Катіонні карбоксамідні похідні трициклічних гетероароматичних сполук: синтез та попередня оцінка антипроліферативної активності
This research was aimed at the synthesis and study of biological activity of the carboxamides of tricyclic heteroaromatic systems, acridone, phenazine and thioxanthone, containing the aliphatic and aromatic cationic substituents at amide fragment. These heterocyclic cores are DNA intercalating agent...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2020
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Ukrainica Bioorganica Acta| _version_ | 1871193595399110656 |
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| author | Kostina, Valentina G. Alexeeva, Inna V. Lysenko, Nadia A. Negrutska, Valentina V. Dubey, Igor Y. |
| author_facet | Kostina, Valentina G. Alexeeva, Inna V. Lysenko, Nadia A. Negrutska, Valentina V. Dubey, Igor Y. |
| author_institution_txt_mv | [
{
"author": "Valentina G. Kostina",
"institution": "Institute of Molecular Biology and Genetics of the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03680, Ukraine"
},
{
"author": "Inna V. Alexeeva",
"institution": "Institute of Molecular Biology and Genetics of the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03680, Ukraine"
},
{
"author": "Nadia A. Lysenko",
"institution": "Institute of Molecular Biology and Genetics of the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03680, Ukraine"
},
{
"author": "Valentina V. Negrutska",
"institution": "Institute of Molecular Biology and Genetics of the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03680, Ukraine"
},
{
"author": "Igor Y. Dubey",
"institution": "Institute of Molecular Biology and Genetics of the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03680, Ukraine"
}
] |
| author_sort | Kostina, Valentina G. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:52Z |
| description | This research was aimed at the synthesis and study of biological activity of the carboxamides of tricyclic heteroaromatic systems, acridone, phenazine and thioxanthone, containing the aliphatic and aromatic cationic substituents at amide fragment. These heterocyclic cores are DNA intercalating agents, whereas the introduction of cationic groups provides additional ionic interactions of the ligands with their biological targets, such as DNA and enzymatic complexes of the system of nucleic acids biosynthesis. A convenient way of the introduction of such groups is a modification of heterocyclic carboxamides. A small library of new cationic amide derivatives of acridone-4-, phenazine-1- and thioxanthone-4-carboxylic acids was obtained. They were synthesized in 37-81% yield by mild and selective quaternization of the nitrogen atoms at N,N-dimethylaminoalkyl (alkyl = ethyl, propyl) and pyridylmethyl fragments of the neutral N-functionalized carboxamides with methyl iodide. Tricyclic heteroaromatic cores were not affected. Convenient protocol for the synthesis of thioxanthone-4-carboxylic acid (TCA) based on the reaction of 2-mercaptobenzoic and 2-iodobenzoic acids followed by cyclization of the intermediate was developed (yield 79%). A series of new N-functionalized neutral amides of TCA, the precursors of corresponding cationic carboxamide, were also obtained via the reaction of acyl chloride with amines. Preliminary in vitro testing of four compounds as potential antitumor agents in U87MG tumor cell culture (human malignant glioma) demonstrated their significant antiproliferative activity at low micromolar concentrations, with growth inhibition values GI50 in the range 1.7-11 µM. These results suggest that cationic carboxamides of tricyclic heteroaromatic systems are promising scaffolds for the design of new antitumor drugs. |
| doi_str_mv | 10.15407/bioorganica2020.01.034 |
| first_indexed | 2025-07-17T12:19:53Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
UDC 547.8:615.277.3
DOI: https://doi.org/10.15407/bioorganica2020.01.034
34
RESEARCH ARTICLE
Сationic carboxamide derivatives of tricyclic heteroaromatic
compounds: synthesis and preliminary evaluation of antiproliferative
activity
Valentina G. Kostina, Inna V. Alexeeva, Nadia A. Lysenko, Valentina V. Negrutska, Igor Y. Dubey*
Institute of Molecular Biology and Genetics of the NAS of Ukraine, 150 Zabolotnogo St., Kyiv, 03680, Ukraine
Abstract: This research was aimed at the synthesis and study of biological activity of the carboxamides of tricyclic heteroaromatic
systems, acridone, phenazine, and thioxanthone, containing the aliphatic and aromatic cationic substituents at amide fragment. These
heterocyclic cores are DNA intercalating agents, whereas the introduction of cationic groups provides additional ionic interactions of the
ligands with their biological targets, such as DNA and enzymatic complexes of the system of nucleic acids biosynthesis. A convenient way
of the introduction of such groups is a modification of heterocyclic carboxamides. A small library of new N-substituted cationic amide
derivatives of acridone-4-, phenazine-1- and thioxanthone-4-carboxylic acids was obtained. They were synthesized in 37-81% yield by
mild and selective quaternization of the nitrogen atoms at N,N-dimethylaminoalkyl (alkyl = ethyl, propyl) and pyridylmethyl fragments of
the neutral N-functionalized carboxamides with methyl iodide. Tricyclic heteroaromatic cores were not affected. Convenient protocol for
the synthesis of thioxanthone-4-carboxylic acid (TCA) based on the reaction of 2-mercaptobenzoic and 2-iodobenzoic acids followed by
cyclization of the intermediate was developed (yield 79%). A series of new N-functionalized neutral amides of TCA, the precursors of
corresponding cationic carboxamide, were also obtained via the reaction of acyl chloride with amines. Preliminary in vitro testing of four
compounds as potential antitumor agents in U87MG tumor cell culture (human malignant glioma) demonstrated their significant
antiproliferative activity at low micromolar concentrations, with growth inhibition values GI50 in the range 1.7-11 µM. These results
suggest that cationic carboxamides of tricyclic heteroaromatic systems are promising scaffolds for the design of new antitumor drugs.
Keywords: acridone; phenazine; thioxanthone; carboxamides; antitumor agents.
