC H (OMe) ꢀ3,4
6 3 2
COC H (OMe) ꢀ3,4
6
3
2
Bz
COC H OMeꢀ4
Jesaconitine
Et
6
4
Antiarrhythmic agents
Arrhythmogenic agents1
toxicity. The removal of all ester groups from the aconitine
molecule also results in the formation of the nontoxic
compound, viz., aconine (18). Based on the experimental
data and the analysis of the literature, it can be concluded that
the hydroxy group at C(13) and the benzoyl group or another
aromatic acid group at O(14) are required for the arrhythꢀ
mogenic properties of C ꢀDTA. The presence of the acetoxy
19
group at the C(8) atom is responsible for toxic properties.
The absence of the hydroxy group at C(13) and the
presence of the aromatic (heteroaromatic) acid or benzyl
group at the position O(1), O(4), O(6), or O(14) are preꢀ
requisites for the manifestation of antiarrhythmic properꢀ
ties. The Nꢀ(βꢀhydroxyethyl) group and the aromatic acid
group at C(1) play an important role in the antiarrhythmic
It should be noted that DTA containing the same skelꢀ
eton and similar functionalization can exhibit both arꢀ
rhythmogenic and antiarrhythmic properties (Table 2).
It was of interest to reveal which functional groups are
responsible for particular properties.
Our research group studied approximately 200 DTA
and their derivatives and revealed structure—antiarrhythꢀ
mic (or arrhythmogenic) activity relationships. Thus the
modeling of the structure of aconitine (Table 3) by selecꢀ
tive acetylation of hydroxy groups showed that the blockꢀ
ing of the hydroxy groups at positions 3 and 15 (15, 16)
does not lead to the disappearance of the aconitineꢀlike
toxicity. However, the acylation of all hydroxy groups,
including position 13 (17), leads to the disappearance of
properties of C ꢀDTA. It should be noted (see Table 1)
20
that certain diterpenoid alkaloids, such as heteratisine (11)
(
C ꢀDTA), songorine (8), napelline (7), and dihydroatꢀ
19
isine (14) (C ꢀDTA), which do not contain ester groups,
20
4
also exhibit pronounced antiarrhythmic properties. Howꢀ
ever, although the antiarrhythmic index of these alkaloids
is quite high, the activity of phytoagents is insufficient for
their use in medicine because of their limited availability.
The revealed relationship allows one to perform the
rational synthesis of compounds with antiarrhythmic acꢀ
tivity from inactive DTA.
Antiarrhythmic agents based on diterpenoid alkaloids
are efficient and often unique. Taking into account the
structure—activity relationship, it is reasonable to design
efficient antiarrhythmic agents based on available alkaꢀ
loids isolated from plants of the genus Delphinium beꢀ
cause these plants are easy to culture.
Table 3. Toxicity of aconitine and its derivatives
Compound
LD50
*
Aconitine (2)
0.125
0.27
3.5
150.0
200.0
16.0
3
3
3
ꢀAcetylaconitine (15)
,15ꢀDiacetylaconitine (16)
,15,13ꢀTriacetylaconitine (17)
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1
4ꢀBenzoylaconine
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*
Studies were carried out in mice, the agent was adminisꢀ
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1
1
1
1
(
Received February 25, 2011;
in revised form April 8, 2011
(