Synthesis of selenium-quinone hybrid compounds with potential antitumor activity via Rh-Catalyzed C-H bond activation and click reactions

Article abstract of DOI:10.3390/molecules23010083

In continuation of our quest for new redox-modulating catalytic antitumor molecules, selenium-containing quinone-based 1,2,3-triazoles were synthesized using rhodium-catalyzed C-H bond activation and click reactions. All compounds were evaluated against five types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), SF295 (human glioblastoma cells), NCIH-460 (human lung cells) and PC3 (human prostate cancer cells). Some compounds showed good activity with IC₅₀ values below 1 μM. The cytotoxic potential of the naphthoquinoidal derivatives was also evaluated in non-tumor cells, exemplified by L929 cells. Overall, these compounds represent promising new lead derivatives and stand for a new class of chalcogenium-containing derivatives with potential antitumor activity.

Full text of DOI:10.3390/molecules23010083

molecules
Article
Synthesis of Selenium-Quinone Hybrid Compounds
with Potential Antitumor Activity via Rh-Catalyzed
C-H Bond Activation and Click Reactions
Guilherme A. M. Jardim 1, Eduardo H. G. da Cruz 1,2, Wagner O. Valença 1, Daisy J. B. Lima 3,
Bruno C. Cavalcanti 3, Claudia Pessoa 3, Jamal Rafique 4 ID , Antonio L. Braga 4, Claus Jacob 2,
*
and Eufrânio N. da Silva Júnior 1,
*
1
Department of Chemistry, Institute of Exact Sciences, Federal University of Minas Gerais, UFMG, 31270-901
Belo Horizonte, Brazil; victimoffate18@gmail.com (G.A.M.J.); eduardoh_cruz@hotmail.com (E.H.G.d.C.);
wagner.valenca1987@gmail.com (W.O.V.)
2
3
4
Division of Bioorganic Chemistry, Department of Pharmacy, University of Saarland, Campus B2 1,
D-66123 Saarbruecken, Germany
Department of Physiology and Pharmacology, Federal University of Ceará, CEP 60180-900 Fortaleza, Brazil;
daisylima@gmail.com (D.J.B.L.); nunim_br@yahoo.com.br (B.C.C.); cpessoa@ufc.br (C.P.)
Department of Chemistry, Federal University of Santa Catarina, 88040-900 Florianópolis, Brazil;
jamal.chm@gmail.com (J.R.); braga.antonio@ufsc.br (A.L.B.)
*
Correspondence: c.jacob@mx.uni-saarland.de (C.J.); eufranio@ufmg.br (E.N.d.S.J.);
Tel.: +49-681-302-3129 (C.J.); +55-31-34095720 (E.N.d.S.J.);
Fax: +49-681-302-3464 (C.J.); +55-31-34095700 (E.N.d.S.J.)
Received: 16 November 2017; Accepted: 22 December 2017; Published: 30 December 2017
Abstract: In continuation of our quest for new redox-modulating catalytic antitumor molecules,
selenium-containing quinone-based 1,2,3-triazoles were synthesized using rhodium-catalyzed C-H
bond activation and click reactions. All compounds were evaluated against five types of cancer cell
lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), SF295
(human glioblastoma cells), NCIH-460 (human lung cells) and PC3 (human prostate cancer cells).
Some compounds showed good activity with IC50 values below 1 µM. The cytotoxic potential of
the naphthoquinoidal derivatives was also evaluated in non-tumor cells, exemplified by L929 cells.
Overall, these compounds represent promising new lead derivatives and stand for a new class of
chalcogenium-containing derivatives with potential antitumor activity.
Keywords: lapachol; naphthoquinone; cancer; selenium; click chemistry; C-H activation
1. Introduction
Cancer is considered one of the major leading causes of death worldwide, accounting for
8.8 million deaths in 2015, and responsible for one in six deaths globally [
for a large group of diseases characterized by abnormal cell growth which can invade adjoining parts
of the body and general organs [ ]. Each year, more than 14 million people are diagnosed with cancer,
the majority of whom live in low- and middle-income countries [ ]. Chemotherapy is one of the
conventional treatments for patients diagnosed with cancer, together with radiation and surgery [ ].
1]. It is a generic term
2
3
4
This systemic treatment consists in the circulation of anticancer drugs through the body by the blood
circulatory system to reach cancer cells wherever they are, with the goal of annihilate both cancerous
colonies and metastasized cancer cells within a patient’s body [5]. The side effects of chemotherapy
are anemia, diarrhea, nausea, vomiting, hair loss and weakening of the immune system, as the actual
anticancer drugs usually present low discrimination between normal and cancer cells [6].
Molecules 2018, 23, 83; doi:10.3390/molecules23010083
www.mdpi.com/journal/molecules