Introduction
Condensed tricyclic heteroaromatic systems are
privileged scaffolds for the design of therapeutic agents for
the treatment of various diseases [1-5]. In particular, a
broad variety of antitumor, antibacterial, and antiviral drugs
belong to this class of compounds, including the derivatives
of acridine, phenazine, and thioxanthone. In most cases,
such compounds target the cellular enzymatic systems of
nucleic acids biosynthesis. Small molecules based on
condensed tricyclic heterocycles were reported as efficient
Received:
Revised:
Accepted:
Published online:
20.05.2020
29.05.2020
12.06.2020
30.06.2020
Corresponding author. Tel.: +380-44-200-0379;
e-mail: dubey@imbg.org.ua (I. Y. Dubey)
ORCID: 0000-0003-4023-4293
inhibitors of a number of enzymes involved in nucleic acids
metabolism, including e.g. DNA and RNA polymerases [6],
topoisomerases [7-19], and telomerase [20-25].
The majority of non-nucleoside inhibitors of the enzymes
of nucleic acid biosynthesis are based on heteroaromatic
polycyclic scaffolds. Their effect is usually associated with
interaction with DNA (duplex and quadruplex structures)
via intercalation or groove binding, or with DNA-enzyme
complexes [26-31]. It should be noted that the planar
aromatic systems of acridines and acridones, phenazines,
thioxanthones, and similar molecules allow efficient
intercalation into DNA via the π-π-stacking with electronic
systems of nucleic base pairs [11, 12, 32, 33].
Easily available functionalized tricyclic heteroaromatic
carboxamides containing N-alkyl and N-aryl substituents
have been extensively studied as potential anticancer,
antibacterial, and antiviral drugs [8-10, 16, 18, 20, 24].
Important factors influencing their biological activity are
© Kostina V. G. 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.
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ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
35
Important factors influencing their biological activity are
the structure of heterocycle, the nature of amide substituent,
and the position of the carboxamide group in the core
molecule [10, 16].
Biological activity of carboxamide derivatives of
acridine and phenazine has been investigated for several
decades. Carboxamides containing the NHCH2CH2NMe2
pharmacophore, such as N-[2-(dimethylamino)-ethyl]
carboxamide derivatives of phenazine [34], acridine
(DACA) [8] and 9-aminoacridine [35] were identified as
efficient antitumor agents and topoisomerase inhibitors.
N-arylamides of acridone-4-carboxylic acid are active
against hepatitis C virus infection inhibiting the
transcription and RNA replication [36]. N-pyridyl
derivatives of acridone carboxamides were found to inhibit
NS3 helicase [36, 37], telomerase [24], and topoisomerase I
[38]. N-aryl(hetaryl)-substituted amides of phenazine-1-
carboxylic acid appeared to be efficient antimicrobial
agents, including the compounds active against drug-
resistant Mуcobacterium tuberculosis strains [39, 40].
Much less attention has been paid to the studies of
bioactivity of compounds based on thioxanthone, a close
acridone analogue. Among thioxanthone derivatives,
antitumor agents have been reported [41-43], although we
were unable to find have not found in the literature data on
the activity of thioxanthone carboxamides.
We have previously obtained a series of carboxamides of
acridone and phenazine whose amide groups were
functionalized with N,N-dimethylaminoalkyl and pyridyl
fragments [38]. The introduced basic functions can be
protonated under physiological conditions to form cationic
moieties. Structure design was based on the fact that the
attachment of basic/cationic substituents to
DNA-intercalating ligands could enhance their binding to
DNA or enzymatic complexes formed by the enzymes of
nucleic acids biosynthesis (topoisomerase, telomerase,
DNA, and RNA polymerases, etc.) by additional
interactions with either anionic DNA phosphates or acidic
groups within the enzymes. At the same time, the aromatic
pyridyl residues could also interact with nucleic acids bases
or aromatic amino acids via the hydrophobic mechanism
further enhancing the binding of ligands to their molecular
targets. Phenazine and acridone derivatives containing
aromatic pyridyl fragments were found to inhibit the
topoisomerase I at 100 μM concentration, whereas their
analogues with aliphatic basic substituents at carboxamide
fragment were less efficient [38]. At the same time, the free
core heterocycles and their non-substituted carboxamides
are inactive against topoisomerase [38] and telomerase [24].
Thus, the introduction of protonable basic substituents
significantly increased the biological activity of tricyclic
carboxamides, and we could expect that the modification of
core heterocycles with cationic fragments would result in
even more efficient inhibitors with potential antitumor
and/or antibacterial properties. In this work, we have
significantly extended the range of N-substituted tricyclic
carboxamides as potential antitumor agents.
Results and discussion
Before we have synthesized a set of neutral carboxamide
derivatives of acridone 1a-e and phenazine 2a-e
Het -COOH Het -COCl Het -CONH-R Het -CONH-R1
i ii iii
1-3 a-e 1-3 f-j
N
H
O
O N
H
R(R1)
N
N
O N
H
R(R1)
S
O
O N
H
R(R1)
1 2 3
R:
N
N
N
N
N
R1:
a b c d e
f g h i j
N
N
+
N
N
+
N
+ + +
Scheme 1. Synthesis of neutral (a-e) and cationic (f-j) derivatives of tricyclic carboxamides. (i). SOCl2, toluene, Py, Δ; (ii). R-NH2,
triethylamine, rt; (iii) methyl iodide, MeOH or CH3CN, 20-50 °C, 37-81%.
V. G. Kostina, I. V. Alexeeva et al.
36
SH
COOH
I
COOH
S
COOH
COOH
S
COOH
O
+
i ii
Scheme 2. Synthesis of thioxanthone-4-carboxylic acid. (i). K2CO3, DMF, 60 °С, 4 h; (ii). conc. H2SO4, 100 °С, 2.5-3 h, 79%.
(Scheme 1). Their amide groups were functionalized with
N,N-dimethylamino and isomeric pyridyl groups attached
via the short (1-3 carbon atoms) alkyl linkers [38]. Taking
into account the above considerations, we have decided to
prepare cationic derivatives of tricyclic heterocycles. One of
the possible ways to obtain compounds of this type would
be a quaternization of nitrogen atoms of basic aliphatic and
aromatic substituents present in the already prepared
carboxamides 1,2a-e. We have also decided to extend the
range of tricyclic heteroaromatic systems by adding their
structural analogue, thioxanthone.
