Diversity-oriented synthesis of spirothiazolidinediones and their biological evaluation

Article abstract of DOI:10.3762/bjoc.15.269

We report a new synthetic approach to assemble spirothiazolidinediones via a [2 + 2 + 2] cyclotrimerization reaction and the derivatives were further functionalized through DA chemistry and click reaction. Using flow cytometry, it was shown for the first

Full text of DOI:10.3762/bjoc.15.269

Diversity-oriented synthesis of spirothiazolidinediones and
their biological evaluation
Sambasivarao Kotha*1, Gaddamedi Sreevani1, Lilya U. Dzhemileva2,3,
Milyausha M. Yunusbaeva2, Usein M. Dzhemilev2 and Vladimir A. D’yakonov2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2774–2781.
1
Department of Chemistry, Indian Institute of Technology Bombay,
doi:10.3762/bjoc.15.269
Powai, Mumbai 400 076, India, 2Laboratory of Catalytic Synthesis,
Institute of Petrochemistry and Catalysis, Russian Academy of
Sciences, Prospect Octyabrya, 141, 450075, Ufa, Russian
Federation, and 3Department of Immunology and Human
Received: 24 July 2019
Accepted: 04 November 2019
Published: 18 November 2019
Reproductive Health Bashkir State Medical University, Lenin Street, 3,
450003, Ufa, Russian Federation
Associate Editor: T. J. J. Müller
Email:
© 2019 Kotha et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Sambasivarao Kotha* - srk@chem.iitb.ac.in
*
Corresponding author
Keywords:
apoptosis; biologically active; [2 + 2 + 2] cycloaddition; flow cytometry;
spiro thiazolidinedione
Abstract
We report a new synthetic approach to assemble spirothiazolidinediones via a [2 + 2 + 2] cyclotrimerization reaction and the deriv-
atives were further functionalized through DA chemistry and click reaction. Using flow cytometry, it was shown for the first time
that the new benzyl alcohol derivatives of thiazolidine-2,4-dione generated here are efficient apoptosis inducers in the HeLa,
Hek293, U937, Jurkat, and K562 cell lines.
Introduction
Heterocyclic compounds play a vital role in the metabolism of reductase inhibitors (ARI) [6,7], anti-inflammatory [8,9], anti-
all living cells. Thus, most of the biologically active and phar- arthritics [10], anticancer [11-13] and antimicrobial [14-18],
maceutically important compounds consist of heterocycles etc., has made them an indispensable anchor for the develop-
[
1-4]. Especially, thiazolidinediones (TZDs) are important ment of new therapeutic agents [19-24]. Thiazolidinedione de-
heterocyclic compounds. In 1954, Visentini reported the first rivatives, such as rosiglitazone, pioglitazone and troglitazone,
ever pharmacological evaluation of a thiazolidinedione deriva- etc., are members of the glitazone family of drugs, used for the
tive, i.e., its anti-TB activity [3]. The promising activity shown treatment of diabetes as potent agonists of the γ-peroxisome
by the compounds containing a thiazolidinedione nucleus cover proliferator activated receptor (PPARγ) [23,24]. The discovery
numerous categories such as antihyperglycaemics [5], aldose of biological activities of TZDs and the development of medici-
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Beilstein J. Org. Chem. 2019, 15, 2774–2781.
nal and pharmaceutical chemistry has led to an enhanced cyclotrimerization strategy with different propargyl halides 6 to
interest in the design of new synthetic methods for the prepara- obtain spirothiazolidinedione derivatives (Scheme 4).
tion of various TZDs. The most conventional method of synthe-
sis of thiazolidinedione derivatives is refluxing chloroacetic
acid (2) with thiourea (1), followed by a Knoevenagel conden-
sation with an aldehyde (Scheme 1) [25].
Results and Discussion
Limited reports are available dealing with the synthesis of spiro
derivatives of thiazolidine-2,4-diones [26-28]. In view of the
importance of thiazolidine-2,4-dione derivatives, we conceived
Scheme 3: Unexpected product 5b obtained in the attempted
NH-protection of thiazolidinedione with (Boc)2O.
a new synthetic strategy to diverse spirocyclic thiazolidine-
diones based on a [2 + 2 + 2] cyclotrimerization [29-51] as a
key step.
In this regard, the required diyne precursor of thiazolidinedione
was prepared from N-methylthiazolidine-2,4-dione (5a) and
propargyl bromide (6a) in the presence of K2CO3 in DMF to
afford the dipropargylated intermediate thiazolidinedione 7a in
Figure 1: Comparison of 13C NMR values of 9 and 5b.
