Synthesis and anticancer activity evaluation of 3-(4-oxo-2-thioxothiazolidin-5-yl)-1H-indole-carboxylic acids derivatives

Article abstract of DOI:10.1080/00397911.2020.1786124

A mild and efficient method for the synthesis of 1-oxo-9H-thiopyrano[3,4-b]indole-3-carboxylic acids and dimerized 3-(4-carboxy-1H-3-indolyl)-2-propenoic acids via alkaline hydrolysis of 3-(rhodanin-5-yl)-1H-indole-2-carboxylic acids derivatives was elaborated. Anticancer activity screening in NCI60-cell lines assay allowed identification of 5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-carboxylic acid methyl ester 2a with significant antimitotic activity at micromolar and submicromolar concentrations.

Full text of DOI:10.1080/00397911.2020.1786124

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis and anticancer activity evaluation
of 3-(4-oxo-2-thioxothiazolidin-5-yl)-1H-indole-
carboxylic acids derivatives
Anna Kryshchyshyn-Dylevych, Myroslav Garazd, Andrew Karkhut, Sviatoslav
Polovkovych & Roman Lesyk
To cite this article: Anna Kryshchyshyn-Dylevych, Myroslav Garazd, Andrew Karkhut, Sviatoslav
Polovkovych & Roman Lesyk (2020): Synthesis and anticancer activity evaluation of 3-(4-oxo-2-
thioxothiazolidin-5-yl)-1H-indole-carboxylic acids derivatives, Synthetic Communications, DOI:
10.1080/00397911.2020.1786124
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1786124
Synthesis and anticancer activity evaluation of 3-(4-oxo-2-
thioxothiazolidin-5-yl)-1H-indole-carboxylic acids
derivatives
Anna Kryshchyshyn-Dylevycha , Myroslav Garazdb, Andrew Karkhutc,
Sviatoslav Polovkovychc, and Roman Lesyka,d
aDepartment of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National
b
c
Medical University, Lviv, Ukraine; Eximed, Kyiv, Ukraine; Department of Technology of Biologically
Active Substances, Pharmacy and Biotechnology, Lviv Polytechnic National University, Lviv, Ukraine;
dDepartment of Public Health, Dietetics and Lifestyle Disorders, Faculty of Medicine, University of
Information Technology and Management in Rzeszow, Rzeszow, Poland
ABSTRACT
ARTICLE HISTORY
Received 4 May 2020
A mild and efficient method for the synthesis of 1-oxo-9H-thiopyrano
[3,4-b]indole-3-carboxylic acids and dimerized 3-(4-carboxy-1H-3-
indolyl)-2-propenoic acids via alkaline hydrolysis of 3-(rhodanin-5-yl)-
1H-indole-2-carboxylic acids derivatives was elaborated. Anticancer
activity screening in NCI60-cell lines assay allowed identification of
5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-car-
boxylic acid methyl ester 2a with significant antimitotic activity at
micromolar and submicromolar concentrations.
KEYWORDS
Anticancer activity; indoles;
Knoevenagel reaction; ring
transformations; 2-thioxo-4-
thiazolidinones
GRAPHICAL ABSTRACT
OH
O
O
R2
OH
O
R3
O
N
R4
OH
NH
S
S
S
S
S
HO
O
R1 = H
R2 = COOMe
R4
R1 = COOH,
N
R4
R1
O
R3
COOMe
N
R2 = H
NH
3
4
2a R1 = COOMe, R3 = F, R2 = R4 = H
mean GI50 = 0.45/0.65 µM (DTP NCI)
O
HO
Introduction
Among a variety of pharmacologically active nitrogen heterocycles, molecules bearing
indole moiety represent a widely distributed class of natural compounds with biological
significance.[1–3] Moreover, the indole system comprises one of the essential parts of dif-
ferent synthetic and semisynthetic drugs as well as compounds with diverse pharmaco-
logical profiles.[4] Recently indole derivatives have been attracting researchers as a
source of possible anticancer agents[5–7] as well as compounds possessing antiviral[8]
CONTACT Roman Lesyk
dr_r_lesyk@org.lviv.net
Department of Pharmaceutical, Organic and Bioorganic
Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
A. KRYSHCHYSHYN-DYLEVYCH ET AL.
O
CH3
CH3
OH
H
N
N
HN
N
CONHOH
OH
O
Apaziquone
Panabinostat
H3C
F
H3C
O
N
N
H
CH3
N
H
CH3
N
O
Sunitinib
H
Figure 1. Examples of antineoplastic drugs based on the indole core.