Carboxamides 1,2a-e have been previously synthesized
from carboxylic acids [38]. To obtain analogues based on
thioxanthone, first of all, we have elaborated an efficient
procedure for the synthesis of thioxanthone-4-carbocylic
acid (TCA). This procedure is similar to that commonly
used for the synthesis of acridone-4-carboxylic acid [44]
and is based on intramolecular cyclization of bis-dicarbo-
xyphenyl sulfide formed in the reaction of 2-mercapto-
benzoic and 2-iodobenzoic acids.
We have modified a published protocol [45] using
potassium carbonate as a base instead of NaOH, and
2-iodobenzoic acid in place of 2-chlorobenzoic acid. The
condensation of two acids at 60 °С followed by the
intermediate cyclization by heating in conc. sulfuric acid
afforded TCA in 79% yield (Scheme 2). The use of less
reactive bromobenzoic acid in the condensation required
heating at a higher temperature (100 °С) and resulted in a
significantly lower total yield of target tricyclic carboxylic
acid (below 50%).
The synthesis of new N-substituted carboxamides of
thioxanthone was based on our previous approach
developed for phenazine and acridone series [38]. This
convenient one-flask process consisted in the formation of
acyl chloride followed by its reaction with amine. Target
neutral amides 3a-e were obtained by the reaction of TCA
chloride with corresponding amines in the presence of TEA
(Scheme 1).
The neutral compounds 1-3a-e were found to easily react
with methyl iodide, and the quaternization of nitrogen
atoms in amide substituents allowed obtaining a series of
novel cationic derivatives 1-3f-j. N-Alkylation reaction was
carried out in polar solvent (methanol, acetonitrile) at room
temperature or with some heating (up to 50 °C). Since salt-
type products precipitated from the reaction mixture, the
use of crude amides instead of analytically pure samples did
not significantly affect the total yield of iodides from
starting carboxylic acids.
The primary centres of N-methylation are obviously
tertiary aliphatic (AlkNMe2) and pyridine nitrogen atoms in
carboxamide fragments. Only one additional methyl group
signal appeared in 1H NMR spectra of all cationic
derivatives. It is known that the quaternization of phenazine
under the applied conditions does not occur, but possible
alkylation of endocyclic nitrogen or exocyclic oxygen atom
of the acridone ring could not be excluded. However, NMR
spectra of the obtained derivatives and their comparison
with the spectral data of reference compounds confirmed
that compounds 1f-j do not contain N-methyl group located
at acridine ring, as one-proton low-field signals at δ ≥ 12
ppm characteristic of the 10-NH ring proton of neutral
carboxamides of acridone carboxylic acid [44] are observed
in the spectra. NMR spectra of cationic TCA carboxamides
also contain the signals of methyl groups only from
trimethylammonium or N-methylpyridinium residues.
Cationic aliphatic trimethylammonium group of
compounds 1-3f-g is represented by singlets at
3.1-3.4 ppm, whereas the spectra of pyridinium derivatives
1h-j, 2i, and 3i contain the signals of cationic N-methyl
group located at 4.2-4.4 ppm. Low-field shift of signals of
the cationic fragments is observed in NMR spectra of the
salts, as compared to corresponding neutral carboxamides.
In general, the deshielding effect of cationic structures
results in the shift of CONH and methylene protons (low-
field shift for 0.1-0.5 and 0.15-0.25 ppm, respectively) in
comparison with neutral precursors.
Thus, we have prepared a series of 11 new compounds
containing trimethylammonium group attached via the ethyl
or propyl linker, and compounds with isomeric
N-methylpyridinium fragments. This small library would
allow analyzing the structure-activity relationship among
the derivatives of three tricyclic systems – phenazine,
acridone, and thioxanthone.
Investigation of antitumor activity of compounds in
vitro
Preliminary evaluation of the antiproliferative activity of
some new compounds was performed in vitro in the culture
of U87MG tumor cells (human malignant glioma). To
determine the effect of quaternization on biological activity,
the representative pairs of the derivatives of two different
heterocycles, acridone and phenazine, containing the same
pyridyl and N-metyylpyridinium fragments (1d, i and 2d, i)
were tested. The cells were cultured in 24-well plates and
treated for 3 days by drugs added at concentrations ranging
from 20 to 0.5 µM.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
37
In vitro cytostatic activity of compounds towards cancer
cell line was determined using the classic MTT assay [46].
MTT test is based on the transformation of MTT reagent
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-
mide) by the mitochondrial dehydrogenase of viable cells
into the blue formazan which can then be measured
spectrophotometrically. The optical density of the probe is
proportional to the number of live cells. From the obtained
data, the plots of the number of live cells in the probe as
compared to a control (cell growth inhibition level) vs. drug
concentration were built, from which the GI50 value was
obtained for each tested carboxamide. GI50 was determined
as a concentration of drug required for 50% of maximal
inhibition of cell proliferation (decreasing cell vitality by
50%) as compared to the non-treated control.
Tested carboxamides demonstrated a significant dose-
dependent antiproliferative activity towards U87MG cells at
low micromolar concentrations, with GI50 below 10 µM for
three of four compounds (Table 1).
Table 1. Antiproliferative activity of compounds in the
culture of U87MG cells (M ± SD).
Compound GІ50, µM
1d 11 ± 2
1i 7.2 ± 1.4
2d 1.7 ± 0.3
2i 5.5 ± 0.9
It is interesting to note that the cationic acridone
derivative 1i (GI50 7.2 µM) was more active than its neutral
analogue 1d (GI50 11 µM), whereas for the pair of
phenazine carboxamides the cationic compound 2i was
three times less efficient as compared to its non-charged
counterpart 2d (GI50 5.5 and 1.7 µM, respectively).
The opposite effects of quaternization on the biological
activity of acridone and phenazine carboxamides may be
due to different molecular targets of the studied compounds
and/or different modes of inhibitor-target interaction.
However, at this moment we have only limited information
on biological properties of a small set of derivatives, and
molecular mechanisms of bioactivity of new compounds
require further investigation. In particular, it will include the
studies on the inhibition of the enzymes of nucleic acid
biosynthesis and ligand interactions with nucleic acids. It
would be also interesting to access the antibacterial activity
of these derivatives.