8
5% yield. Diyne 7a was then reacted with propargyl bromide
6a) in the presence of Mo(CO)6 in acetonitrile at 90 °C under
microwave irradiation (MWI) conditions to give the co-trimer- Further, the dibromo N-methyl derivative of thiazolidinedione
(
ized spiro derivative 8a (Scheme 2).
8b was converted to sultine 13 using rongalite and tetra-n-butyl-
ammonium bromide (TBAB) in DMF. Then, sultine 13 was
The free NH moiety of thiazolidinedione 3 was alkylated using treated with different dienophiles 14 in a DA fashion and
alkyl or aryl halides in the presence of Et3N using DCM as sol- linearly fused spirocyclic derivatives 15 were isolated in good
vent. To our surprise, during an attempted protection with yields (Scheme 5).
(
Boc)2O, we obtained N-tert-butylthiazolidinedione 5b rather
than the expected N-Boc-protected thiazolidinedione 9 as re- Since TZDs are pharmaceutically important targets, we
ported by Paladhi et al. [52] (Scheme 3). The formation of com- intended to prepare spirocyclic derivatives of thiazolidinedione.
pound 5b was confirmed on the basis of spectral data. We ob- In this context, N-carboxy ester and N-propargyl derivatives of
served only two peaks in the carbonyl region of the 13C NMR thiazolidinedione were prepared, which on further modification,
spectrum and no third carbonyl peak (Figure 1). Finally, mass can generate new derivatives suitable for the multiple interac-
spectral (HRMS) data confirmed the molecular formula. Next, tion sites. Further, the antitumour activity of these compounds
we prepared the diyne precursors and examined the [2 + 2 + 2] were studied.
Scheme 1: Conventional method of synthesis of thiazolidine-2,4-dione derivatives.
Scheme 2: [2 + 2 + 2] Cyclotrimerization of N-methylthiazolidinedione.
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Beilstein J. Org. Chem. 2019, 15, 2774–2781.
Scheme 4: [2 + 2 + 2] Cyclotrimerization of dipropargylthiazolidinediones with propargyl halides.
Scheme 5: Formation of sultine 13 from compound 8b followed by DA reaction.
Therefore, we synthesized the required diyne derivatives of yields. During the [2 + 2 + 2] cycloaddition of compound 7e
thiazolidinedione for [2 + 2 + 2] cycloaddition, in the presence with 3-butyn-1-ol (16b) we were able to isolate the self trimer-
of propargyl bromide and K2CO3 in DMF. The dipropargyl de- ized derivative 20 as a minor product (Scheme 7).
rivatives 7e and 7f were then treated with different propargyl
alcohols 16 in the presence of Wilkinson’s catalyst/Ti(OiPr)4 The ester derivative of thiazolidinedione 18 was hydrolyzed
under ethanol reflux conditions [53] to obtain the correspond- under AcOH, HCl reflux conditions to obtain N-acid derivative
ing [2 + 2 + 2] cyclotrimerized alcohols 17–19 and 21 in good 22 in 90% yield (Scheme 8) [54].
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Beilstein J. Org. Chem. 2019, 15, 2774–2781.
Scheme 6: Dipropargylation of 2,4-thiazolidinedione derivatives.
Scheme 7: [2 + 2 + 2] Cycloaddition in the presence of Wilkinson’s catalyst.
Scheme 8: N-Ester derivative 18 hydrolysis to N-acid derivative 22.
Fused 1,2,3-triazoles represent an important class of nitrogen- click chemistry using 4-nitrophenyl azide (23) and the corre-
containing biologically active compounds which exhibit various sponding triazolo alcohol derivative 24 was obtained as yellow
biological properties, such as antiviral, antibacterial and anti- solid in 80% yield (Scheme 9) [58].
cancer, etc. [55-58]. Recently, the use of 1,2,3-triazole deriva-
tives as drug candidates has been increased for clinical therapy All alcohol derivatives of thiazolidinedione were used to study
of various diseases. Hence, we also modified the N-propargyl the cytotoxic activity in comparison with camptothecin and
alcohol derivative 21 to 1,2,3-triazolo alcohol derivative 24 by etoposide on Jurkat, K562, HEK293, HELA, A549 and U937
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Beilstein J. Org. Chem. 2019, 15, 2774–2781.