Molecules 2018, 23, 83
2 of 16
Naphthoquinones are known to be widely distributed in Nature, occurring in animals [
7],
plants [ ], and microorganisms [ ]. This group of molecules is considered privileged structures
8
9
in Medicinal Chemistry due to the variety of biological activities they display, such as antiallergic [10],
antifungal [11], antiviral [12], antibacterial [13], and anti-inflammatory properties [14], among
others [15–17]. Most of these activities are associated with the—often catalytic—generation
of Reactive Oxygen Species (ROS) [18]. Among the various quinones, 1,4-naphthoquinones
are well represented in cancer therapy by solid tumour anticancer drugs such as doxorubicin,
mitomycin and mitoxantrone [19]. Considering natural quinones, we also find important cytotoxic
1,4-naphthoquinones, including lapachol [20], plumbagin [21] and shikonin [22].
Over the years our research group has concentrated its efforts on the investigation of the naturally
occurring quinones from the tree species of the Bignoniaceae family, especially the ones extracted from
the Ipe tree, like lapachol and
various cancer molecular targets [24
solid tumors [26]. Derivatization of
an interesting strategy for enhancement of cytotoxic activity, and
β
-lapachone [23]. The last one has a history of anticancer activity against
25], being in Phase II clinical trials in the US for the treatment of
-lapachone by insertion of the 1,2,3-triazole moiety proved to be
-lapachone-based 1,2,3-triazoles
,
β
β
were obtained in moderate to high yields, showing significant activities against HCT-8 cell-lines [27].
The underlying mode of cytotoxic biological action of such quinones is rather interesting and in
many aspects sets these redox active agents apart from conventional anticancer agents. Various studies
have demonstrated that cancer cells exhibit an abnormal redox status associated with increased basal
levels of ROS and alterations of the antioxidant systems [28]. The use of redox-modulating and often
catalytic compounds therefore appears as an efficient therapeutic approach by taking advantage of this
biochemical singularity to selectively target cancer cells, as long as normal cells maintain their own
redox homeostasis by controlling the balance between ROS generation and elimination [29]. Indeed,
normal cells often can tolerate a certain level of exogenous ROS whereas cancer cells cannot [30].
Eventually, this pre-existing difference between cancer cells on the one side, and normal cells on the
other, may provide a certain degree of selectivity which would be most welcome in any targeted
anticancer therapy.
Following this notion of redox regulation in cancer cells by redox active small molecules, the
strategy of combining—catalytic—ROS generators such as 1,4-naphthoquinones with ROS modulators
such as selenium atoms in the same molecule for enhanced activity and selectivity has already been
successfully explored by Jacob and co-workers a couple of years ago (Scheme 1A) [31–33]. These initial
studies have confirmed that the selectivity of quinone compounds can be improved by these kinds of
“molecular hybridization” without compromising the cytotoxicity of the compounds. Chalcogens, such
as selenium and tellurium, are known to play a major role in the chemoprevention and possibly even in
the treatment of cancer, a notion highlighted once more by the recent publications of Kieliszek, Lipinski,
˙
Błazejak and colleagues [34
is therefore evident. Indeed, in fine agreement with these pioneering studies, our research group has
recently described chalcogen-containing -lapachones with remarkable activity against some cancer
cell lines, including HL-60 with IC50 values of 0.94 M and 0.53 M and MOLT-4 (leukaemia) with
IC50 values between 0.73 and 1.89 M [37]. In previous work, selenium-containing -lapachone-based
–36]. The choice of one or more chalcogen atoms as additional redox site(s)
β
µ
µ
µ
β
1,2,3-triazoles derivatives were also synthesized and exhibited high activity with IC50 values below
2 µM against cancer cells such as HL-60 and PC3 (human prostate) cells [38] (Scheme 1B).
Encouraged by these results, we now report the synthesis and biological evaluation of new
selenium containing 1,4-naphthoquinone derivatives, obtained by two main synthetic strategies:
C-H bond activation [39
(Scheme 1C). Chalcogen-containing
activity has been evaluated against cancer and normal cell lines.
–
41], and copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) [42
–45]
β
-lapachones derivatives were also synthesized and their biological