and other types of biological activity.[9] Moreover, several synthetic and natural-derived
indole derivatives were developed as active anticancer agents that inhibit tubulin poly-
merization.[10] The approved anticancer drugs based on the indole system with other
modes of action are: Apaziquone—an indol alkylating agent used for bladder cancer
treatment, Panabinostat—used for multiple myeloma treatment as nonselective histone
deacetylase inhibitor, tyrosine kinase inhibitor Sunitinib (Figure 1). Novel aryl-substi-
tuted N-hydroxyindole-2-carboxylates were reported as “first-in-class” inhibitors of
human lactate dehydrogenase (hLDH5) that constitutes a relatively new and untapped
anticancer target.[11]
Development of efficient, easy to conduct methods for the synthesis of different kinds
of molecules bearing indole core is an important task for the medicinal chemistry.
Taking into account rich pharmacological profile of thiazolidinone derived com-
pounds,[12–14] the investigation of hybrid molecules combining above-mentioned cores
with indole ring is quite promising direction and may lead to novel potent antimicro-
bial, antiparasitic and/or anticancer agents. An additional argument in favor of the
indole analogs had become the results of their anti-trypanosomal activity study that
allowed identifying the hit compounds with nanomolar IC50 values.[15] Moreover, these
compounds showed low cytotoxicity upon human primary fibroblasts as well as rela-
tively low acute toxicity. It should be mentioned that the thiazolidinone fragment in
molecules may facilitate further chemical optimization of the hit compounds.
Results and discussion
The starting 2-methoxycarbonyl-indole-3-carboxaldehyde 1a was synthesized from the
corresponding indoles by Vilsmeier-Haack formylation with POCl3 and N,N-dimethyl-
formamide. The 3-formylindole-2-carboxylic acids 1 b,c were obtained in the hydrolysis
reaction of appropriate 2-methoxycarbonyl-indole-3-carboxaldehydes as described else-
where (Scheme 1).[16]
The target 3-(4-oxo-2-thioxothiazolidine-5-yl)-1H-indole-2-carboxylic acids’ deriva-
tives 2a-c (Scheme 2) and 4a,b (Scheme 3) were synthesized in the Knoevenagel con-
densation of the indole-3-carboxaldehydes with 2-thioxo-4-thiazolidinone (rhodanine).
The reaction proceeds in the acetic acid medium in the presence of sodium acetate
under reflux for 3–4 h.
Further modification included the hydrolysis of compounds 2a–c that gave fused
tricyclic derivatives
ꢀ
1-oxo-9H-thiopyrano[3,4-b]indole-3-carboxylic acids 3a–c.

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3
CHO
CHO
R1
R1
R1
O
O
O
a
b
N
OMe
N
H
N
OH
OMe
H
H
1b R1 = H
1a R1 = F
1c R1 = OMe
Scheme 1. Synthesis of the starting 3-formylindolines 1a–c. Reagents and conditions: (a) appropriate
methyl indole-2-carboxylate (0.15 mol), POCl3 (12mL, 0.16 mol), DMF (10 mL), 30 min (r.t.), 40–60 ꢁC
(4 h), aqueous NaOH to pH 5–6, 85–89%; (b) appropriate methyl 3-formylindole-2-carboxylate
(0.15 mol), KOH (8.4g, 0.15 mol) in H2O (50 mL), EtOH (50 mL), 3 h (r.t.), diluted HCl to pH
5–6, 89–92%.