Scheme 9: Synthesis of triazolo derivative 24 via click reaction.
cell lines. Compounds 20 and 17 showed the highest activity using a Bruker (Maxis Impact) or a Micromass Q-ToF spec-
IC50 = 0.29 and 0.36 nM, respectively) for leukemic mono- trometer. The melting points recorded are uncorrected. The
(
cytic lymphoma cells (U937), and 22 was active against T-cell microwave used here was a Discover® SP by CEM Corpora-
leukemia (Jurkat) with an IC50 value of 0.34 nM. Further, these tion and all the microwave reactions were performed under the
three compounds (22, 20 and 17) were used to study apoptosis standard method, where time and temperature can be moni-
and the cell cycle in cells of the corresponding cell cultures. tored manually.
The highest percentage of apoptosis was observed when com-
pound 22 was added to the culture of Jurkat cells at a concentra- Cell culture: Cells (Jurkat, K562, U937) were purchased from
tion of 0.75 nM and was 68.65%. Under similar conditions, the Russian Cell Culture Collection (Institute of Cytology of the
compound 20 showed about 95% in K562 cells of late apopto- Russian Academy of Sciences) and cultured according to stan-
sis and compound 17 about 30.28% for cell line U937. The dard mammalian tissue culture protocols and sterile technique.
results of flow cytometry showed that in all three cell lines, Human cancer cell lines HEK293 and HeLa were obtained from
Jurkat, K562 and U937, a hypodiploidal DNA peak appears the HPA Culture Collections (UK). All cell lines used in the
2
4 hours after the action of compounds 22, 20 and 17, which study were tested and shown to be free of mycoplasma and viral
shows the inability to stop the fission cycle at the checkpoints, contamination.
and ultimately, leads to cell death.
Cell culture was performed in a similar manner as described in
[59]. HEK293 and HeLa cell lines were cultured as monolayers
Conclusion
In summary, we have synthesized spirothiazolidinedione deriv- and maintained in Dulbecco’s modified Eagle’s medium
atives via a [2 + 2 + 2] cyclotrimerization strategy with (DMEM, Gibco BRL) supplemented with 10% foetal bovine
propargyl halides. We have also shown the synthesis of linearly serum and 1% penicillin streptomycin solution at 37 °C in a
fused spirocyclic alcohol derivatives of thiazolidinedione using humidified incubator under a 5% CO2 atmosphere.
Wilkinson’s catalyst and these compounds were tested for their
anticancer activity. We have shown for the first time that the Cells were maintained in RPMI 1640 (Jurkat, K562, U937)
new benzyl alcohol derivatives of thiazolidinedione generated (Gibco) supplemented with 4 mM glutamine, 10% FBS (Sigma)
here are efficient apoptosis inducers in the HeLa, Hek293, and 100 units/mL penicillin streptomycin (Sigma). All types of
U937, Jurkat, and K562 cell lines.
cells were grown in an atmosphere of 5% CO2 at 37 °C. The
cells were subcultured at 2–3 days intervals. Adherent cells
(HEK293, HeLa) were suspended using trypsin/EDTA and
Experimental
General: All commercially available products were used as counted after they have reached 80% confluency. Cells were
received without further purification and moisture-sensitive then seeded in 24 well plates at 5 × 104 cells per well and incu-
reagents were transferred by using syringe–septum techniques. bated overnight. Jurkat, K562, U937 cells were subcultured at
All the solvents used as reaction media were dried over oven- 2 day intervals with a seeding density of 1 × 105 cells per
dried molecular sieves (4 Å). Column chromatography was per- 24 well plates in RPMI with 10% FBS.
formed with silica gel (100–200 mesh) using mixtures of petro-
leum ether and EtOAc as eluent. 1H NMR and 13C NMR spec- MTT Assay: The MTT assay is a colorimetric assay for evalua-
tral data were recorded with 400 MHz and 100 MHz or tion of cell metabolic activity. The NADPH-dependent cellular
5
(
00 MHz and 125 MHz spectrometers using tetramethylsilane oxidoreductases present in the living cell can reflect, under
TMS) as an internal standard and chloroform-d as a solvent. certain conditions, the cell viability. These enzymes can reduce
High resolution mass spectrometry (HRMS) was performed the tetrazolium dye, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-
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Beilstein J. Org. Chem. 2019, 15, 2774–2781.
