Індольний алкалоїд еліптицин як ефективна багатоцільова сполука
First isolated from the tropical plant Oschrosia elliptica, indole alkaloid ellipticine provoked huge interest since it demonstrated antitumor activity was demonstrated along with limited toxic side effects and a complete lack of hematological toxicity. In this work, a five-step Cranwell and Saxton...
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| Date: | 2022 |
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| Main Authors: | , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2022
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Ukrainica Bioorganica Acta| _version_ | 1871193546820681728 |
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| author | Shvydenko, Kostiantyn V. Grafova, Iryna A. Shvydenko, Tetiana I. Kostyuk, Aleksandr N. Picanço, Neila S. Silva, Luiz F.R. Kropfitsch, Anya Wyrepkowski, Claudia D.C. Zerbini, Luiz F. Tadei, Wanderli P. Pereira, Antonia M.R.F. Leskelä, Markku Grafov, Andriy V. |
| author_facet | Shvydenko, Kostiantyn V. Grafova, Iryna A. Shvydenko, Tetiana I. Kostyuk, Aleksandr N. Picanço, Neila S. Silva, Luiz F.R. Kropfitsch, Anya Wyrepkowski, Claudia D.C. Zerbini, Luiz F. Tadei, Wanderli P. Pereira, Antonia M.R.F. Leskelä, Markku Grafov, Andriy V. |
| author_institution_txt_mv | [
{
"author": "Kostiantyn V. Shvydenko",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv, 02660, Ukraine"
},
{
"author": "Iryna A. Grafova",
"institution": "Department of Chemistry, University of Helsinki, Helsinki 01560, Finland"
},
{
"author": "Tetiana I. Shvydenko",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv, 02660, Ukraine"
},
{
"author": "Aleksandr N. Kostyuk",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv, 02660, Ukraine"
},
{
"author": "Neila S. Picanço",
"institution": "Laboratory of Malaria and Dengue, National Institute of Amazonian Research (INPA), Manaus 69067-375, Amazonas, Brazil"
},
{
"author": "Luiz F.R. Silva",
"institution": "Biotechnology Center of Amazonia, INPA, Manaus 69067-375, Amazonas, Brazil"
},
{
"author": "Anya Kropfitsch",
"institution": "International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7935, South Africa"
},
{
"author": "Claudia D.C. Wyrepkowski",
"institution": "Laboratory of Leishmaniasis and Chagas Disease, INPA, Manaus 69067-375, Amazonas, Brazil"
},
{
"author": "Luiz F. Zerbini",
"institution": "International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7935, South Africa"
},
{
"author": "Wanderli P. Tadei",
"institution": "Laboratory of Malaria and Dengue, National Institute of Amazonian Research (INPA), Manaus 69067-375, Amazonas, Brazil"
},
{
"author": "Antonia M.R.F. Pereira",
"institution": "Laboratory of Leishmaniasis and Chagas Disease, INPA, Manaus 69067-375, Amazonas, Brazil"
},
{
"author": "Markku Leskelä",
"institution": "Department of Chemistry, University of Helsinki, Helsinki 01560, Finland"
},
{
"author": "Andriy V. Grafov",
"institution": "Department of Chemistry, University of Helsinki, Helsinki 01560, Finland"
}
] |
| author_sort | Shvydenko, Kostiantyn V. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:53Z |
| description | First isolated from the tropical plant Oschrosia elliptica, indole alkaloid ellipticine provoked huge interest since it demonstrated antitumor activity was demonstrated along with limited toxic side effects and a complete lack of hematological toxicity. In this work, a five-step Cranwell and Saxton synthesis was used for obtaining ellipticine (Ell). Ellipticine hydrochloride salt (Ell×HCl) was also synthesized. Detailed in vitro studies of anticancer, antimalarial, and leishmanicidal activities were performed. Antiproliferation assay using DU145 cancer cell line treated with Ell showed a consistent reduction in cell proliferation and cell viability when treated with 5 μmol Ell. Anti-proliferation activity was more pronounced for the Ell×HCl solutions. Both the Ell and Ell×HCl revealed moderate activity in vitro against Leishmania amazonensis promastigotes, which is related to insufficient solubility of the drugs. IC50 values of Ell and Ell×HCl were determined in vitro against multidrug resistant Plasmodium falciparum strain K1. The Ell×HCl was shown to be almost three times more potent than the Ell in DMSO. Upon dilution with water, Ell solubility and activity drops down, while the activity and solubility of Ell×HCl is enhanced up to 10 times in 50:50 aqueous DMSO solutions. |
| doi_str_mv | 10.15407/bioorganica2022.01.092 |
| first_indexed | 2025-07-17T12:19:27Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
UDC 547.752 + 547. 94
DOI: https://doi.org/10.15407/bioorganica2022.01.092
92
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
Indole alkaloid ellipticine as efficient multitarget compound
Kostiantyn V. Shvydenko1, Iryna A. Grafova2, Tetiana I. Shvydenko1, Aleksandr N. Kostyuk1,
Neila S. Picanço3, Luiz F. R. Silva4, Anya Kropfitsch5, Claudia D. C. Wyrepkowski6,
Luiz F. Zerbini5, Wanderli P. Tadei3, Antonia M. R. F. Pereira6, Markku Leskelä2, Andriy V. Grafov2*
1 Institute of Organic Chemistry of the NAS of Ukraine, 5 Murmanska St., Kyiv, 02094, Ukraine
2 Department of Chemistry, University of Helsinki, Helsinki 01560, Finland
3 Laboratory of Malaria and Dengue, National Institute of Amazonian Research (INPA), Manaus 69067-375, Amazonas, Brazil
4 Biotechnology Center of Amazonia, INPA, Manaus 69067-375, Amazonas, Brazil
5 International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town 7935, South Africa
6 Laboratory of Leishmaniasis and Chagas Disease, INPA, Manaus 69067-375, Amazonas, Brazil
Abstract: First isolated from the tropical plant Oschrosia elliptica, indole alkaloid ellipticine provoked huge interest since it demonstrated
antitumor activity was demonstrated along with limited toxic side effects and a complete lack of hematological toxicity. In this work, a
five-step Cranwell and Saxton synthesis was used for obtaining ellipticine (Ell). Ellipticine hydrochloride salt (Ell×HCl) was also
synthesized. Detailed in vitro studies of anticancer, antimalarial, and leishmanicidal activities were performed. Antiproliferation assay
using DU145 cancer cell line treated with Ell showed a consistent reduction in cell proliferation and cell viability starting from 5 μM Ell
concentrations. Anti-proliferation activity was more pronounced for the Ell×HCl solutions. Both the Ell and Ell×HCl revealed moderate
activity in vitro against Leishmania amazonensis promastigotes, which is related to insufficient solubility of the drugs. IC50 values of Ell
and Ell×HCl were determined in vitro against multidrug resistant Plasmodium falciparum strain K1. The Ell×HCl was shown to be almost
three times more potent than the Ell in DMSO. Upon dilution with water, Ell solubility and activity drops down, while the activity and
solubility of Ell×HCl is enhanced up to 10 times in 50:50 aqueous DMSO solutions.