O
CHO
R1
R1
O
O R2
O
NH
N
H
S
O
NH
S
S
2a R1 = F, R2 = OCH3
S
N
c
2b R1 = R2 = H
H
R2
O
2c R1 = OCH3, R2 = H
1) NaOH
2) HCl
d
R1
R1
O
O
OH
OH
SH
OH
S
3a R1 = F
3b R1 = H
N
N
H
H
O
3c R1 = OCH3
O
Scheme 2. Synthesis of 3-(4-oxo-2-thioxothiazolidin-5-yl)-1H-indole-2-carboxylic acids derivatives 2a–c
and products of their transformations 3a–c. Reagents and conditions: (c) 4-thioxo-2-thiazolidinone
(0.01 mol), 1a–c (0.010 mol), AcONa (0.01), AcOH (20mL), reflux, 2 h, 64–80%; (d) 2a–c (0.01 mol),
NaOH (1.4 g, 0.035 mol) in H2O (5 mL), 30 min, reflux, conc. HCl (4 mL, 0.035mol), 60–78%.
According to the data about alkaline hydrolysis of related rhodanines,[17,18] the reaction
goes through the formation of appropriate 3-substituted-2-mercaptoacrylic acids that
undergo spontaneous heterocyclization to form target compounds 3a–c (Scheme 2).
Utilizing the methyl 3-formyl-1H-indole-4-carboxylates with rhodanine in
Knoevenagel reaction, we aimed at synthesis of 7-membered ring systems 6a,b.
Interestingly, that the hydrolysis reaction of the 4a,b did not proceed as expected. The
3-(1H-3-indolyl)-2-mercaptoacrylic acids derivatives linked by the disulfide bridge 5a,b
were obtained instead (Scheme 3). The hydrolysis was performed in the presence of
30% NaOH solution under reflux for 30 min.
To evaluate the possibility of the formation of 7-membered cycle (6a,b) the changes
of reactions Gibbs free energy were calculated on DFT level (Table 1). All reported geo-
metries and energies were obtained using hybrid M06-2X[19] functional with 6-
311 G(d,p) basis set included in the GAUSSIAN 09 Rev.01D[20] program in PCM[21]
solvation model (water). For optimized structures confirmation of reaching a minimum
and thermochemical data were obtained using vibrational analysis on the same level.

4
A. KRYSHCHYSHYN-DYLEVYCH ET AL.
O
O
H3C
O
H3C
CHO
O
O
O
4a R3 = CH3
4b R3 = C2H5
N
NH
S
NH
S
R3
S
S
N
R3
c
R3
1) NaOH
2) HCl
d
O
N
OH
OH
HO
O
S
OH
O
O
O
S
O
OH
O
S
HO
R3
SH
O
N
N
R3
R3
HO
N
6a R3 = CH3
6b R3 = C2H5
5a R3 = CH3
5b R3 = C2H5
Scheme 3. Synthesis of 3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-4-carboxylic acid
derivatives 4a,b and products of their transformations 5a,b. Reagents and conditions: (c) 4-thioxo-2-
thiazolidinone (0.01 mol), methyl 3-formyl-1H-indole-4-carboxylate (0.010mol), AcONa (0.01), AcOH
(20 mL), reflux, 2 h, 84–90%; (d) 4a,b (0.01 mol), NaOH (1.4 g, 0.035 mol) in H2O (5 mL), 30 min, reflux,
conc. HCl (4 mL, 0.035 mol), 79–80%.
Table 1. Relative Gibbs free energies for the reac-
tion products.
Calculated product
DGrxn, kcal/mol
3a
3b
3c
6a
6b
ꢀ10.1
ꢀ10.8
ꢀ10.5
þ1.5
þ1.7
Both compounds with 6- (3a-c) and 7- (6a,b) membered cycles are predicted to be flat
due to the formation of conjugative system. Accordingly, the 7-membered cycle is
strained and therefore energetically unfavorable. DG of cyclization is ꢀ10.8 to
ꢀ10.1 kcal/mol for six-membered and þ1.5, þ1.7 kcal/mol for seven-membered cycle.
Thus, first cyclization is thermodynamically favorable unlike second cyclization where
equilibrium is shifted to the starting compound. It causes passing the competitive reac-
tion of oxidative dimerization in disulfide.