Conclusions
A convenient protocol was proposed for the synthesis of
cationic N-functionalized carboxamide derivatives of
acridone, phenazine, and thioxanthone, the tricyclic systems
with DNA-intercalating properties. A series of compounds
with aliphatic and aromatic cationic substituents were
obtained. Their heteroaromatic cores contained the
carboxamide functions modified with
N-methylpyridiniumyl and N,N,N-trimethylammonium
groups. Preliminary evaluation of the antiproliferative
activity of several compounds in tumor cell culture in vitro
demonstrated that cationic tricyclic carboxamides could be
suitable scaffolds for the development of new efficient
antitumor agents.
Experimental section
Reagents and solvents for synthesis were purchased from
UkrOrgSynthez (Ukraine), Fluka (Switzerland), and Sigma-
Aldrich (Germany). Solvents were purified and dried by
standard methods. DMSO for molecular biology and MTT
reagent (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-
lium bromide) were obtained from Sigma (USA). 1H NMR
spectra were recorded on a Mercury-400 instrument
(400 MHz, Varian, USA) in DMSO-d6 with tetramethyl-
silane as an internal standard; chemical shifts are given in
ppm. Thin-layer chromatography (TLC) was performed on
Silica gel 60F254 plates (Merck, Germany) in following
solvent systems: CHCl3/MeOH 9:1 (A); CHCl3/MeOH 1:1
(B); CHCl3/HOAc/acetone 10:0.125:0.125 (C);
i-PrOH/NH4ОН/H2O 7:1:2 (D), CHCl3/HOAc/acetone (E).
Melting points were determined using a Boethius PNMK 05
apparatus (Nagema, Germany).
Chemistry
Acridone and phenazine carboxamide derivatives 1,2a-e
were obtained as previously reported [38].
9-Oxo-9H-thioxanthene-4-carboxylic acid (TCA).
The mixture of 2-mercaptobenzoic acid (1.16 g,
7.53 mmol), 2-iodobenzoic acid (1.89 g, 7 mmol) and
powdered К2СО3 (2.09 g, 15.2 mmol) in 10 ml of dry DMF
was stirred at 60 °С for 7.5 h. After cooling, 60 ml of water
was added and insoluble material was filtered off. The
filtrate was neutralized with 10% HCl, the precipitate was
collected by filtration, washed with water and dried. The
obtained crude 2-(2-carboxyphenylthio)benzoic acid (1.94
g) was kept in 7.5 ml of conc. sulfuric acid for 2.5-3 h at
100 °С (control TLC in system E). The reaction mixture
was cooled and poured into ice-cold water, and the
precipitate was filtered and extensively washed with water.
After its re-precipitation from 20 ml of 10% NаОН with
10% НСl the crude product (1.52 g) was crystallized from
DMF. Yield of yellow crystals 79%, mp 332-335 °С.
1Н NMR (400 MHz, DMSO-d6) δ 8.78 (d, 1H, J 8.0 Hz,
Ar), 8.49 (d, 1H, J 7.6 Hz, Ar), 8.43 (d, 1H, J 8.0 Hz, Ar),
7.92 (d, 1H, J 8.0 Hz, Ar), 7.81 (t, 1H, J 7.2 Hz, Ar), 7.70
(t, 1H, J 7.6 Hz, Ar), 7.61 (t, 1H, J 7.6 Hz, Ar).
General procedure for the synthesis of N-substituted
amides of thioxanthone-4-carboxylic acid (3а-e).
0.5 Mmol (128 mg) of TCA was suspended in 3 ml of
dry toluene, and 50 µl of thionyl chloride and 60 µl of dry
pyridine (0.7 mmol each) were added with stirring and the
mixture was heated at 90 °С for 1.5-2 h. After cooling to
room temperature corresponding amine (1.25 mmol) and
triethylamine (1.25 mmol) were added, and the mixture was
V. G. Kostina, I. V. Alexeeva et al.
38
stirred at ambient temperature until the reaction was
complete (control TLC). The mixture was evaporated, the
residue was treated with 10 ml of chloroform and washed
with saturated NаНСО3 (3×5 ml). The organic phase was
dried over Nа2SО4 and evaporated to dryness. The product
was crystallized from the appropriate solvent.
9-Oxo-9H-thioxanthene-4-carboxylic acid (2-
dimethylaminoethyl)-amide (3a)
was obtained from 146 mg (0.57 mmol) TCA and 138 µl
(1.26 mmol) N,N-dimethylaminoethylene diamine. Yield
26%, mp 160-163 °С (acetonitrile). 1Н NMR (400 MHz,
DMSO-d6) δ 8.72 (br t, 1H, CONH), 8.63 (d, 1H, J 8.0 Hz,
Ar), 8.42 (dd, 1H, J 8.0 Hz, 0.8 Hz, Ar), 7.98 (d, 1H, J 6.4
Hz, Ar), 7.85 (m, 1H, Ar), 7.79 (t, 1H, J 7.6 Hz, Ar), 7.66
(t, 1H, J 8.4 Hz, Ar), 7.58 (t, 1H, J 7.6 Hz, Ar), 3.44 (m,
2H, NHCH2), 2.40 (t, 2H, J 6.4 Hz, CH2N), 2.21 (s, 6H,
NMe2).
9-Oxo-9H-thioxanthene-4-carboxylic acid (3-dimethyl-
aminopropyl)-amide (3b)
was obtained from 128 mg (0.5 mmol) of ТCA and
120 µl (1.25 mmol) of N,N-dimetylaminopropylene-1,3-
diamine. Yield 58 mg (34%), mp 162-165 °С (acetonitrile).
1Н NMR (400 MHz, DMSO-d6) δ 8.80 (br t, 1H, J 5.6 Hz,
СОNH), 8.62 (dd, 1H, J 8.4 Hz, 1.2 Hz, Ar), 8.43 (dd, 1H,
J 8.0 Hz, 0.8 Hz, Ar), 7.99 (dd, 1H, J 7.4 Hz, 1.2 Hz, Ar),
7.88-7.84 (m, 1H, Ar), 7.80-7.76 (m, 1H, Ar), 7.66 (t, 1H,
J 7.6 Hz, Ar), 7.59 (t, 1H, J 7.6 Hz, Ar), 3.35 (m, 2H,
NHCH2), 2.34 (t, 2H, J 7.2 Hz, CH2N), 2.17 (s, 6H, NMe2),
1.70 (t, 2H, J 7.2 Hz, CH2).