Keywords: ellipticine; in vitro; anticancer; antimalarial; antileishmanial activity.
Introduction
Recently, indole alkaloid ellipticine and its derivatives
have been thoroughly studied as therapeutics against
different forms of cancer and as potent antimalarials [1-2].
Ellipticine (Ell) is one of the simplest naturally occurring
alkaloids with a planar structure, which has been the center
of attention of many research groups owing to its antitumor
activity. The alkaloid was first isolated from leaves of the
tropical plant Oschrosia elliptica (Apocynaceae) by
Goodwin et al. [3].
Received:
Revised:
Accepted:
Published online:
19.04.2022
27.04.2022
25.05.2022
30.06.2022
Corresponding author. Tel.: +358-50-416-0547;
e-mail: andriy.grafov@helsinki.fi (A. V. Grafov)
ORCID: 0000-0002-7387-3676
Subsequently, Ell was isolated from several other plants
of Ochrosia genus like O. vieillardii, O. acuminate, and O.
moorei, as well as from Strychnos dinkagei (Loganiaceae).
Currently most commercially available ellipticine is derived
from plants.
Ellipticine exhibits rather limited toxic side effects and a
complete lack of hematological toxicity [4-6]. Different
hypotheses on ellipticine action mechanisms have been
proposed. In the last decade, evidence of different cell-cycle
effects of Ell has come to light [7]. Particularly, the alkaloid
is capable of interacting with p53 tumor suppressor protein,
Akt- and c-Kit kinases, while its effect on other cellular
proteins is still under investigation. Thus, ellipticine
exhibits a multimodal cytotoxic activity that is not specified
[7]. A bio-oxidation pathway was originally proposed [8]
with ellipticine as a possible substrate for peroxidases in
vivo. Stiborová’s group demonstrated that ellipticine
covalently binds to DNA after being enzymatically
© Grafov A. V. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
mailto:andriy.grafov@helsinki.fi
https://orcid.org/0000-0001-6167-076X
Grafov A. V. et al.
93
activated with cytochromes P450 or peroxidases [9].
Pharmacological properties, such as strong DNA
topoisomerase II inhibition activity, and the formation of
covalent DNA adducts mediated by ellipticine oxidation
could also explain the antimalarial activity of ellipticine
derivatives [10].
Malaria is one of the oldest infectious parasitic diseases
in the world that remains a serious public health problem
worldwide [11]. The disease is caused by protozoan
parasites of the genus Plasmodium. Six species that mainly
infect humans are P. falciparum, P. vivax, P. malariae, P.
ovale (P. ovale curtisi, P. ovale wallikeri), P. knowlesi, and
P. cynomolgi [12]. Active substances of plant origin
contribute to malaria chemotherapy, either directly as
antimalarials or as prototypes of synthetic drugs such as
chloroquine, primaquine, mefloquine, etc. [13].
Traditional Amazonian medicine uses the bark of
Aspidosperma vargasii (Apocynaceae) tree as an
antimalarial remedy [14]. Alkaline ethanol extract of the
bark contains ellipticine that showed a high in vitro activity
against P. falciparum [15-17]. The antimalarial activity in
vitro was further confirmed by two independent studies, as
shown in Table 1. However, the IC50 values reported in the
literature often show significant differences. This fact is due
to the use of different parasite strains that have different
responses to substances under investigation, which are often
associated with genetic mutations that alter the response to
the drug.
To the best of our knowledge, the experimental data
about the leishmanicidal activity of ellipticine are
practically absent in the literature. Ogungbe et al. [18]
studied the Ell interaction with Leishmania proteins by
molecular docking, but no obvious activity was reported.
Other research was devoted to ex vivo splenic explant
system screening for anti-leishmanial activity [19], where
ellipticine was classified as an antiprotozoal compound.
A variety of positive ellipticine functions prompted a
need to develop a reliable scalable synthetic pathway to
produce Ell and its analogues [7]. Up to date, a very high
ellipticine price of about $10/mg (cf. Merck, Santa Cruz
Biotec, Calbiochem) is a critical point that has limited
considerably the use of the compound.
Taking into account the huge interest in ellipticine,
various synthetic routes have been developed, starting from
R. B. Woodward’s approach [20]. Generally, synthetic
strategies leading to the target molecule are classified
according to assembly of the last ring as B, C, D, and B + C
types (Passemar et al., 2011) [10] (see Figure 1). Among
the different synthetic routes available [21-29], the method
originally proposed by Cranwell and Saxton appears to be
the most practical one [21, 30]. It consists of a five-stage
‘‘D-type’’ procedure starting from appropriately substituted
indoles or carbazoles.
N
H
H3C
CH3
N
1 2
3
4567
8
9 10
11
A
B C
D
Figure 1. The structural formula of ellipticine with the IUPAC
numbering of atoms.
Table 1. Antimalarial activity of ellipticine derivatives against P.falciparum.
Compound
strain FcM29-Cameroon
[10]
strain K1 [17] strain 3D7 [17]
µg/mL µmol/mL µg/mL µmol/mL µg/mL µmol/mL
Ellipticine 0.28 1.13 0.19 0.81 0.085 0.35
Ellipticine×HCl 0.17 0.6
3,4-Dihydroellipticine 0.25 1.01
9-Hydroxyellipticine [a] 0.08 0.3
9-Methoxyellipticine 0.32 1.15
7,9-Dibromoellipticine :
9-Bromoellipticine 3:1a
0.30 0.20
9-Nitroellipticinea 0.20 0.55
Chloroquine 0.4 0.17 0.33 0.061 0.11
a Semisynthetic, obtained by modification of natural compounds.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
94
Figure 2. Synthesis of ellipticine 10 (admixture products are shown in red color).
