2H-1,2,3-Triazole-chalcones as novel cytotoxic agents against prostate cancer

Article abstract of DOI:10.1016/j.bmcl.2020.127454

Prostate cancer is an important cause of death in the male population and for which there is no satisfactory chemotherapy. Herein a new series of chalcone hybrids containing 2H-1,2,3-triazole core as the ring B has been synthesized and evaluated in vitro

Full text of DOI:10.1016/j.bmcl.2020.127454

Bioorganic&MedicinalChemistryLetters30(2020)127454
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2H-1,2,3-Triazole-chalcones as novel cytotoxic agents against prostate
cancer
⁎
Sergio Pinheiroa, , Jaqueline C. Pessôaa, Erick M.C. Pinheirob, Estela M.F. Murib,
Eclair Venturini Filhoc, Laiza B. Loureiroc, Maria Clara R. Freitasd, Carlos M.D. Silva Juniora,
Rodolfo G. Fiorota, José Walkimar M. Carneiroa, Karina M. Rotamiroe, Anderson R.A. Guimarãesf,
⁎
Karin J.P. Rocha-Britof, Sandro J. Grecoc,
a Chemistry Institute, Fluminense Federal University, Outeiro de S. João Batista s/n, Centro, 24020-141 Niterói, RJ, Brazil
b Department of Pharmaceutical Technology, Faculty of Pharmacy, Fluminense Federal University, Niterói, RJ, Brazil
c Department of Chemistry, Espírito Santo Federal University, Av. Fernando Ferrari 514, Goiabeiras, 29075-910 Vitória, ES, Brazil
d Department of Chemistry, Rio de Janeiro Rural Federal University, Seropédica, RJ, Brazil
e Laboratory of Technological Innovation in Drugs and Cosmetics Development, State University of Maringá, Maringá, PR, Brazil
f Department of Medicine, University Center of Maringá, Maringá, PR, Brazil
A R T I C L E I N F O
A B S T R A C T
Keywords:
Prostate cancer is an important cause of death in the male population and for which there is no satisfactory
chemotherapy. Herein a new series of chalcone hybrids containing 2H-1,2,3-triazole core as the ring B has been
synthesized and evaluated in vitro against PC-3 prostate cancer cell line. Compounds 4a, 4c and 4e significantly
reduced cell viability and showed IC50 of 28.55, 15.64 and 25.56 µM, respectively. The structure-activity re-
lationship supported by computational chemistry points that the polarity of the molecular surface area should
have some relevance to the efficiency of the compounds, in particular the ratio of the partial positive charge sites
and the total molecular surface area exposed to the cell environment.
1,2,3-Triazole
Chalcone
Hybridization
Prostate cancer
Endocrine cancer
Endocrine cancers are included as one of the major worldwide
problems in terms of morbidity and mortality. Among them, prostate
cancer is the second most common in the male population worldwide
and the fifth leading cause of cancer mortality, showing the greatest
incidence in Europe, North America, and Oceania.1–3
triazoles play an important role in medicinal chemistry.5,6 These azoles
have gained relevance due to the ability to form hydrogen bond, which
improves the solubility and ability to bind to different biological tar-
gets, maintaining a good pharmacokinetic profile and resulting in
highly potent bioactive agents. Furthermore, the hybridization of 1,2,3-
triazole framework with other anticancer pharmacophores have the
potential to reduce side effects and overcome the drug resistance since
hybrids may also own multiple action mechanisms.7
The management of prostate cancer is wide ranging, from indolent
diseases that require active surveillance only to an aggressive malig-
nancy that requires active treatment, especially for metastatic dis-
eases.1–3 For prostate cancer metastasis that does not respond to hor-
monal therapy, the chemotherapy with the taxane family drugs
docetaxel and cabazitaxel has been used.1–3 These drugs promote the
aggregation of tubulins in the formation of stable microtubules and
improve median overall survival from 43 to 65 months, but presents
adverse effects related to the lack of selectivity such as neutropenia,
anemia and severe infections. Therefore, despite the many existing
anticancer therapies,4 there is enormous scientific and commercial in-
terest in the discovery of safe, potent, and selective drugs against
prostate cancer.
Extensive studies have been conducted on 1H-1,2,3-triazole-hybrids
with significant antiproliferative effect and marked cytotoxicity against
prostate cancer cell lines.8–14 Compound I is a more recent example of a
potent compound against PC-3 cell line, where the triazole ring forms
hydrogen bond with topoisomerase II (Fig. 1).12 To the best of our
knowledge only few examples of isomeric 2H-1,2,3-triazole-hybrids
showed potent cytotoxic activity against prostate cancer.13,14 Among
them, the compound II showed growth inhibition both PC-3 and DU-
145 cell lines in nanomolar ranges acting as a tubulin polymerization
inhibitor, where the triazole ring acts as a pharmacophore interacting
with the colchicine and combretastatin A-4 site bind.13
Among the different five-membered nitrogen heterocycles, 1,2,3-
⁎ Corresponding authors.
E-mail addresses: spinuff@gmail.com (S. Pinheiro), grecosj@outlook.com (S.J. Greco).
https://doi.org/10.1016/j.bmcl.2020.127454
Received 16 June 2020; Received in revised form 23 July 2020; Accepted 24 July 2020
Availableonline28July2020
0960-894X/©2020ElsevierLtd.Allrightsreserved.