9-Oxo-9H-thioxanthene-4-carboxylic acid (pyridin-2-
ylmethyl)-amide (3c)
was obtained from o-aminomethylpyridine. Yield 19%,
mp 192-194 °С (EtOH). 1Н NMR (400 MHz, DMSO-d6) δ
9.45 (t, 1H, J 6.0 Hz, СОNH), 8.65 (dd, 1H, J 8.4 Hz, 1.2
Hz, Ar), 8.55 (d, 1H, J 4.8 Hz, Ar), 8.43 (dd, 1H, J 8.4 Hz,
1.2 Hz, Ar), 8.16 (dd, 1H, J 7.6 Hz, 1.6 Hz, Ar), 7.87-7.78
(m, 3H, Ar), 7.70 (t, 1H, J 7.6 Hz, Ar), 7.59 (dt, 1H, J 8.0
Hz, 1.2 Hz, Ar), 7.43 (d, 1H, J 7.6 Hz, Ar), 7.31 (dd, 1H,
J 7.6 Hz, 6.8 Hz, Ar), 4.57 (d, 2H, J 6.0 Hz, CH2).
9-Oxo-9H-thioxanthene-4-carboxylic acid (pyridin-3-yl-
methyl)-amide (3d)
was obtained from 207 mg (0.81 mmol) of TCA and
147 µl (1.45 mmol) of m-aminomethylpyridine. Yield 152
mg (54%), mp 194-198 °С (acetonitrile/i-PrOH). 1Н NMR
(400 MHz, DMSO-d6) δ 9.41 (br t, 1H, J 4.4 Hz, СОNH),
8.65 (m, 2H, Ar), 8.51 (d, 1H, J 3.2 Hz, Ar), 8.43 (d, 1H,
J 6.4 Hz, Ar), 8.11 (d, 1H, J 6.0 Hz, Ar), 7.88-7.75 (m, 3H,
Ar), 7.67 (t, 1H, J 6.4 Hz, Ar), 7.57 (t, 1H, J 6.0 Hz, Ar),
7.44-7.40 (m, 1H, Ar), 4.57 (d, 2H, J 4.8 Hz, CH2).
9-Oxo-9H-thioxanthene-4-carboxylic acid (pyridin-4-
ylmethyl)-amide (3e)
was obtained from p-aminomethylpyridine. Yield 30%,
mp 194-197 °С (EtOH). 1Н NMR (400 MHz, DMSO-d6) δ
9.45 (t, 1H, J 6.0 Hz, СОNH), 8.66 (dd, 1H, J 7.6 Hz, 1.2
Hz, Ar), 8.55 (m, 2H, Ar), 8.43 (dd, 1H, J 8.0 Hz, 0.8 Hz,
Ar), 8.15 (dd, 1H, J 7.6 Hz, 1.6 Hz, Ar), 7.88-7.85 (m, 1H,
Ar), 7.78 (dt, 1H, J 7.6 Hz, 1.2 Hz, Ar), 7.71 (t, 1H, J 7.6
Hz, Ar), 7.60 (dt, 1H, J 7.6 Hz, 1.2 Hz, Ar), 7.40 (dd, 2H,
J 4.4 Hz, 1.6 Hz, Ar), 4.57 (d, 2H, J 6.0 Hz, CH2).
General procedure for the quaternization of
carboxamides.
Neutral heterocyclic N-substituted carboxamide 1-3a-e
(0.1 mmol) and 150 µl of methyl iodide in 2 ml of methanol
or acetonitrile were kept at room temperature or with weak
heating (up to 50 °C) until the reaction was complete
(control TLC). The precipitated product (1-3f-j) was
collected by filtration and crystallized from the appropriate
solvent.
Trimethyl-{2-[(9-oxo-9,10-dihydroacridine-4-carbonyl)-
amino]-ethyl}-ammonium iodide (1f).
Yield 75%, mp 260-263 °С (EtOH). 1Н NMR (400 MHz,
DMSO-d6) δ 12.26 (s, 1H, NH (Ar)), 9.28 (br t, 1H,
СОNH), 8.48 (d, 1H, J 7.6 Hz, Ar), 8.24 (m, 2H, Ar), 7.78-
7.70 (m, 2H, Ar), 7.40 (t, 1H, J 7.6 Hz, Ar), 7.34 (t, 1H,
J 7.2 Hz, Ar), 3.80 (m, 2H, NHCH2), 3.61 (br t, 2H, CH2N),
3.19 (s, 9H, N+Me3).
Trimethyl-{3-[(9-oxo-9,10-dihydroacridine-4-carbonyl)-
amino]-propyl}-ammonium iodide (1g).
Yield 64%, mp 262-264 °С (acetonitrile). 1Н NMR (400
MHz, DMSO-d6) δ 12.40 (s, 1H, NH (Ar)), 9.10 (br t, 1H,
СОNH), 8.46 (d, 1H, J 8.0 Hz, Ar), 8.27 (m, 1H, Ar), 7.79-
7.71 (m, 2H, Ar), 7.39-7.31 (m, 2H, Ar), 3.45-3.39 (m, 4H,
NHCH2, CH2N), 3.19 (s, 9H, N+Me3), 2.05 (br t, 2H, CH2).
1-Methyl-2-{[(9-oxo-9,10-dihydroacridine-4-carbonyl)-
amino]-methyl}-pyridinium iodide (1h).
Yield 37%, mp 269-273 °С (DMF). 1Н NMR (400 MHz,
DMSO-d6) δ 12.10 (s, 1H, NH (Ar)), 9.86 (t, 1H, J 4.8 Hz,
СОNH), 9.06 (d, 1H, J 4.8 Hz, Ar), 8.58-8.52 (m, 2H, Ar),
8.44 (d, 1H, J 7.6 Hz, Ar), 8.24 (d, 1H, J 8.4 Hz, Ar), 8.17
(d, 1H, J 8.4 Hz, Ar), 8.06 (m, 1H, Ar), 7.78-7.74 (m, 1H,
Ar), 7.68 (d, 1H, J 8.4 Hz, Ar), 7.43 (m, 1H, Hz, Ar), 7.32
(m, 1H, Ar), 5.0 (d, 2H, J 4.8 Hz, CH2), 4.44 (s, 3H, N+Me).