Since then, various improvements have been proposed to
make it more convenient and to increase the total yield.
However, there are still some problematic synthetic steps,
e.g. the formylation and the cyclization reactions (see
Figure 2). In the former case, the difficulty stems from the
fact that carbazole has three sites for an electrophilic attack,
and thus a mixture of products is formed [31-32]. At the
cyclization step (see Figure 2), a mixture of N-tosyl-1,2-
dihydroellipticine and ellipticine is obtained. That mixture
is difficult to separate leading to a significant decrease in
the ellipticine yield.
In the present paper, we propose a significantly improved
Cranwell and Saxton’s procedure and performed different
biological activity assays in vitro. Ell and Ell×HCl were
used to investigate their activity against human prostate
cancer DU145 cells, multidrug-resistant K1 strain of P.
falciparum, and Leishmania amazonensis promastigo-tes.
We hypothesize that the more water-soluble ellipticine
hydrochloride would exhibit better activity compared to the
more hydrophobic ellipticine.
Results and discussion
The most convenient synthetic pathway to ellipticine
(5,11-dimethyl-6H-pyrido[4,3-b]carbazole, 10) was
proposed by Cranwell and Saxton [21] with later
modifications [30-44] (see Figure 2). We supposed that it
might be possible to further improve the overall procedure
by improving the synthesis of 1,4-di-methylcarbazole 2, the
Vilsmeier-Haack formylation, and the cyclization steps. In
the first case, all previously described procedures required
purification of dimethylcarbazole 2 by chromatography and
the use of ethanol as a solvent. We performed the reaction
in toluene which has a higher boiling point and it gives the
possibility of removing the evolving water with a Dean-
Stark apparatus. That change led to an essential increase in
yield (70%) and allowed us to substitute a chromatographic
purification of the product with a much more practical
crystallization one. Predominantly, the subsequent
Vilsmeier-Haack formylation of 1,4-dimethylcarbazole was
carried out using N-methylformanilide and phosphorus
oxychloride in o-di-chlorobenzene. For that step, we
adopted the procedure proposed by Deane et al. involving
POCl3 and DMF in chlorobenzene [30]. It should be noted
that formylation of 2 proceeded non-regioselectively
affording a mixture of isomers: 3-formyl-1,4-
dimethylcarbazole 3 as a major product (about 9:1) and
6-formyl-1,4-dimethylcarbazole 4 [30]. To improve the
yield, the workup of the reaction mixture after
neutralization and evaporation of the volatile products was
modified by performing three extractions with hot ethyl
acetate. The mixture of 3 and 4 were used for further
transformations without separation. The two following steps
were carried out according to the literature [21, 30-31, 35-
36]. Subsequently, the mixture of 7 and 8 was tosylated
with p-toluenesulfonyl chloride at the exocyclic amino
group to give N-tosyl-3-(2,2-diethoxy-ethylaminomethyl)-
1,4-dimethylcarbazole 9. Usually, the tosylation reaction is
carried out in pyridine at room temperature for 3 days [30-
Grafov A. V. et al.
95
31, 35, 41]. We applied a more rapid procedure in aqueous
tetrahydrofuran [43], but used potassium carbonate as a
base; the reaction was complete at room temperature
overnight. Pure compound 9 was separated by
recrystallization.
The last step, the cyclization of N-tosyl-3-(2,2-
diethoxyethylaminomethyl)-1,4-dimethylcarbazole 9 into
ellipticine was carried out using a standard procedure by
heating a dioxane solution with aqueous HCl. Here, the
major problems of the reaction mixture workup arose from
poor solubility of ellipticine and its contamination with an
intermediate N-tosyl-3,4-dihydroellipticine. The mixture is
usually separated by chromatography. According to the
literature, a mixture of dichloromethane : methanol 9:1 is
the most frequently used eluent [30]. A complete separation
of the two products was achieved using consecutive flash-
chromatography treatments with two different eluents: ethyl
acetate and methanol. First, the N-tosyl-3,4-dihydro-
ellipticine was eluted with ethyl acetate, then ellipticine 10
was eluted with methanol as a single pure product.
Antiproliferation activity of Ell and Ell×HCl against the
DU145 cells was assessed spectrophotometrically by a
MTT assay. The percentage of inhibition was determined
by comparing the absorbance values of drug-treated cells
with that of untreated controls. Experimental data and
percentages of the cell viability are shown in Figure 3.
As shown in the figure, a decrease in cell viability with
an increase in the drug concentration was observed. Such a
tendency is more pronounced for Ell×HCl owing to its
better solubility and hence, bioavailability. Perceptible drug
activity was recorded at all concentrations except 0.625 μM.
5.0 μM was the first concentration of Ell that provoked a
considerable reduction in the cancer cell viability (~62%).
The viable DU145 count of only ~6% was registered for
treatment with 20.0 μM of Ell. Antiproliferation activity is
more pronounced for the Ell×HCl treatment. Thus, about
50% of viable cells were observed after treatment with
5.0 μM of the drug. Moreover, only ~3-5% of the viable
DU145 cells were observed at 10.0 μM and 20.0 μM.
The results of antimalarial activity in vitro for ellipticine
and ellipticine hydrochloride against P. falciparum strain
K1 are shown in Table 2. The data demonstrate a marked
advantage of the Ell×HCl over Ell. In DMSO, the Ell×HCl
was almost three times more potent than Ell (cf. IC50 = 0.7
µmol/mL and 2.3 µmol/mL, respectively) and was of
comparable potency to chloroquine which was used as a
positive control (IC50 = 0.4 µmol/mL). In 50:50 aqueous
DMSO solution, the ellipticine hydrochloride was more
efficient than Ell by an order of magnitude (cf IC50 = 0.5
µmol/mL and 5.0 µmol/mL, respectively). Further dilution
(DMSO:H2O = 25:75) resulted in a decrease in the Ell×HCl
activity. At that dilution, the ellipticine-base became
insoluble and hence inactive so the measurement was not
performed. Therefore, the 50:50 aqueous DMSO was found
to be the best solvent for the ellipticine hydrochloride.