S. Pinheiro, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127454
Fig. 1. Triazole and chalcone motifs against prostate cancer for hybridization to novel 2H-1,2,3-triazole-chalcone hybrids.
Naturally occurring and synthetic chalcones are small active mole-
cules against a large array of cancer cell lines acting by several me-
chanisms.15,16 In oncology, chalcones have enjoyed a surge in popu-
larity because may be devoid of important side effects related to
genotoxic effects.17 Moreover, some chalcone and chalcone-based
compounds are not toxic to normal cells, reach reasonable plasma
concentrations in clinical trials, did not cause toxicity and are able to
cross the brain blood barrier.18
There are some examples of 1H-1,2,3-triazole-chalcone hybrids with
activity against prostate cancer cell lines.19–22 Among them, the ma-
jority present the 1H-1,2,3-triazole ring attached to ring B of the
chalcone backbone as shown in compound III where the heterocyclic
ring links the chalcone moiety to the β-lactam pharmacophore.21 As in
these cases, the interaction of the triazole rings with the biological
targets were not studied,19–22 it is not clear if the 1H-1,2,3-triazole
moieties act as pharmacophores or just passive linkers between the
chalcone core and a second pharmacophore.
It has been reported that the anticancer importance of some alpha
branched chalcones and a 1H-1,2,3-triazole compound comes from the
consideration that they are cis-restricted analogs of Combretastatin A4
in inhibiting tubulin polymerization by interaction with the colchicine
binding site of β-tubulin.23–26
Scheme 1. Synthesis of 2H-1,2,3-triazole-chalcone hybrids 4 and 5.
aryl-3-(2-phenyl-2H-1,2,3-triazol-4-yl)prop-2-en-1-ones 5a, 5 g and 5 h
in good yields after recrystallization from ethanol.
Considering the concept of fragment-based drug design, we en-
visaged the synthesis of novel active 2H-1,2,3-triazole-chalcone hybrids
by a reasonable combination of compounds II and III, having them-
selves activities against PC-3 prostate cancer cell line providing a pos-
sibility of a synergic mode of action (Fig. 1). Such hybrids have the
potential to reduce side effects and overcome the drug resistance.
Herein we report the first examples of chalcone hybrids possessing a
2H-1,2,3-triazole as the ring B with in vitro activity against PC-3 cell
line opening the possibility that this heterocyclic ring can be a phar-
macophore in chalcone class of compounds. Structure-activity re-
lationship (SAR) in the rings A with complementary electronic char-
acteristics supported by computational chemistry was performed to
clarify the structural features of such 1,2,3-triazole-chalcones hybrids
and the characteristics important to design more active compounds.
The Claisen-Schmidt condensation27 for the preparation of chal-
cones is attractive since it predominantly generates the (E)-isomers.24,27
On the other hand, the reaction of propiophenones usually leads to
mixtures of (E)- and (Z)-α-branched chalcones where the (E)-isomers
are largely favored (ca, 5: 1).23–25 After separation by chromatography
on silica gel followed by recrystallization, the (Z)-isomer of a α-methyl
chalcone showed the signal of its vinyl hydrogen near 6 ppm in the 1H
NMR spectrum,24 whereas the (E)-isomers of some α-methyl chalcones
presented signals of this hydrogen around 7 ppm with allylic coupling
constants near 2.0 Hz.23–25
The IR, 1H, and 13C NMR spectra are consistent with the structures
of the novel compounds 5a, 5g, and 5h. All compounds showed bands
near 1630 cm−1 in the IR spectra for the C]O stretch of chalcones.
After recrystallization from ethanol, compounds 5a, 5g and 5h were
obtained as single isomers whose (E) geometries of the double bonds in
5a, 5g, and 5h were assigned by 1H NMR according to the litera-
ture.23–25 For example, for compound 5a the signal of the vinyl hy-
drogen at 7.20 ppm with J = 1.5 Hz is in agreement with the (E)
geometry of the double bond.
Crystallization of 5a with hot ethanol provided a single crystal for
X-ray diffraction study (Fig. 2). The direct method using the OLEX 2
software30 revealed the (E) geometry for chalcone 5a, which in solid
state adopts a s-trans conformation.
Thus, the reaction of commercially available acetophenones 1a-g
and 1i-k with the known 1,2,3-triazole aldehyde 328 produced the re-
spective (E)-1-aryl-3-(2-phenyl-2H-1,2,3-triazol-4-yl)prop-2-en-1-ones
4a-g and 4i-k in moderate to good yields after recrystallization, as
previously described by our group (Scheme 1).29 Under these reaction
conditions, the condensation of propiophenones 2a, 2 g and 2 h with 3
after stirring for 5 h furnished the corresponding novel (E)-2-methyl-1-
Fig. 2. Olex 2 diagram of compound 5a shown in atomic numbering system.
CCDC deposition number: 2009950.
2