1-Methyl-3-{[(9-oxo-9,10-dihydroacridine-4-carbonyl)-
amino]-methyl}-pyridinium iodide (1i).
Yield 75%, mp 240-244 °С (acetonitrile). 1Н NMR (400
MHz, DMSO-d6) δ 12.27 (s, 1H, NH (Ar)), 9.73 (br t, 1H,
СОNH), 9.06 (s, 1H, Ar), 8.92 (s, 1H, Ar), 8.61 (d, 1H,
J 8.8 Hz, Ar), 8.50 (d, 1H, J 7.2 Hz, Ar), 8.39 (d, 1H, J 8.4
Hz, Ar), 8.46 (d,1H, J 8.4 Hz, Ar), 8.13 (s, 1H, Ar), 7.79-
7.77 (m, 2H, Ar), 7.45-7.29 (m, 2H, Ar), 4.78 (d, 2H, J 5.6
Hz, CH2), 4.37 (s, 3H, N+Me).
1-Methyl-4-{[(9-oxo-9,10-dihydroacridine-4-carbonyl)-
amino]-methyl}-pyridinium iodide (1j).
Yield 66%, mp 206-209 °С (acetonitrile). 1Н NMR (400
MHz, DMSO-d6) δ 12.29 (br s, 1H, NH (Ar)), 9.83 (br s,
1H, СОNH), 8.95 (m, 2H, Ar), 8.45-8.55 (m, 2H, Ar), 8.30-
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 1
39
8.12 (m, 3H, Ar), 7.80-7.65 (m, 2H, Ar), 7.45-7.25 (m, 2H,
Ar), 4.86 (br t, 2H, CH2), 4.31 (s, 3H, N+Me).
Trimethyl-{2-[(phenazine-1-carbonyl)-amino]-ethyl}-
ammonium iodide (2f).
Yield 42%, mp 272-276 °С (EtOH/DMF). 1Н NMR (400
MHz, DMSO-d6) δ 10.55 (br t, 1H, СОNH), 8.67 (d, 1H,
J 7.2 Hz, Ar), 8.45-8.52 (m, 2H, Ar), 8.32 (d, 1H, J 8.0 Hz,
Ar), 8.16-8.05 (m, 3H, Ar), 4.02 (d, 2H, J 6.0 Hz, NHCH2),
3.70 (br t, 2H, CH2N), 3.25 (s, 9H, N+Me3).
Trimethyl-{3-[(phenazine-1-carbonyl)-amino]-propyl}-
ammonium iodide (2g).
Yield 76%, mp 277-280 °С (butanol/DMF). 1Н NMR
(400 MHz, DMSO-d6) δ 10.42 (s, 1H, СОNH), 8.67 (d, 1H,
J 6.0 Hz, Ar), 8.48 (m, 2H, Ar), 8.32 (d, 1H, J 6.8 Hz, Ar),
8.14-8.01 (m, 3H, Ar), 3.62 (br s, 2H, NHCH2), 3.47 (br t,
2H, CH2 N), 2.17 (s, 9H, N+Me3), 2.15 (br t, 2H, CH2).
1-Methyl-3-{[(phenazine-1-carbonyl)-amino]-methyl}-
pyridinium iodide (2i).
Yield 81%, mp 236-238 °С (EtOAc). 1Н NMR (400
MHz, DMSO-d6) δ 10.94 (br t, 1H, СОNH), 9.11 (s, 1H,
Ar), 8.92 (d, 1H, J 6.0 Hz, Ar), 8.73 (d, 1H, J 8.4 Hz, Ar),
8.66 (d, 1H, J 6.8 Hz, Ar), 8.54 (d, 1H, J 8.0 Hz, Ar), 8.48
(d, 1H, J 8.4 Hz, Ar), 8.34 (d, 1H, J 7.6 Hz, Ar), 8.19 (dd,
1H, J 7.2, 6.0 Hz, Ar), 8.12-8.02 (m, 3H, Ar), 4.97 (d, 2H,
J 6.0 Hz, CH2), 4.37 (s, 3H, N+Me).
Trimethyl-{2-[(9-oxo-9H-thioxanthene-4-carbonyl)-
amino]-ethyl}-ammonium iodide (3f).
Yield 39%, mp 267-270 °С (butanol/DMF). 1Н NMR
(400 MHz, DMSO-d6) δ 9.12 (br.t, 1H, СОNH), 8.67 (d,
1H, J 7.6 Hz, Ar), 8.44 (d, 1H, J 7.2 Hz, Ar), 8.06 (d, 1H,
J 6.0 Hz, Ar), 7.85-7.78 (m, 2H, Ar), 7.73-7.69 (m, 1H, Ar),
7.61 (m, 1H, Ar ), 3.75 (d, 2H, J 6.0 Hz, NHCH2), 3.60
(br t, 2H, CH2N), 3.24 (s, 9H, N+Me3).
Trimethyl-{3-[(9-oxo-9H-thioxanthene-4-carbonyl)-
amino]-propyl}-ammonium iodide (3g).
Yield 52%, mp 263-265 °С (EtOH). 1Н NMR (400 MHz,
DMSO-d6) δ 8.90 (br.s, 1H, СОNH), 8.66 (br s, 1H, Ar),
8.43 (br s, 1H, Ar), 8.11 (br s, 1H, Ar), 7.85-7.60 (m, 4H,
Ar), 3.52-3.33 (m, 4H, NHCH2, CH2N), 3.09 (s, 9H,
N+Me3), 2.05 (br t, 2H, CH2)
1-Methyl-3-{[(9-oxo-9H-thioxanthene-4-carbonyl)-
amino]-methyl}-pyridinium iodide (3i).