Leishmanicidal activity of ellipticine and ellipticine
hydrochloride against L. amazonensis promastigotes was
Figure 3. Proliferation assay. DU145 cells were treated with
ellipticine, and ellipticine hydrochloride (0.625, 1.25, 2.5, 5, 10,
and 20 μM). DMSO 0.1% treatment (no drug) was used as a
control throughout the experiments. Proliferation was measured 24
hours post-treatment. Data shown are mean±SD of triplicate
independent experiments. (A) Absorbance at 595 nm (B) The cell
viability is shown as a percentage of the control treatment (DMSO
0.1%; No drug) set as 100%.
Table 2. IC50 of Ell and Ell×HCl in vitro against P. falci-
parum strain K1.
assessed. Ell×HCl noticeably inhibited the promastigote
growth, leaving only 26.7% of viable cells after 48 h
treatment at the concentration of 250 µg/mL, when
compared to the negative control (Figure 4). The IC50 value
was found to be 11.02 µg/mL.
The leishmanicidal activity found for both Ell and
Ell×HCl was rather low when compared to commercial
drug pentamidine isethionate (Pentacarinat®) which was
used as the positive control. In the case of pentamidine,
Sample IC50
(µg/mL)
IC50
(µmol/mL)
Ellipticine in DMSO 0.55 2.3
Ellipticine in
DMSO:H2O (50:50)
1.25 5.0
Ellipticine.HCl in DMSO 0.21 0.7
Ellipticine.HCl in
DMSO:H2O (50:50)
0.14 0.5
Ellipticine.HCl in
DMSO:H2O (25:75)
0.47 1.7
Chloroquine in DMSO 0.25 0.4
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
96
Figure 4. Leishmanicidal activity of Ell and Ell×HCl against promastigotes of L. amazonensis (MHO/BR/2009/IM5584): 106 cells mL-1
were incubated with different individual concentrations at 25 °C. Pentacarinat® solutions 10 µg/mL, 5 µg/mL, and 2.5 µg/mL were used
as the positive control. Schneider medium containing 4% of DMSO was used as the negative control.
only 1.5% of promastigotes remained viable at the end of
the experiment with the concentration of 10 µg/mL. At the
same time, such an activity was never reached for all Ell
and Ell×HCl concentration values. As expected, no
leishmanicidal activity was detected for the negative control
sample, a 4% aqueous DMSO solution. The best activity for
both Ell and Ell×HCl was found at the concentration of 250
µg/mL; however, 54.4% of the parasites remained viable
upon treatment with Ell, while a viability of 26.7% was
observed for Ell×HCl. Our experimental data confirms
previously obtained theoretical results [18]. The authors had
studied molecular docking of ellipticine with Leishmania
proteins, but no conspicuous activity was calculated.
Moderate activity values for the ellipticine and its salt may
also be associated with poor solubility of the active
compounds in the culture medium containing insufficient
DMSO quantities (4%).
Conclusions
Ellipticine and its hydrochloride salt were synthesized by
an improved, reliable, and scalable procedure. Detailed
study in vitro of their anticancer, antimalarial, and
antileishmanial activity was performed. High to very high
anticancer and antimalarial activities were demonstrated
along with rather moderate antileishmanial activity. As low
solubility of ellipticine in aqueous media is an obstacle to
its efficacy, we were able to partially circumvented it by
obtaining the ellipticine hydrochloride. Ell×HCl exhibited
much better biological activity, owing to its better solubility
and thus bioavailability.
Experimental section
All reagents were purchased from Sigma-Aldrich (Merck
KGaA, Darmstadt, Germany) unless otherwise specified.
Solvents were purified by standard procedures used in
synthetic organic chemistry.
Synthesis
1H NMR spectra were recorded on a Varian Mercury 300
instrument operating at 300 MHz.
1,4-Dimethylcarbazole (2)
A single neck round-bottom flask 250 mL was charged
with indole 1 (3.2 g, 27 mmol), hexane-2,5-dione (4.1 g, 36
mmol), p-toluenesulfonic acid (0.6 g, 3 mmol), and toluene
(100 mL). The flask was fitted with a Dean-Stark apparatus.
First, the flask was kept at 93 °С for 1 h and then refluxed
on an oil bath for 2.5 h collecting water, keeping the
temperature of the bath at 150 °С. The hot reaction mixture
was decanted from a tar formed. The solvent was
evaporated to give a red powder. The latter was re-dissolved
in boiling cyclohexane (3 x 35 mL). The combined solvent
were reduced to the volume of 40 mL. The precipitated pink
crystals were collected by filtration, and washed with
cyclohexane (20 mL) to give the target 1,4-di-
methylcarbazole 2 (3.94 g, 74%). M.p. 93 °С. 1Н NMR
(300 MHz, CDCl3) 8.21 (d, J 7.1 Hz, 1H, C5-H), 7.83 (br
s, 1H, NH), 7.41-7.50 (m, 2H, C7-H and C8-H), 7.28 (dd,
J1 7.6 Hz, 1H, C6-H), 7.16 (d, J 7.3 Hz, 1H, C2-H), 6.97 (d,
J 7.3 Hz, 1H, C3-H), 2.88 (s, 3Н, C4-CH3), 2.55 (s, 3Н,
C1-CH3).
Grafov A. V. et al.