S. Pinheiro, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127454
Table 1
Medium IC50 values of substances 4a, 4c, 4e and 4k.
Compound
Structure
IC50/24 h (µM)
4a
28.55
15.64
25.56
11.05
3.48
9.71
4c
4e
Fig. 3. Cell viability of prostate cancer cells after treatment, for 24 h with
100 µM of the compounds in relation to the control.
4k
47.86
13.25
The PC-3 cell line comes from a bone metastatic site established
from the metastasis of a grade IV prostate adenocarcinoma (ATCC,
2019). Through the cellular model of the study, it was possible to start
the investigation of the antitumor effect of the compounds on these
cells. All 2H-1,2,3-triazole-chalcones 4 and 5 at 100 µM concentration
were evaluated in duplicate (two wells for each compound) and in two
independent experiments (Fig. 3). The compounds 4a, 4c, 4e and 4k
were able to significantly reduce cell viability (< 0.005) when com-
pared to control viability (100%).31 Unlike other anticancer α-methyl
chalcones acting by β-tubulin polymerization inhibitors,23–26 the pre-
sence of a-methyl substituents in compounds 5a, 5g, and 5h did not
show a significant effect on cell viability when compared to the control.
With that, the group of compounds with significant effect was se-
lected for evaluation from a concentration curve, in order to determine
the IC50. Thus, compounds 4a, 4c, 4e and 4k were evaluating in three
independent experiments, at concentrations of 100, 50, 25 and 10 µM
in triplicate (three wells for each concentration). All these substances
showed to be cytotoxic to PC-3 cells. From Fig. 4, it is possible to ob-
serve a reduction in cell viability for all compounds.
4k, the following percentages of cell viability observed, respectively:
6.38%, 0%, 5.37% and 24.23%. Substance 4c showed a viability value
of 3% when tested at a concentration of 50 µM, and 0% viability at a
concentration of 100 µM.
With the cell viability curves, it was possible to determine the
medium IC50 values of the 2H-1,2,3-triazole-chalcone hybrids 4a, 4c,
4e and 4k (Table 1). Against PC-3 cells the 2,4-dimethyl substitution at
ring A of 4c was the most desirable whilst the presence of the sulfur
heterocyclic ring A in 4k was less attractive.
Although the mechanism of action of 4c has not been studied, the
possibility that the antiproliferative effect is related to the cell cycle
arrest can be raised, in the same way as already described for other
1,2,3-triazole chalcones.19,21
From the values of cell viability of prostate cancer cell after treatment
for 24 h with 100 µM of 2H-1,2,3-triazole-chalcones hybrids 4a-g, 4i, 4k,
5a, 5g and 5h (Fig. 3), we attempted to develop a preliminary Quanti-
tative Structure-Activity Relationship (QSAR) study to identify possible
molecular descriptors relevant to the activities of these compounds
against PC-3 cell line. We employed the fully optimized structures (AM1
semiempirical method32) of the 13 chalcone hybrids to calculate a set of
molecular descriptors based on structural, thermodynamic, and electronic
parameters33 for each structure. Although it was not possible to find any