Antitumor activity studies were performed for the compounds 2a,c, 3a,c, 5a according to
the NCI DTP (USA) standard protocol.[22–25] In the first (prescreening) stage the com-
pounds were tested at one dose assay (10ꢀ5 M) toward a panel of approximately sixty cancer
cell lines representing different types of cancer (leukemia, melanoma, lung, colon, CNS,
ovarian, renal, prostate and breast cancers). The highest growth inhibition rates were
observed for the methyl 5-fluoro-3-[(4-oxo-2-thioxothiazolidin-5-ylidene)methyl]-1H-
indole-2-carboxylate 2a. The other compounds were inactive (ESI, Supplementary Table
S1). Interestingly, the replacement of the fluorine atom by a methoxy group in structurally

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5
Table 2. The influence of compound 2a on the growth
of some individual tumor cell lines.
Cell line (disease)
GI50, mMa
K-562 (leukemia)
NCI-H460
NCI-H522
HCT-116
HCT-15
SW-620
SF 539 (CNS cancer)
SNB-75
M14 (melanoma)
MDA-MB-435 (melanoma)
OVCAR-3
NCI/ADR-RES (ovarian cancer)
ACNH (renal cancer)
RXF 393 (renal cancer)
HS 578T (breast cancer)
0.0413/0.0490
0.0901/0.0717
0.0266/0.0496
0.0431/0.0507
0.0615/0.0715
0.0489/0.0509
0.0903/0.0611
0.0211/0.0429
0.0537/0.0550
0.0216/0.0251
0.0479/0.0407
0.0768/0.0646
0.0577/0.0841
0.0636/0.0912
0.060/0.0448
aCompound was tested twice.
similar derivatives or the transition from a rhodanine derivatives to 9H-thiopyrano[3,4-
b]indoles resulted in the complete loss of activity. This phenomenon needs a detailed study.
Compound 2a was selected for the in-depth screening at concentrations ranging from
10ꢀ4 to 10ꢀ8 M. Two independent experiments were performed toward 59 and 58 cell
lines, respectively (Table 2, ESI, Supplementary Table S2). Compound 2a inhibited
growth of all tested cancer cell lines at submicromolar and micromolar concentrations.
The average meanings of three dose-response parameters: GI50 (molar concentration of
the compound that inhibits 50% net cell growth), TGI (molar concentration of the com-
pound leading to the total inhibition) and LC50 (molar concentration of the compound
leading to 50% net cell death) were 0.45/0.65 mM, 31.50/44.02 mM and 91.96/93.66 mM,
respectively. It is important to note that the compound 2a was active in the
concentration range of 0.02–0.09 lM toward the following cell lines: K-562 (Leukemia);
NCI-H-460, NCI-H522 (Non-Small Cell Lung cancer) HCT-116, HCT-15, SW-620
(Colon cancer); SNB-75, SF 539 (CNS cancer); M14, MDA-MB-435 (Melanoma);
OVCAR-3, NCI/ADR-RES (Ovarian cancer); ACNH, RXF 393 (Renal cancer); HS 578 T
(Breast cancer).
The selectivity indices for 2a were calculated by dividing the full panel MG_MID
(lM) of the 2a by the individual parameter’s value for each cell line (lM). Ratios
between 3 and 6 mean moderate selectivity, ratios greater than 6 indicate high selectiv-
ity toward the corresponding cell line, while compounds not meeting either of these cri-
teria are rated nonselective.[26] At GI50 level 2a selectively inhibited growth of 12 cancer
cell lines, for which the SI were more than 6 in both assays. Moreover, the selectivity
indices calculated at TGI level were from 12.80 to 605.8 for 4 cell lines (ESI,
Supplementary Table S2). The best SI values, taking into account two above-mentioned
parameters calculated in two assays, were observed for the lines: NCI-H522 (Non-Small
Cell Lung cancer) and MDA-MB-435 (Melanoma).
NCI’s COMPARE algorithm allows to predict biochemical mechanisms of action of
the novel compounds on the basis of their in vitro activity profiles comparing to those
of the standard agents. For the compound 2a the COMPARE analysis[23–25]

6
A. KRYSHCHYSHYN-DYLEVYCH ET AL.
computations were performed against the NCI “Standard Agents” database at the GI50
and TGI levels (ESI, Supplementary Table S3). Values of the Pearson correlation coeffi-
cients (PCC) higher than 0.5 were chosen as noteworthy. However, the calculated
Pearson correlation coefficients (PCC) did not allow prediction of cytotoxicity mechan-
ism of the tested compound 2a with high probability (ESI, Supplementary Table S3).