97
A mixture of 3-formyl-1,4-dimethylcarbazole (3) and
6-formyl-1,4-dimethylcarbazole (4)
1,4-Dimethylcarbazole formylation procedure was
adopted by Deane et al. [30] using POCl3 and DMF in
chlorobenzene. The reaction proceeded non-regioselectively
affording a mixture of 3-formyl-1,4-dimethylcarbazole (3)
as a major product and 6-formyl-1,4-dimethylcarbazole 4
(ca. 9:1) [30]. POCl3 (2.5 mL, 27 mmol) was added
dropwise to an ice-cold solution of 1,4-dimethylcarbazole 2
(5.15 g, 26 mmol) and dimethylformamide (DMF, 2.06 mL)
in chlorobenzene (80 mL). The reaction mixture was kept at
0 °С for 15 min, and then the temperature was raised to
140 °С and maintained for 3.5 h. At that stage, the reaction
mixture was cooled down and DMF (0.4 mL) and POCl3
(0.5 mL) were added. The reaction mixture was then heated
and kept at 140 °С for an additional 3 h. After cooling the
mixture to room temperature, an aqueous solution of
sodium acetate (29 mL) prepared from CH3COONa×3H2O
(7.3 g) was added. The reaction mixture was evaporated
to dryness and the residue was extracted with hot EtOAc
(3x30 mL). The EtOAc solution was cooled to room
temperature, washed with water (70 mL), brine (70 mL),
and dried over anhydrous Na2SO4. After removal of the
solvent, a brown powder 5.3 g (91%) was obtained as a
mixture of 3 and 4 (ca. 9:1). 1Н NMR (300 MHz, CDCl3)
(major isomer 3) 10.44 (s, 1H, CHO), 8.54 (br s, 1H, NH),
8.25 (d, J 8.0 Hz, 1H, C5-H), 7.74 (s, 1H, C2-H), 7.47-7.53
(m, 2H, C7-H and C8-H), 7.29-7.34 (m, 1H, C6-H), 3.16 (s,
3Н, C4-CH3), 2.55 (s, 3Н, C1-CH3).
The two following steps, viz. condensation with
aminoacetaldehyde diethyl acetal with a further reduction to
a mixture of 3-(2,2-diethoxyethylaminomethyl)-1,4-
dimethylcarbazole 7 as a major isomer and 6-(2,2-diethoxy-
ethylaminomethyl)-1,4-dimethylcarbazole 8 (ca. 9:1) were
carried out according to the literature [21, 30-31, 35-36].
A mixture of 3-(2,2-diethoxyethyliminomethyl)-1,4-
dimethylcarbazole (5) and 6-(2,2-diethoxyethyl-
iminomethyl)-1,4-dimethylcarbazole (6)
A mixture of 3- and 6-formyl-1,4-dimethylcarbazoles (3
and 4) (ca. 9:1) (4.5 g, 20.1 mmol) and aminoacetaldehyde
diethyl acetal (3.06 mL, 21 mmol) was heated at 110 °С
with stirring for 4 h. The reaction mixture was then cooled,
diluted with toluene (15 mL), and evaporated under reduced
pressure to give a mixture of 3- and 6-(2,2-diethoxy-
ethyliminomethyl)-1,4-dimethylcarbazoles (5 and 6) as an
orange oil (6.42 g, 94%) that was used without further
purification.
A mixture of 3-(2,2-diethoxyethylaminomethyl)-1,4-
dimethylcarbazole (7) and 6-(2,2-diethoxyethyl-
aminomethyl)-1,4-dimethylcarbazole (8)
To a cooled (0 °С) solution of the mixture of 3- and 6-
(2,2-diethoxyethyliminomethyl)-1,4-dimethylcarbazoles (5
and 6) (8.30 g, 24.6 mmol) in methanol (200 mL), 4.67 g
(123 mmol) of NaBH4 was added portion-wise with stirring
during 20 min. The reaction mixture was kept at room
temperature for 2 h with stirring. Subsequently, the reaction
mixture was evaporated to dryness and 1 М aqueous HCl
solution was added until pH 6. The aqueous phase was
decanted from the tar formed, and neutralized by a 20%
aqueous NaOH solution until the pH reached 7. The
solution was extracted with toluene (3x50 mL). The organic
layer was separated, washed with brine (2x30 mL), and
dried over anhydrous Na2SO4. The solvent was evaporated
to dryness to give a mixture of 3- and 6-(2,2-diethoxy-
ethylaminomethyl)-1,4-dimethylcarbazoles (7 and 8) (ca.
9:1) as a brown oil (7.26 g, 87%), which was used without
further purification. 1Н NMR (300 MHz, CDCl3) (major
isomer 7) 8.24 (d, J 8.0 Hz, 1H, C5-H), 8.07 (br s, 1H,
NH), 7.38-7.48 (m, 2H, C7-H and C8-H), 7.18-7.27 (m, 2H,
C2-H and C6-H), 4.67 (t, J 5.6 Hz, 1H, CH(OEt)2), 3.98 (s,
2H, ArCH2NH), 3.65-3.75 (m, 2H, OCH2CH3), 3.49-3.59
(m, 2H, OCH2CH3), 2.87 (s, 3Н, C4-CH3), 2.85 (m, 2H,
NHCH2CH), 2.50 (s, 3Н, C1-CH3), 1.81 (br s, 1H,
ArCH2NH), 1.22 (t, J 7.0 Hz, 6H, 2×OCH2CH3).
N-tosyl-3-(2,2-diethoxyethylaminomethyl)-1,4-dimethyl-
carbazole (9)
To a mixture of 3- and 6-(2,2-diethoxyethyl-
aminomethyl)-1,4-dimethylcarbazoles (7 and 8) (ca. 9:1)
(5.42 g, 16 mmol) in THF (87 mL) 42 mL of water were
added, followed by the addition of solid K2CO3 (3.34 g, 24
mmol) and p-toluenesulfonyl chloride (4.52 g, 24 mmol).
The reaction mixture was stirred at room temperature for
16 h (Vehar et al., 2011). Subsequently, 50 mL of water
followed by 100 mL of EtOAc were added. The organic
layer was separated and washed successively with 1 М HCl
(2x50 mL), water (50 mL), saturated solution of NaHCO3
(50 mL), water (50 mL), brine (50 mL), and dried over the
anhydrous Na2SO4. After the removal of the solvents, the
solid residue was recrystallized from a boiling mixture of
hexane : EtOAc (2:1) (90 mL). The obtained solution was
left overnight at room temperature, the precipitate was
separated by filtration, and washed with hexane to give
4.80 g (61%) of the target compound 9 as beige crystals.