Yield 81%, mp 228-231 °С (MeOH/DMF). 1Н NMR
(400 MHz, DMSO-d6) δ 9.57 (br t, 1H, СОNH), 9.06 (s,
1H, Ar), 8.93 (d, 1H, J 5.6 Hz, Ar), 8.68 (d, 1H, J 8.0 Hz,
Ar), 8.61 (d, 1H, J 8.4 Hz, Ar), 8.43 (d, 1H, J 8.0 Hz, Ar),
8.23 (d, 1H, J 7.6 Hz, Ar), 8.16 (m, 1H, Ar), 7.85-7.81 (m,
2H, Ar), 7.73 (m, 1H, Ar), 7.62 (m, 1H, Ar), 4.73 (d, 2H,
J 5.6 Hz, CH2), 4.39 (s, 3H, N+Me).
In vitro antitumor assay.
Antiproliferative activity of compounds was evaluated in
the culture of human malignant glioma cells (U87MG line).
The cells were grown in 24-well plastic plates (ТТР,
Switzerland) in CO2-incubator at 37 °C, 5% CO2. The cells
(2x103 per well) were cultured in Dulbecco’s modified
Eagle’s medium (DMEM, Sigma, USA) supplemented with
2.5% fetal bovine serum (Sigma, USA). In 24 h after cell
seeding, tested compounds in DMSO were added to the
culture at concentrations 20, 10, 5, 2, 1 and 0.5 µM (final
drug concentration in the medium) using a serial dilution
approach, and then cells were incubated for 72 h. In all
cases, DMSO content in the medium was 0.2%. Preliminary
experiments confirmed that DMSO at this concentration did
not affect cell growth. The cells cultured in the presence of
0.2% DMSO without drugs were used as a control. After
the incubation of cells with or without drugs, the number of
viable cells in each well was determined using a standard
MTT colorimetric assay [46]. After the treatment wit MTT
reagent, optical density in the wells was measured at
570 nm using BioTek ELx800 plate reader (BioTek, USA).
Using the absorbance measurements, the percent of growth
inhibition as compared with a non-treated control was
calculated for each drug concentration. Growth inhibition
levels were plotted against inhibitor concentrations, and
GI50 parameter (drug concentration giving a 50% growth
inhibition in comparison with a control culture) was
determined for each compound. Each experiment was
performed in triplicate. The data are presented as the mean
(M) ± standard deviation (SD).
Notes
Acknowledgments. The authors are grateful to
Dr. O. Balynska for assistance with biological testing of
compounds.
The authors declare no conflict of interest.
Author contributions. V. G. K.: synthesis of
compounds, investigation. I. V. A.: investigation, NMR
spectra analysis, writing the experimental part (chemistry).
N. A. L.: synthesis of compounds. V. V. N.: biological
experiments, writing the experimental part (biology).
I. Y. D.: supervision, data analysis, writing, and editing the
manuscript.
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Катіонні карбоксамідні похідні трициклічних гетероароматичних сполук: синтез та
попередня оцінка антипроліферативної активності
В. Г. Костіна, І. В. Алексєєва, Н. А. Лисенко, В. В. Негруцька, І. Я. Дубей*
Інститут молекулярної біології і генетики НАН України, вул. Заболотного, 150, Київ, 03680, Україна
Резюме: Метою роботи був синтез і вивчення біологічної активності карбоксамідів трициклічних гетероароматичних систем акридону, феназину
та тіоксантону, що містять катіонні замісники в амідній функції. Вказані гетероциклічні ядра є ДНК-інтеркаляторами, а введення в них катіонних
груп може забезпечити додаткові йонні взаємодії лігандів з їхніми біологічними мішенями, зокрема, ДНК й ферментативними комплексами
системи біосинтезу нуклеїнових кислот. Модифікацію вказаних гетероциклів такими групами зручно здійснювати через карбоксамідні похідні.
Виходячи з цього, було отримано невелику бібліотеку N-заміщених аліфатичних і ароматичних катіонних похідних амідів акридон-4-, феназин-1-
та тіоксантон-4-карбонових кислот. Їх синтезували з виходом 37-81% з використанням м’якої селективної реакції кватернізації йодистим
метилом атомів азоту в N,N-диметиламіноалкільних (алкіл = етил, пропіл) і піридилметильних фрагментах нейтральних N-функціоналізованих
карбоксамідів. При цьому трициклічні ядра не реагують. Розроблено зручний протокол синтезу тіоксантон-4-карбонової кислоти (ТСА), що
ґрунтується на реакції 2-меркаптобензойної та 2-йодбензойної кислот із наступною циклізацією інтермедіату (вихід 79%). Отримано також серію
нових нейтральних N-функціоналізованих амідів ТСА, які є прекурсорами відповідних катіонних карбоксамідів, взаємодією її хлорангідриду з
амінами. Попереднє тестування чотирьох карбоксамідів in vitro як потенційних протипухлинних засобів проводили в культурі клітин U87MG
(злоякісна гліома людини). Сполуки виявили значну антипроліферативну активність у низьких мікромолярних концентраціях; їхні показники
інгібування клітинного росту GI50 знаходяться в межах 1.7-11 мкМ. Отримані дані свідчать про те, що катіонні карбоксаміди трициклічних
гетероароматичних систем є перспективними скафолдами для дизайну нових протипухлинних препаратів.
Ключові слова: акридон; феназин; тіоксантон; карбоксаміди; протипухлинні засоби.
3. Buus, J.; Nielsen, J. Phenazine natural products: biosynthesis, synthetic analogues, and biological activity. Chem. Rev. 2004, 104, 1663-1686.
42. Palmeira, A.; Vasconcelos, M. H.; Paiva, A.; Fernandes, M. X.; Pinto, M.; Sousa, E. Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones. Biochem. Pharmacol. 2012, 83, 57-68.