Molecules 2018, 23, 83
3 of 16
Scheme 1. Overview of the different generations of hybrid redox molecules for the first and second
generation (Panel ( )) to the third generation with lapachones (Panel ( )) and the products of
A
B
Rh-activated C-H bond activation and click reactions (Panel (C)).
2. Results and Discussion
2.1. Chemistry
Recently, our research group developed methodologies which enable the functionalization of
quinones via rhodium catalyzed C-H activation [46 47], paving the way to new molecules containing
,
iodine, bromine and selenium atoms with remarkable biological activity [48]. Encouraged by that
fact, the same catalyst system was explored with other electrophilic selenium sources, focusing on
obtaining new molecules with a substituent in the phenyl selenium moiety. 1,4-naphthoquinone (
1)
was reacted with substituted phenyl hypochloroselenoites and derivatives were obtained with
2–5
moderate yields. The reaction failed when electron deficient perfluorophenyl hypochloroselenoite was
employed and only traces of product were observed for p-tolyl hypochloroselenoite (Scheme 2).

Molecules 2018, 23, 83
4 of 16
Scheme 2. Functionalization of 1 via rhodium-catalyzed C-H activation.
Menadione (6) was reacted with hydrogen peroxide in methanol resulting in menadione oxide,
that was promptly acidified with H2SO4 to obtain 2-hydroxy-3-methyl-1,4-naphthoquinone [49].
Methylation of the hydroxyl group was achieved by reaction with iodomethane and Ag2O in CHCl3
under reflux overnight, affording
7 in 48% over two steps. Next, 7 was reacted with NBS and benzoyl
peroxide in CCl4 and bromination occurred in 76% yield [50]. Reaction with NaN3 in DMF gave
quantitative yield (Scheme 3).
8 in
Scheme 3. Synthetic pathway for obtaining azide derivative 8.
Since 2002, copper-catalyzed “click” cycloadditions offer access to an almost unlimited array
of triazole-containing structures [51]. For this reaction, copper(II) sulfate in aqueous media in the
presence of sodium ascorbate, both in catalytic amounts, constitute the preferred catalytic system for
this sort of transformation due to practicality, cost and robustness [52–54]. Besides more complicated
multicomponent reactions, such as the Passerini or Ugi reaction, click reactions are ideally suited to
assemble hybrid molecules, such as catalysts featuring two or more redox centers. Hence the second
class of compounds was designed by adding a triazole portion in the 1,4-naphthoquinone backbone.
In order to obtain 1,2,3-triazole derivatives, a classical copper(I) catalyzed “click” reaction [51
was employed to generate derivatives with substitution pattern in the 4-position of the benzene ring.
Reaction with phenyl acetylene afforded in 96% yield. Treatment of a more electron-deficient alkyne
,55]
9
gave derivative 10 in excellent yield. Alkynes with electron donating groups, such as methoxy and
methyl afforded derivatives 11 and 12 in good yields. Reaction with alkyne with presence of bromine
in the benzene ring afforded 13 in moderate yield (Scheme 4).

Molecules 2018, 23, 83
5 of 16
Scheme 4. 1,2,3-triazole derivatives obtained via classical copper(I) catalyzed “click” reaction.
Next, in order to investigate the effect of a selenium atom in the bioactivity of the previous
molecules, azide was reacted with two different phenyl(prop-2-yn-1-yl)selanes substituted at the
8
position 4 of the benzene ring (Scheme 5).
Scheme 5. Selenium containing-1,2,3-triazole derivatives obtained via classical copper(I) catalyzed
“click” reaction.
In contrast to menadione and its para-quinone derivatives, lapachones represent a class of highly
reactive ortho-quinones and are renowned for their high activity against trypomastigote forms of
Trypanossoma cruzi [56], the causative agent of Chagas disease. In this context, β-lapachone, in particular,
is considered an effective substance against Trypanossoma cruzi [57]. This pathogenic microorganism
seems to be rather sensitive to redox changes and therefore also to agents able to modulate its
intracellular redox homeostasis. Recently, our research group has reported a novel selenium-containing
β
-lapachone derivative that showed remarkable activity against a series of cancer cell lines, proving
that insertion of a second redox center contributes to an enhanced biological activity [38].
Motivated by those findings, -lapachone-1,2,3-triazole-selenium derivatives were synthesized
β
using CuAAc and were obtained in poor to good yields. Substituents at the aromatic ring of the
selenium alkynes have shown to affect the yield of the reaction, and derivatives 17 and 18 containing
chlorine and fluorine atoms in the position 4 of the aromatic ring were obtained in 25% and 43% yield,
respectively. Electron-rich selenium alkyne bearing a methoxy group in the same position afforded
derivative 19 in 76% yield. Interestingly, insertion of a methylene group in the alkyl chain and a less
electron donating group such as methyl had a drastic effect on the reaction and derivatives 20 and 21
were obtained in moderate to poor yields. Modification of the benzene terminal group by a heterocyclic
ring such as thiophene and an alkyl chain also influenced reactivity and derivatives 22 and 23 were