M.p. 180 °С (177-179 °С [30]). 1Н NMR (300 MHz,
CDCl3) 8.19 (d, J 7.8 Hz, 1H, C5-H), 8.04 (br s, 1H, NH),
7.74 (d, J 8.2 Hz, 2H, Tos, C2'-H and C6'-H), 7.38-7.48 (m,
2H, C7-H and C8-H), 7.21-7.28 (m, 3H, Tos, C3'-H, C5'-H
and C6-H), 4.67 (s, 2H, ArCH2N),6.97 (s, 1H, C2-H), 4.43
(t, J 5.4 Hz, 1H, CH(OEt)2), 3.48-3.58 (m, 2H, OCH2CH3),
3.26-3.36 (m, 2H, OCH2CH3), 3.21 (d, J 5.5 Hz, 2H,
NHCH2CH), 2.80 (s, 3Н, C4-CH3), 2.42 (s, 3Н, Tos, C4'-
CH3), 2.39 (s, 3Н, C1-CH3), 1.07 (t, J 7.0 Hz, 6H,
2×OCH2CH3).
Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole)
(10)
The compound 9 (1.94 g, 3.9 mmol) was dissolved in
77 mL of dioxane and 19 mL of 23% aqueous HCl solution
were added. The reaction mixture was heated at 110-115 °С
with stirring for 6.5 h [30-32, 35], and its color turned dark-
green. The total volume was reduced on a rotary evaporator
to approximately one-quarter of the initial one. Then 50 mL
of water and 50 mL of 20% NaHCO3 solution were added
successively. The aqueous layer was extracted with
methylene chloride (5x100 mL). The combined extracts
were washed with brine (100 mL) and dried over an
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
98
anhydrous Na2SO4. The solvents were evaporated to give a
green slurry (5 mL) of N-tosyl-1,2-dihydroellipticine and
ellipticine 10. The slurry was placed on top of a short silica
gel column. The mixture was separated using flash
chromatography. First, EtOAc was used as the eluent to
collect mainly N-tosyl-1,2-dihydroellipticine (0.3 g) as
brown crystals, and then the eluent was changed to MeOH
to collect the ellipticine 10 as dark-yellow crystals (0.49 g,
52%). M.p. >300 °С. 1Н NMR (300 MHz, DMSO-d6)
11.41 (s, 1H, NH), 9.66 (s, 1H, C1-H), 8.39 (d, J 6.0 Hz,
1H, C3-H), 8.34 (d, J 8.0 Hz, 1H, C10-H), 7.87 (d, J 6.0
Hz, 1H, C4-H), 7.47-7.57 (m, 2H, C8-H and C7-H), 7.23 (t,
J 8.0 Hz, 1H, C9-H), 3.21 (s, 3Н, C11-CH3), 2.76 (s, 3Н,
C5-CH3).
Ellipticine hydrochloride (11)
2 mL of concentrated aqueous HCl (~36%) were added
to the ellipticine 10 (0.11 g, 0.45 mmol) solution in 50 mL
of methanol and thoroughly mixed. After the removal of the
solvents, 30 mL of acetone was added to the residue. The
ellipticine hydrochloride 11 precipitated as yellowish-green
crystals, yield 0.12 g (95%). M.p. >300 °С. 1Н NMR (300
MHz, DMSO-d6) 12.19 (s, 1H, NH), 9.78 (s, 1H, C1-H),
8.26-8.33 (m, 3H, C4-H, C10-H, and C3-H), 7.57 (br s, 2H,
C8-H and C7-H), 7.27-7.30 (m, 1H, C9-H), 3.14 (s, 3Н,
C11-CH3), 2.72 (s, 3Н, C5-CH3).
Activity studies
In vitro bioassays. Cell lines and culture
Human prostate cancer cell line DU145 was purchased
from ATCC (American Type Culture Collection, Rockville,
MD, USA). The cells were authenticated by the cell bank
using DNA profile (STR) and cytogenetic analysis. The
cells were cultured in a culture media (Life Technologies,
Carlsbad, CA) and supplemented with 10% of fetal bovine
serum (FBS), 50 U of penicillin/mL, and 50 mg strepto-
mycin/mL (Life Technologies, Carlsbad, CA, USA) and
maintained in a 5% CO2 humidified incubator at 37 ºC. The
specific growth media for DU145 cells were DMEM and
the cell line was routinely frozen within 2 passages after
receipt from the cell bank and used within less than 6
months after recovery.
Proliferation Assay
Ell and Ell×HCl were dissolved in DMSO (Sigma-
Aldrich) and diluted to get final concentrations of 0.625,
1.25, 2.5, 5.0, 10.0, and 20.0 μM. 0.1% DMSO was used as
a negative control. The proliferation assay was performed
using Cell Proliferation Kit I (MTT; Roche, Basel,
Switzerland) according to the manufacturer’s protocol.
Ninety six well tissue culture plates (SPL Life Sciences,
Korea) were used to seed 2×103 cells/well. Following the
drug treatment, 10μl of yellow thiazolyl blue tetrazolium
bromide (MTT) (5 mg/mL) dissolved in sterile 1×PBS pH
7.4 was added to the cells and incubated for 4 hours, to
quantify the cell proliferation. The yellow MTT solution
was converted into a dark blue/purple formazan crystals by
mitochondrial dehydrogenases of live actively metabolizing
cells and was solubilized following the 4-hour incubation
by the addition of 100 μL of solubilization reagent (10%
sodium lauryl sulfate, 0.01 M HCl in H2O) and incubation
for 16 hours. Subsequently, the absorbance at 595 nm was
measured using a MultiskanTM FC microplate photometer.
Culture and in vitro inhibition assay of P. falciparum
Multidrug-resistant strain K1 (MRA-159, MR4, ATCC
Manassas Virginia) of P. falciparum used in the assay were
maintained in continuous culture according to Trager and
Jensen method [45]. Initial parasitemia of 1-2% and
hematocrit of 2% were used for the assay. RPMI 1640
(Sigma-Aldrich) supplemented with 10% human serum
(Sigma-Aldrich) and containing 25 mmol of HEPES and
2 mmol of glutamine was used as a complete medium. The
substances were solubilized in DMSO at a stock
concentration of 10 mg/mL and subsequently diluted in the
complete medium to obtain seven test concentrations
(0.006-100 μg/mL). Ellipticine and ellipticine×HCl stock
solutions of 10 mg/mL were prepared both in pure DMSO
and in DMSO mixtures with water in the ratios of 50:50 and
25:75 v/v. The stock solutions were subsequently diluted in
the complete RPMI 1640 culture medium to obtain seven
different concentrations between 0.006 and 100 μg/mL. The
assay was performed as described by Andrade-Neto et al.