2
H-tetrazolium bromide (МТТ) or yellow tetrazole, to give distinguish four types of cells: living cells (annexin V−/PI−),
insoluble formazan, which develops purple color particularly in early apoptosis (annexin V+/PI−), late apoptosis (annexin V+/
living cells. Thus, the color gradient can serve to determine the PI+), and necrosis (annexin V−/PI+).
degree of cytostatic activity (shift from proliferation to
dormancy) of drug candidates and toxic compounds. In vitro Apoptosis was quantified by the detection of phos-
cytotoxicity was assessed using a standard MTT colorimetric phatidylserine surface exposure on apoptotic cells using an
assay in a similar manner as described in [60,61]. HEK293 cells Alexa Fluor® 488 Annexin V/Dead Cell Apoptosis Kit.
were plated in 96-well microassay culture plates (1 × 104 cells HEK293 cells were incubated with or without the testing com-
per well) and grown overnight at 37 °C in a 5% CO2 incubator. pound for 24 h. The adherent and floating cells were collected
The cells were then incubated with the test compounds at differ- and washed twice with cold PBS. Then, the cells were resus-
ent concentrations for an additional 24 h. Control wells were pended in 90 μL of annexin V binding buffer (10 mM HEPES,
prepared by the addition of dimethyl sulfoxide (DMSO, 1%). At 140 mM NaCl, 2.5 mM CaCl2; pH 7.4). Annexin V (5 μL) and
the end of this incubation, 20 μL of MTT (5 mg/mL in PBS) 1 μL of propidium iodide were added to the reaction mixture
was added to each well. After incubation for 4 h, the formazan and incubated for 15 min at room temperature in the dark. After
crystals were dissolved in 150 μL of DMSO, and the absor- the addition of 300 μL of binding buffer, the stained cells were
bance was determined at 595 nm using a microplate spectropho- analyzed with a NovoCyteTM 2000 FlowCytometry System
tometer. The IC50 value was determined from plots of percent (ACEA).
viability against the dose of the compound added.
Supporting Information
Cytotoxicity assay: Viability (live/dead) assessment was per-
formed by staining cells with 7-AAD (7-aminoactinomycin D,
Supporting Information File 1
Experimental details, characterization data and copies of
spectra.
Biolegend) in a similar manner as described in [62]. In brief,
after treatment cells were harvested, washed 1–2 times with
phosphate-buffered saline (PBS) and centrifuged at 400g for
[
https://www.beilstein-journals.org/bjoc/content/
5
minutes. Cell pellets were resuspended in 200 µL of flow
supplementary/1860-5397-15-269-S1.pdf]
cytometry staining buffer (PBS without Ca2+and Mg2+, 2.5%
FBS) and stained with 5 µL of 7-AAD staining solution for
1
5 minutes at room temperature in the dark. Samples were Acknowledgements
acquired on a NovoCyteTM 2000 Flow Cytometry System S. K. thanks the Department of Science and Technology for the
ACEA) equipped with a 488 nm argon laser. Detection of award of a J. C. Bose fellowship and Praj Industries for the
-AAD emission was collected through a 675/30 nm filter in award of chair professor (Green chemistry). G. S. thanks the
(
7
FL4 channel.
CSIR-New Delhi for the award of a research fellowship. We
also thank DST, New Delhi for the financial support. V. A. D.
Annexin V-FITC/PI assay: The apoptosis-inducing activity of thanks the Russian Foundation for Basic Research (Grants No.
the compounds was analyzed quantitatively using an Alexa 18-33-20058, 18-29-09068) and the Grant of the RF President
Fluor® 488 Annexin V/Dead Cell Apoptosis Kit in a similar (Sci. Sh.-5240.2018.3) for financial support.
way as described in [60]. Phosphatidylserine externalization on
the outer surface of the plasma membrane is an exact and reli- ORCID® iDs
able indication of cell apoptosis or necrosis. The difference be-
tween these two forms of cell death is that in the early stages of
apoptosis, the cell membrane remains relatively undamaged,
whereas upon necrosis, the cell membrane loses integrity. In the
Sambasivarao Kotha - https://orcid.org/0000-0002-7173-0233
Milyausha M. Yunusbaeva - https://orcid.org/0000-0001-7729-7699
Vladimir A. D’yakonov - https://orcid.org/0000-0002-7787-5054
living, normally functioning cells, phosphatidylserine is present References
on the cell surface membrane in minor quantity; hence, its inter-
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phatidylserine molecules appear on the cell surface but the
membrane is still impermeable for DNA-binding dyes (such as
propidium iodide). The membrane integrity is lost at later stages
of the cell death. Thus, while detecting the apoptosis, one can
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