Although, the highest values of PCC (PCC ꢂ 0.50) at GI50 level were observed for pyr-
imidine biosynthesis inhibitors Brequinar and Dichloroallyl Lawsone, inhibitors of DNA
synthesis Emofolin sodium and 5-Azacytidine; at TGI level the best correlation was
with Maytansine that acts on microtubules, with the Vinblastine and Vincristine and
with tubulin polymerization inhibitor Rhizoxin.
Conclusions
In summary, we have developed an efficient procedure for the synthesis of 1-oxo-9H-
thiopyrano[3,4-b]indole-3-carboxylic acids and 2-[1-carboxy-2-(4-carboxy-1H-3-
indolyl)-1-ethenyldisulfanyl]-3-(4-carboxy-1H-3-indolyl)-2-propenoic acids via the
alkaline hydrolysis of 3-(4-oxo-2-thioxothiazolidine-5-yl)-1H-indole-2-carboxylic acids
derivatives. Synthesized 4-thiazolidinone-indole hybrid molecules and their derivatives
might be a useful source of drug-like molecules and are interesting reagents for further
chemical transformations.
Experimental
All reagents and solvents were purchased from commercial suppliers and were used directly
without further purification. NMR spectra were determined with Varian Unity Plus 400
(400 MHz) and Bruker 170 Avance 500 (500 MHz) spectrometers, in DMSO-d6 and CDCl3
using tetramethylsilane (TMS) as an internal standard. Melting points were measured on a
Kofler hot-stage and are uncorrected. LC-MS was performed using a system with an Agilent
1100 Series HPLC equipped with diode-array detector and Agilent LC\MSD SL mass-select-
ive detector using chemical ionization at atmospheric pressure (APCI).
General procedure of 3-(4-oxo-2-thioxothiazolidin-5-yl)-1H-indole-2-carboxylic
acids derivatives 2a-c, 4a,b synthesis
A mixture of appropriate 3-formyl-1H-indole-carboxylic acid or corresponding methyl
ester (0.01 mol) and 4-thioxo-2-thiazolidinone (0.01 mol) in the medium of acetic acid
(20 mL) and the presence of sodium acetate (0.01 mol) was refluxed for 2 h. Obtained
solid product was collected after cooling by filtration and recrystallized from acetic acid.
5-Fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-carboxylic
acid
1
methyl ester (2a). Yield: 64%, mp 240–242 ꢁC. H NMR (400 MHz, DMSO-d6): d (ppm)
3.93 (s, 3H, OMe), 7.29 (dt, 1H, J ¼ 2.3, 9.1 Hz, arom.), 7.54 (dd, 1H, J ¼ 2.2, 10.1 Hz,
arom.), 7.57 (dd, 1H, J ¼ 4.7, 9.1 Hz, arom.), 8.21 (s, 1H, ¼CH), 12.88 (s, 1H, NH),
13.73 (br.s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d (ppm) 52.9 (OCH3), 106.5 (d,
6-Cind, JCF ¼ 24.6 Hz), 115.0 (d, 7-Cind, JCF ¼ 5.0 Hz), 115.2, 115.4, 115.6 (d, 4-Cind
,
JCF¼10.3 Hz), 124.2, 124.3, 128.9, 133.7 (¼CH), 153.6 (d, 6-C, JCF ¼ 236.5 Hz), 161.1

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SYNTHETIC COMMUNICATIONSV
7
(C¼O), 169.4 (COO), 195.6 (C¼S). LCMS (ESI): m/z 337 (100.0%, [M þ H]þ). Anal.
calcd. for C14H9FN2O3S2: C 49.99%; H 2.70%; N 8.33%. Found: C 49.70%; H 2.40%;
N 8.60%
General procedure of 1-oxo-9H-thiopyrano[3,4-b]indole-3-carboxylic acids 3a-c
and (Z)-2-[(Z)-1-carboxy-2-(4-carboxy-1H-3-indolyl)-1-ethenyldisulfanyl]-3-(4-
carboxy-1H-3-indolyl)-2-propenoic acids 5a,b synthesis
3-(4-Oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-carboxylic acid or correspond-
ing methyl ester (0.01 mol) was stirred with the aqueous solution of NaOH (0.035 mol)
and refluxed for 30 min. The reaction mixture was then cooled and neutralized with
HCl concentrated solution (0.035 mol). Products of the hydrolysis reactions were col-
lected by filtration, washed with water, dried and crystallized from the mixture of DMF/
ethanol (1:5) or acetic acid (for 3b).