[15]. Dilutions of the samples were applied to microplate
wells containing parasitized erythrocytes. Each dilution was
tested in triplicate. The plate was incubated at 37 °C for
48 h. Viable parasites were counted by a hemocytometer.
Parasite growth inhibition was determined by comparison to
the growth controls without the sample. The half-maximal
inhibitory responses (IC50) as compared to the drug-free
controls were estimated by interpolation using MicroCal
Origin software. The concentration values in log µg/mL
were plotted against the parasite viability (ratio of the
average parasitemias of test wells to the average
parasitemias of the control wells) for each concentration
using the sigmoidal fitting analysis function to generate a
smooth curve. The IC50 values were obtained from the
graph and correspond to viability of 0.5.
Antileishmanial assays
Leishmania (Leishmania) amazonensis strain
MHO/BR/2009/IM5584 cryopreserved and kept at the
Laboratory of Leishmaniasis and Chagas disease, CSAS,
INPA. The promastigotes used in the bioassays were
maintained and cultured in a complete Schneider
Drosophila Medium (Sigma-Aldrich) supplemented with a
heat-inactivated 10% Fetal Bovine Serum (FBSi, Sigma-
Aldrich) and gentamycin (40 µg/mL) and kept in an oven at
25 °C, according to Morel [46]. A growth curve was
performed before the bioassay realization. The strain J774
of murine macrophages was maintained in RPMI-1640
(Himedia®) in culture bottles in an oven at 37 °C.
Evaluation of antileishmanial activity was performed in 96
well culture plates using promastigotes in the late log phase
(106 cells/mL), according to Fumarola et al. [47]. The active
compounds were dissolved in dimethylsulfoxide (DMSO,
Vetec®, 4% v/v) and Schneider medium and then filtered
Grafov A. V. et al.
99
through 0.22 µm Millipore membrane in a sterile
environment. The samples were evaluated at concentrations
of 1.95 µg/mL to 250 µg/mL. Pentamidine (Pentacarinat®)
was used as a positive control at a maximum concentration
of 10 µg/mL and DMSO (4% v/v) was used as a negative
control. The activity of the samples was assessed by growth
inhibition and mortality of the L. amazonensis proma-
stigotes in periods of 24 and 48 hours at 25 °C. The
bioassays were performed in triplicates. Viable parasites
were counted by a hemocytometer. The average number of
live cells was used to calculate the IC50 values.
Notes
Acknowledgments and finances. The authors gratefully
acknowledge the financial support of the presented research
by: the University of Helsinki and the Magnus Ehrnrooth
Foundation, Finland; the European Union international staff
exchange project Horizon2020 MSCA-RISE-2016-734759,
acronym VAHVISTUS; the International Centre for
Genetic Engineering and Biotechnology and National
Research Foundation of South Africa (LFZ); the National
Institute of Amazonian Research and the Ministry of
Scientific and Technological Development of Brazil.
The authors declare no conflict of interest.
Author contributions. K. V. S.: Synthesis of
compounds, writing experimental section. I. A. G.: Formal
analysis. T. I. S.: Synthesis of compounds. A. N. K.: review
& editing N. S. P.: Investigation, L. F. R. S.: Investigation,
A. K.: Investigation, C. D. C. W.: Investigation, L. F. Z.:
Investigation, W. P. T.: Investigation, A. M. R. F. P.:
Investigation, M. L.: Conceptualization, A. V. G.:
Supervision, Writing most of the manuscript.
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Індольний алкалоїд еліптицин як ефективна багатоцільова сполука
К. В. Швиденко1, І. О. Графова2, Т. І. Швиденко1, О. М. Костюк1, Н. С. Пікансо3, Л. Ф. Р. Сильва4, A. Кропфіч5,
К. Д. С. Вирепковська6, Л. Ф. Зербіні5, В. П. Тадей3, A. M. Р. Ф. Перейра6, M. Лескеля2, А. В. Графов2*
1 Інститут органічної хімії НАН України, вул. Мурманська, 5, Київ, 02094, Україна
2 Гельсінський університет, Гельсінкі, 01560,Фінляндія
3 Лабораторія малярії та денге, Національний інститут досліджень Амазонії (НІДА), Манаус 69067-375, Амазонас, Бразилія
4 Біотехнологічний центр Амазонії, НІДА, Манаус 69067-375, Амазонас, Бразилія
5 Міжнародний центр генної інженерії та біотехнології, Кейптаунський Компонент, Кейптаун, 7935, Південна Африка
6 Лабораторія лейшманіозу та хвороби Шагаса, НІДА, Манаус 69067-375, Амазонас, Бразилія
Резюме: Вперше виділений з тропічної рослини Oschrosia elliptica, індольний алкалоїд еліптицин викликав величезний інтерес, оскільки була
продемонстрована протипухлинна активність разом з обмеженими токсичними побічними ефектами та повною відсутністю гематологічн ої
токсичності. У цій роботі для отримання еліптицину (Ell) був використаний п'ятистадійний синтез по Cranwell і Saxton. Також був синтезований
гідрохлорид еліптицину (Ell×HCl). Було проведено детальне дослідження in vitro протипухлинної, протималярійної та лейшманіцидної дії. Аналіз
антиракової активності проведений з використанням лінії ракових клітин DU145, обробленої Ell, показав послідовне зниження проліферації та
життєздатності клітин при обробці Ell починаючи з концентрації 5 мкмоль/л. Антипроліфераційна активність була більш вираженою для
розчинів Ell×HCl. Як Ell, так і Ell×HCl виявили помірну активність in vitro щодо промастигот Leishmania amazonensis, що пов’язано з
недостатньою розчинністю препаратів. Значення IC50 Ell та Ell×HCl визначали in vitro проти штаму K1 Plasmodium falciparum, стійкого до
багатьох лікарських засобів. Було показано, що Ell×HCl майже втричі потужніший, ніж Ell в ДМСО. При розведенні водою розчинність і
активність Ell падають, тоді як у випадку Ell×HCl, вони збільшуються до 10 разів у водному розчині DMSO 50:50.