significant correlation (mainly due to the low variance in the experi-
mental data), the results clearly point that the polarity of the molecular
surface area should have some relevance to the efficiency of the com-
pounds. In particular, the ratio of the partial positive charge sites that
contributes to the molecular surface polarity and the total molecular
surface area (TMSA) exposed to the cell environment.34,35
It is interesting to note that all compounds generated a more pro-
nounced dose-dependent reduction in cell viability. In addition, com-
pounds 4a, 4c and 4e significantly reduced cell viability at a con-
centration of 25 µM (44.70%, 39.03% and 16.03%, respectively) when
compared to cell viability at a concentration of 10 µM (73.62%, 85.61%
and 73.03%, respectively) for the same compounds. Finally, compound
4k possessing a thiophene ring produced the least cytotoxic effect in
PC-3, and the concentration capable of reducing cell viability by 50%
was around 50 µM. However, it is important to note that when the cells
treated at a concentration of 100 µM of all compounds 4a, 4c, 4e and
Assuming this hypothesis, there should be some relation between
these parameters and the efficiency. Bioactive structure 4a has the
smallest TMSA (total molecular surface area), given the absence of
substituents on the triazole-chalcone backbone, enhancing the ratio of
partial positive charge sites per unit of surface area. In 4b, the methyl
group in the para position (R4′) allows dispersion of the partial positive
charge on the carbonyl carbon, in addition of increasing TMSA.
According to our model, this suggests why 4b is less effective than 4a.
On the other hand, the presence of an additional methyl group in the
ortho position (R2′), as in chalcone 4c, substantially increases the bio-
logical response. There are two important dihedral angles that may
mediate the partial charge dispersion and the accessible molecular
surface area. Fig. 5 shows the dihedral angles ϕ1 and ϕ2 for the re-
spective hybrids 4b and 4c. The dihedral angle between the ring A
(contained in green plane C1a-C2a-C2) and the carbonyl group (enclosed
in pink plane O1-C2-C2a), defined as ϕ1, and the dihedral angle between
the C]C (in orange plane C2-C3-C4) and the carbonyl group (in blue
plane O1-C2-C3) in the enone moiety, defined as ϕ2. One can observe
that raising ϕ1 from 26.7° (in 4b) to 38.3° (in 4c), increases the
Fig. 4. Cell viability of PC-3 cells after treatment, for 24 h with 100, 50, 25 and
10 µM of compounds 4a, 4c, 4e and 4k in relation to the control.
3

S. Pinheiro, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127454
Acknowledgments
This study was financed in part by the Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior-Brasil, Brazil (CAPES)-
Finance Code 001. The authors thank to the Conselho Nacional de
Desenvolvimento Científico e Tecnológico, Brazil (CNPq) and the
Fundação de Amparo à Pesquisa do Espírito Santo, Brazil (FAPES) for
financial support.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2020.127454.
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