6-Fluoro-1-oxo-9H-thiopyrano[3,4-b]indole-3-carboxylic acid (3a). Yield: 60%, mp
1
227–229 ꢁC. H NMR (DMSO-d6): d (ppm) 7.41 (t, 1H, J ¼ 8.5 Hz, arom.), 7.60 (dd,
1H, J ¼ 3.0, 8.5 Hz, arom.), 8.71 (d, 1H, J ¼ 8.5 Hz), 8.79 (s, 1H, ¼CH), 12.96 (s, 1H,
NH), 13.89 (br.s, 1H, COOH). 13C NMR (100 MHz, DMSO-d6): d (ppm) 106.7 (d, 7-C,
JCF ¼ 24.3 Hz), 114.9 (d, 8-C, JCF ¼ 9.5 Hz), 117.2 (d, 5-C, JCF ¼ 27.0 Hz), 123.2 (4-C),
123.9 (d, 8a-C, JCF ¼ 5.0 Hz), 124.6 (d, 4 b-C, JCF ¼ 11.0 Hz), 126.3 (3-C), 132.0 (4a-C),
135.4 (9a-C), 158.0 (d, 6-C, JCF ¼ 236.8 Hz), 163.7 (COOH), 176.4 (C ¼ O). LCMS (ESI):
m/z 264 (100.0%, [M þ H]þ). Anal. calcd. for C12H6FNO3S: C 54.75%; H 2.30%; N
5.32%. Found: C 54.60%; H 2.50%; N 5.50%.
2-[1-Carboxy-2-(4-carboxy-1-methyl-1H-3-indolyl)-1-ethenyldisulfanyl]-3-(4-carboxy-1-
methyl-1H-3-indolyl)-2-propenoic acid (5a). Yield: 80%, mp 232–233 ꢁC. 1H NMR
ꢃ
(DMSO-d6): d (ppm) 3.83 (s, 6H, 2 CH3), 7.26 (t, 2H, J ¼ 7.3 Hz, arom.), 7.60 (d, 2H,
ꢃ
J ¼ 7.6 Hz, arom.), 7.67 (d, 2H, J ¼ 8.0 Hz, arom.), 8.59 (s, 2H, 2 ¼CH), 8.85 (s, 2H,
2 NH), 12.82 (br.s, 4H, 4 COOH). 13C NMR (100 MHz, DMSO-d6): d (ppm) 33.8
(CH3), 109.9, 115.0, 119.6, 122.0, 124.2, 125.2, 125.3, 136.1, 137.8, 142.6 (¼C–S), 168.1
(COOH), 169.8 (COOH). LCMS (ESI): m/z 551 (96.5%, [M–H]þ). Anal. calcd. for
C26H20N2O8S2: C 56.51%; H 3.65%; N 5.07%. Found: C 56.70%; H 3.45%; N 5.25%.
Supplementary data (spectral and analytical data for compounds 1a–c, 2b,c 3b,c, 4a,b
and 5b, anticancer activity data for compounds 2a,c, 3a,c and 5a) associated with this
article can be found, in the online version, at http://dx.doi.org/xxxxxxxxxxx.
ꢃ
ꢃ
Acknowledgements
We are grateful to Dr. G. Morris from Drug Synthesis and Chemistry Branch, National Cancer
Institute, Bethesda, MD, USA, for in vitro evaluation of anticancer activity. Authors express their
deep gratitude to the STC “Institute for Single Crystals” NAS of Ukraine for the provided soft-
ware and computational facilities.
ORCID
Anna Kryshchyshyn-Dylevych
http://orcid.org/0000-0002-8713-7020
Roman Lesyk http://orcid.org/0000-0002-3322-0080

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A. KRYSHCHYSHYN-DYLEVYCH ET AL.
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