Ключові слова: фтор; піролізидин; індолізидин; хінолізидинові алкалоїди; стратегія синтезу.
Notes
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| id | oai:ojs2.bioorganica.com.ua:article-18 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:26Z |
| publishDate | 2022 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/c7/2bca93afe35cf311d684b7ccbaa285c7.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-182026-07-19T14:56:53Z Indole alkaloid ellipticine as efficient multitarget compound Індольний алкалоїд еліптицин як ефективна багатоцільова сполука Shvydenko, Kostiantyn V. Grafova, Iryna A. Shvydenko, Tetiana I. Kostyuk, Aleksandr N. Picanço, Neila S. Silva, Luiz F.R. Kropfitsch, Anya Wyrepkowski, Claudia D.C. Zerbini, Luiz F. Tadei, Wanderli P. Pereira, Antonia M.R.F. Leskelä, Markku Grafov, Andriy V. ellipticine in vitro anticancer antimalarial antileishmanial activity фтор піролізидин індолізидин хінолізидинові алкалоїди стратегія синтезу First isolated from the tropical plant Oschrosia elliptica, indole alkaloid ellipticine provoked huge interest since it demonstrated antitumor activity was demonstrated along with limited toxic side effects and a complete lack of hematological toxicity. In this work, a five-step Cranwell and Saxton synthesis was used for obtaining ellipticine (Ell). Ellipticine hydrochloride salt (Ell×HCl) was also synthesized. Detailed in vitro studies of anticancer, antimalarial, and leishmanicidal activities were performed. Antiproliferation assay using DU145 cancer cell line treated with Ell showed a consistent reduction in cell proliferation and cell viability when treated with 5 μmol Ell. Anti-proliferation activity was more pronounced for the Ell×HCl solutions. Both the Ell and Ell×HCl revealed moderate activity in vitro against Leishmania amazonensis promastigotes, which is related to insufficient solubility of the drugs. IC50 values of Ell and Ell×HCl were determined in vitro against multidrug resistant Plasmodium falciparum strain K1. The Ell×HCl was shown to be almost three times more potent than the Ell in DMSO. Upon dilution with water, Ell solubility and activity drops down, while the activity and solubility of Ell×HCl is enhanced up to 10 times in 50:50 aqueous DMSO solutions. Вперше виділений з тропічної рослини Oschrosia elliptica, індольний алкалоїд еліптицин викликав величезний інтерес, оскільки була продемонстрована протипухлинна активність разом з обмеженими токсичними побічними ефектами та повною відсутністю гематологічної токсичності. У цій роботі для отримання еліптицину (Ell) був використаний п'ятистадійний синтез по Cranwell і Saxton. Також був синтезований гідрохлорид еліптицину (Ell×HCl). Було проведено детальне дослідження in vitro протипухлинної, протималярійної та лейшманіцидної дії. Аналіз антиракової активності проведений з використанням лінії ракових клітин DU145, обробленої Ell, показав послідовне зниження проліферації та життєздатності клітин при обробці Ell починаючи з концентрації 5 мкмоль/л. Антипроліфераційна активність була більш вираженою для розчинів Ell×HCl. Як Ell, так і Ell×HCl виявили помірну активність in vitro щодо промастигот Leishmania amazonensis, що пов’язано з недостатньою розчинністю препаратів. Значення IC50 Ell та Ell×HCl визначали in vitro проти штаму K1 Plasmodium falciparum, стійкого до багатьох лікарських засобів. Було показано, що Ell×HCl майже втричі потужніший, ніж Ell в ДМСО. При розведенні водою розчинність і активність Ell падають, тоді як у випадку Ell×HCl, вони збільшуються до 10 разів у водному розчині DMSO 50:50. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2022-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/18 10.15407/bioorganica2022.01.092 Ukrainica Bioorganica Acta; Vol. 17 No. 1 (2022): Ukrainica Bioorganica Acta; 92-100 Ukrainica Bioorganica Acta; Том 17 № 1 (2022): Ukrainica Bioorganica Acta; 92-100 1814-9766 1814-9758 10.15407/bioorganica2022.01 en https://bioorganica.com.ua/index.php/journal/article/view/18/21 Copyright (c) 2022 Kostiantyn V. Shvydenko, Iryna A. Grafova, Tetiana I. Shvydenko, Aleksandr N. Kostyuk, Neila S. Picanço, Luiz F.R. Silva, Anya Kropfitsch, Claudia D.C. Wyrepkowski, Luiz F. Zerbini, Wanderli P. Tadei, Antonia M.R.F. Pereira, Markku Leskelä, Andriy V. Grafov https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | фтор піролізидин індолізидин хінолізидинові алкалоїди стратегія синтезу Shvydenko, Kostiantyn V. Grafova, Iryna A. Shvydenko, Tetiana I. Kostyuk, Aleksandr N. Picanço, Neila S. Silva, Luiz F.R. Kropfitsch, Anya Wyrepkowski, Claudia D.C. Zerbini, Luiz F. Tadei, Wanderli P. Pereira, Antonia M.R.F. Leskelä, Markku Grafov, Andriy V. Індольний алкалоїд еліптицин як ефективна багатоцільова сполука |
| title | Індольний алкалоїд еліптицин як ефективна багатоцільова сполука |
| title_alt | Indole alkaloid ellipticine as efficient multitarget compound |
| title_full | Індольний алкалоїд еліптицин як ефективна багатоцільова сполука |
| title_fullStr | Індольний алкалоїд еліптицин як ефективна багатоцільова сполука |
| title_full_unstemmed | Індольний алкалоїд еліптицин як ефективна багатоцільова сполука |
| title_short | Індольний алкалоїд еліптицин як ефективна багатоцільова сполука |
| title_sort | індольний алкалоїд еліптицин як ефективна багатоцільова сполука |
| topic | фтор піролізидин індолізидин хінолізидинові алкалоїди стратегія синтезу |
| topic_facet | ellipticine in vitro anticancer antimalarial antileishmanial activity фтор піролізидин індолізидин хінолізидинові алкалоїди стратегія синтезу |
| url | https://bioorganica.com.ua/index.php/journal/article/view/18 |
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