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| id | oai:ojs2.bioorganica.com.ua:article-6 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:12Z |
| publishDate | 2020 |
| 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/fa/00709a5166fde26b44b3784c848acffa.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-62026-07-19T14:56:52Z Сationic carboxamide derivatives of tricyclic heteroaromatic compounds: synthesis and preliminary evaluation of antiproliferative activity Катіонні карбоксамідні похідні трициклічних гетероароматичних сполук: синтез та попередня оцінка антипроліферативної активності Kostina, Valentina G. Alexeeva, Inna V. Lysenko, Nadia A. Negrutska, Valentina V. Dubey, Igor Y. acridone phenazine thioxanthone carboxamides antitumor agents акридон феназин тіоксантон карбоксаміди протипухлинні засоби This research was aimed at the synthesis and study of biological activity of the carboxamides of tricyclic heteroaromatic systems, acridone, phenazine and thioxanthone, containing the aliphatic and aromatic cationic substituents at amide fragment. These heterocyclic cores are DNA intercalating agents, whereas the introduction of cationic groups provides additional ionic interactions of the ligands with their biological targets, such as DNA and enzymatic complexes of the system of nucleic acids biosynthesis. A convenient way of the introduction of such groups is a modification of heterocyclic carboxamides. A small library of new cationic amide derivatives of acridone-4-, phenazine-1- and thioxanthone-4-carboxylic acids was obtained. They were synthesized in 37-81% yield by mild and selective quaternization of the nitrogen atoms at N,N-dimethylaminoalkyl (alkyl = ethyl, propyl) and pyridylmethyl fragments of the neutral N-functionalized carboxamides with methyl iodide. Tricyclic heteroaromatic cores were not affected. Convenient protocol for the synthesis of thioxanthone-4-carboxylic acid (TCA) based on the reaction of 2-mercaptobenzoic and 2-iodobenzoic acids followed by cyclization of the intermediate was developed (yield 79%). A series of new N-functionalized neutral amides of TCA, the precursors of corresponding cationic carboxamide, were also obtained via the reaction of acyl chloride with amines. Preliminary in vitro testing of four compounds as potential antitumor agents in U87MG tumor cell culture (human malignant glioma) demonstrated their significant antiproliferative activity at low micromolar concentrations, with growth inhibition values GI50 in the range 1.7-11 µM. These results suggest that cationic carboxamides of tricyclic heteroaromatic systems are promising scaffolds for the design of new antitumor drugs. Метою роботи був синтез і вивчення біологічної активності карбоксамідів трициклічних гетероароматичних систем акридону, феназину та тіоксантону, що містять катіонні замісники в амідній функції. Вказані гетероциклічні ядра є ДНК-інтеркаляторами, а введення в них катіонних груп може забезпечити додаткові йонні взаємодії лігандів з їхніми біологічними мішенями, зокрема, ДНК й ферментативними комплексами системи біосинтезу нуклеїнових кислот. Модифікацію вказаних гетероциклів такими групами зручно здійснювати через карбоксамідні похідні. Виходячи з цього, було отримано невелику бібліотеку N-заміщених аліфатичних і ароматичних катіонних похідних амідів акридон-4-, феназин-1- та тіоксантон-4-карбонових кислот. Їх синтезували з виходом 37-81% з використанням м’якої селективної реакції кватернізації йодистим метилом атомів азоту в N,N-диметиламіноалкільних (алкіл = етил, пропіл)  і піридилметильних фрагментах нейтральних N-функціоналізованих карбоксамідів. При цьому трициклічні ядра не реагують. Розроблено зручний протокол синтезу тіоксантон-4-карбонової кислоти (ТСА), що ґрунтується на реакції 2-меркаптобензойної та 2-йодбензойної кислот із наступною циклізацією інтермедіату (вихід 79%). Отримано також серію нових нейтральних N-функціоналізованих амідів ТСА, які є прекурсорами відповідних катіонних карбоксамідів, взаємодією її хлорангідриду з амінами. Попереднє тестування чотирьох карбоксамідів in vitro як потенційних протипухлинних засобів проводили в культурі клітин U87MG (злоякісна гліома людини). Сполуки виявили значну антипроліферативну активність у низьких мікромолярних концентраціях; їхні показники інгібування клітинного росту GI50 знаходяться в межах 1.7-11 мкМ. Отримані дані свідчать про те, що катіонні карбоксаміди трициклічних гетероароматичних систем є перспективними скафолдами для дизайну нових протипухлинних препаратів V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2020-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/6 10.15407/bioorganica2020.01.034 Ukrainica Bioorganica Acta; Vol. 15 No. 1 (2020): Ukrainica Bioorganica Acta; 34-41 Ukrainica Bioorganica Acta; Том 15 № 1 (2020): Ukrainica Bioorganica Acta; 34-41 1814-9766 1814-9758 10.15407/bioorganica2020.01 en https://bioorganica.com.ua/index.php/journal/article/view/6/8 Copyright (c) 2020 Valentina G. Kostina, Inna V. Alexeeva, Nadia A. Lysenko, Valentina V. Negrutska, Igor Y. Dubey https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | акридон феназин тіоксантон карбоксаміди протипухлинні засоби Kostina, Valentina G. Alexeeva, Inna V. Lysenko, Nadia A. Negrutska, Valentina V. Dubey, Igor Y. Катіонні карбоксамідні похідні трициклічних гетероароматичних сполук: синтез та попередня оцінка антипроліферативної активності |
| title | Катіонні карбоксамідні похідні трициклічних гетероароматичних сполук: синтез та попередня оцінка антипроліферативної активності |
| title_alt | Сationic carboxamide derivatives of tricyclic heteroaromatic compounds: synthesis and preliminary evaluation of antiproliferative activity |
| title_full | Катіонні карбоксамідні похідні трициклічних гетероароматичних сполук: синтез та попередня оцінка антипроліферативної активності |
| title_fullStr | Катіонні карбоксамідні похідні трициклічних гетероароматичних сполук: синтез та попередня оцінка антипроліферативної активності |
| title_full_unstemmed | Катіонні карбоксамідні похідні трициклічних гетероароматичних сполук: синтез та попередня оцінка антипроліферативної активності |
| title_short | Катіонні карбоксамідні похідні трициклічних гетероароматичних сполук: синтез та попередня оцінка антипроліферативної активності |
| title_sort | катіонні карбоксамідні похідні трициклічних гетероароматичних сполук: синтез та попередня оцінка антипроліферативної активності |
| topic | акридон феназин тіоксантон карбоксаміди протипухлинні засоби |
| topic_facet | acridone phenazine thioxanthone carboxamides antitumor agents акридон феназин тіоксантон карбоксаміди протипухлинні засоби |
| url | https://bioorganica.com.ua/index.php/journal/article/view/6 |
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