Molecules 2018, 23, 83
6 of 16
obtained in 47% and 31% yield, respectively. Finally, exchanging the selenium atom by a sulfur one
afforded derivative 24 in 47% yield (Scheme 6).
Scheme 6. β-Lapachone selenium containing-1,2,3-triazoles. Note: Compounds were obtained in
racemic form, but the stereochemistry trans was defined by X-ray crystallography as part of previous
studies [27].
2.2. Biology
The various compounds synthesized as part of this study were subsequently evaluated for possible
activity against different cancer cell lines, including HL-60, HCT-116, SF295, NCIH-460 and PC3 and
one normal cell line, L929 (murine fibroblasts normal cells) (Table 1). Overall the IC50 and CI 95%
values obtained reflect a considerable cytotoxicity associated with the quinones under investigation.
Nonetheless, there are also some striking differences. Glancing over the data available so far, it is
immediately apparent that the lapachone derivatives exhibit a considerably higher activity when
compared to the menadiones. Whilst the IC50 values for the 1,4-quinones are usually between 10 and
100
of the most active lapachones, such as compound 18, even active in sub-micromolar concentrations.
Indeed, this compound exhibits IC50 values of 0.59 M, 0.37 M and 0.36 M against HL-60, HCT-116
µM, the lapachone derivatives are active well below this, generally between 1 and 10 µM, with some
µ
µ
µ
and L929 cell lines, which are in the range of the ones measured for the benchmark anticancer drug
doxorubicin (0.21 µM and 1.72 µM against HCT-116 and L929 cell lines, respectively).

Molecules 2018, 23, 83
7 of 16
Interestingly, the exceptional activity of compound 18 seems to result from a combination of
(a) the lapachone; (b) selenium and (c) an electron-withdrawing substituent in para-position to Se
which may render this chalcogen more (re-)active. Although the data available to date is very limited,
and hence any structure-reactivity relationship is still highly speculative, there is some support for
this notion. First of all, the menadione-derivatives, as mentioned already, are considerably less
active, often with a factor of ten or even more between their activities and the ones of the lapachones.
Secondly, compound 24, which contains a sulfur instead of selenium, is the least active of the lapachone
derivatives tested—although its activity still compares favourably with the ones of the menadione
derivatives. And finally, the electron-donating analogues of compound 18 are also less active, although
the differences are minor.
Apart from the considerable activity of some of the compounds presented, which compares
well with the one of the common drug doxorubicin, there is also some selectivity against certain
cancer cell lines. These differences in IC50 values are minor yet notable. Still, there is no significant
“selective cytotoxicity” against one particular cell line, which is somewhat disappointing yet not entirely
unexpected, as none of the cell lines employed in this study represents truly “normal human cells”.
Table 1. Cytotoxic activity expressed by IC50
µM (95% CI) of compounds in cancer and normal
cell lines after 72 h exposure, obtained by nonlinear regression for all cell lines from three
independent experiments.
Compounds
HL-60
HCT-116
SF295
NCIH-460
PC3
L929
2
3
4
5
8
1.96 (1.66–2.33)
4.68 (3.93–5.58)
2.25 (1.88–2.71)
2.16 (1.81–2.59)
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
9
5.39 (3.78–7.73)
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
10
11
12
13
14
15
17
18
19
20
21
22
23
24
DOXO
2.32 (1.72–3.25)
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
0.81 (0.73–0.86)
0.59 (0.45–0.70)
1.28 (1.16–1.31)
1.00 (0.93–1.07)
1.00 (0.91–1.03)
0.53 (0.48–0.59)
0.71 (0.61–0.76)
1.94 (1.85–2.08)
0.02 (0.01–0.02)
>8.0
2.60 (2.47–2.72)
1.48 (1.34–1.63)
1.75 (1.57–1.82)
3.12 (2.91–3.24)
1.63 (1.42–1.84)
2.13 (2.01–2.43)
3.43 (3.20–3.69)
2.34 (2.16–2.44)
0.41 (0.21–0.47)
2.06 (1.95–2.22)
1.32 (1.23–1.53)
2.33 (2.23–2.45)
3.26 (3.15–3.42)
1.49 (1.38–1.59)
2.75 (2.54–3.00)
2.64 (2.44–2.90)
4.91 (4.70–5.26)
0.15 (0.13–0.18)
2.03 (1.90–2.25)
1.06 (0.90–1.27)
1.55 (1.40–1.94)
2.70 (3.15–3.42)
1.77 (1.66–1.98)
2.47 (2.26–2.68)
1.64 (1.55–1.69)
2.10 (1.85–2.28)
0.76 (0.59–0.93)
0.52 (0.44–0.81)
0.36 (0.30–0.49)
0.68 (0.53–0.82)
0.61 (0.58–0.68)
1.28 (1.19–1.38)
3.16 (3.04–3.27)
2.12 (1.92–2.27)
0.84 (0.71–1.06)
1.72 (1.58–1.87)
0.37 (0.24–0.56)
>8.0
2.03 (1.79–2.28)
>8.0
>8.0
0.97 (0.88–1.10)
4.38 (4.24–4.54)
0.21 (0.16–0.29)
3. Materials and Methods
3.1. General Information
Starting materials available from commercial suppliers were used as received, unless stated
otherwise. All reagents requiring purification were purified using standard laboratory techniques,
according to methods published by Perrin, Armarego, and Perrin (Pergamon Press, 1966). Catalytic
reactions were performed under an atmosphere of dry nitrogen or argon; glassware, syringes and
needles were either flame dried immediately prior to use or placed in an oven (200 ◦C), for at least
2 h, and allowed to cool either in a desiccator or under an atmosphere of nitrogen or argon; liquid
reagents, solutions or solvents were added via syringe through rubber septa; solid reagents were added
inside a glovebox. Column chromatography was performed on silica gel (SiliaFlash G60 UltraPure
1
60–200
µ
m, 60 Å, Quebec City, QC, Canada). H- and 13C-NMR were recorded at room temperature
using an AVANCE DRX200 or an DRX400 MHz instrument (Bruker, Billerica, MA, USA) in the solvents
indicated. Chemical shifts ( ) are given in parts per million (ppm) and coupling constants (J) in Hertz
(Hz). All assignments of NMR spectra were based on 2D NMR data (DEPT-135, COSY, HSQC and
δ

Molecules 2018, 23, 83
8 of 16
HMBC). Mass spectra were recorded using a FT-ICRMS Apex 4e 7.0T FT-MS (ESI+ mode) (Bruker
Daltonics) or a GCMS QP2010+ (EI+ mode) instrument (Shimadzu). Infrared spectra were recorded on
a Spectrum One FTIR spectrometer (Perkin Elmer, 710 Bridgeport Avenue, Shelton, CT, USA) as thin
films or solids compressed on a diamond plate and are uncorrected. Data were processed employing
Bruker Data Analysis software version 4.0. Compounds were named following IUPAC rules as applied
by ChemBioDraw Ultra (version 12.0).
1,4-Naphthoquinone (1) and menadione (6) were purchased from Sigma Aldrich (St. Louis, MI,
USA), purified via reduced pressure sublimation using a cold finger sublimation apparatus (50 ◦C,
0.9 mbar) and stored in a glovebox to prevent contact with moisture. Lapachol was extracted from
the heartwood of Tabeluia sp. (Tecoma). A saturated aqueous sodium carbonate solution was added
to the sawdust of ipe tree. Upon observing rapid formation of lapachol sodium salt, hydrochloric
acid was added, allowing the precipitation of lapachol. Subsequently, the solution was filtered and a
yellow solid was obtained. This solid was purified by recrystallizations with hexane.
was synthesised from lapachol by cyclization with concentrated sulfuric acid.
β-Lapachone
3.1.1. General Procedure for Phenylselenation at the 2-Position
An oven dried re-sealable tube was charged with 1,4-naphthoquinone (1) (15.8 mg, 0.10 mmol),
[RhCptCl2]2 (3.75 mol %, 2.6 mg), silver bis(trifluoromethanesulfonyl)imide (20 mol %, 7.8 mg),
anhydrous copper sulfate (220 mol %, 0.22 mmol, 34.9 mg) and the corresponding substituted
phenylselenyl chloride (120 mol %, 0.12 mmol). The tube was connected to a Schlenk line and
an inert atmosphere was achieved. Anhyd◦rous CH2Cl2 (1 mL) was added via a syringe and the tube
was sealed. The mixture was heated at 100 C for 18 h. After cooling, the mixture was filtered through
a pad of Celite and purified via column chromatography (toluene) under the conditions noted.
2-(Phenylselanyl)naphthalene-1,4-dione (
2): Phenylselenyl chloride (23.0 mg, 0.12 mmol) was used as
substrate. The product was obtained in 61% yield as red crystals; m.p. (◦C) = 152.8–153.7; IR
−1
) ν
: 2930 (w), 1664 (s), 1296 (m), 690 (s); HRMS (EI+): 313.9848 [M]+. Cald. for [C16H10SeO2]:
(solid, cm
313.9846; 1H-NMR (400 MHz, CDCl3)
δ: 8.14 (dd, J = 7.2, 1.9 Hz, 1H), 8.03 (dd, J = 6.1, 1.9 Hz, 1H),
7.82–7.67 (m, 2H), 7.68–7.61 (m, 2H), 7.57–7.42 (m, 3H), 6.40 (s, 1H); 13C-NMR (100 MHz, CDCl3)
δ: 183.0, 181.7, 157.0, 137.1, 134.3, 133.3, 132.8, 132.3, 131.6, 130.4, 130.2, 126.9, 126.7, 124.4.
2-((4-Methoxyphenyl)selanyl)naphthalene-1,4-dione (3): 4-Methoxyphenylselenyl chloride (26.6 mg,
0.12 mmol) was used. The product was obtained in 53% yield as an orange solid; m.p. (◦C) =
140.7–148.3; IR (solid, cm−1
)
ν
: 2921 (w), 1641 (s), 1246 (m), 694 (w); HRMS (ESI+): 345.0015 [M + H]+.
Cald. for [C17H13SeO3]+: 345.0024; H-NMR (400 MHz, CDCl3)
δ
: 8.14 (d, J = 6.9 Hz, 1H), 8.05 (d,
1
J = 7.1 Hz, 1H), 7.77–7.69 (m, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 6.40 (s, 1H), 3.89 (s,
3H). 13C-NMR (100 MHz, CDCl3)
126.9, 126.7, 116.2, 114.5, 55.4.
δ: 183.1, 181.7, 161.3, 157.7, 138.6, 134.3, 133.3, 132.8, 132.4, 131.8,
2-((4-Chlorophenyl)selanyl)naphthalene-1,4-dione (4): 4-Chlorophenylselenyl chloride (27.1 mg, 0.12 mmol)
was used. The product was obtained in 42% yield as an orange solid; m.p. (◦C) = 154.8–155.7; IR
(solid, cm−1
)
ν
: 2917 (m), 1648 (s), 1085 (m), 694 (m); HRMS (ESI+): 348.9515 [M + H]+. Cald. for
[C16H10ClSeO2]+: 348.9529; H-NMR (400 MHz, CDCl3)
δ
: 8.12 (dd, J = 6.7, 2.1 Hz, 1H), 8.04 (dd,
1
J = 6.7, 2.1 Hz, 1H), 7.78–7.68 (m, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.37 (s, 1H).
13C-NMR (100 MHz, CDCl3)
127.0, 126.8, 122.6.
δ: 182.9, 181.6, 156.4, 138.4, 137.0, 134.4, 133.4, 132.8, 132.30, 131.6, 130.7,
2-((4-Fluorophenyl)selanyl)naphthalene-1,4-dione (5): 4-Fluorophenylselenyl chloride (25.1 mg, 0.12 mmol)
was used. The product was obtained in 41% yield as an orange solid; m.p. (◦C) = 139.2–139.9; IR
(solid, cm−1
)
ν
: 2924 (w), 1651 (s), 1243 (m), 690 (w); HRMS (EI+): 332.9810 [M + H]+. Cald. for
[C16H10FSeO2]+: 332.9825; H-NMR (400 MHz, CDCl3)
δ
: 8.13 (dd, J = 7.3, 1.7 Hz, 1H), 8.04 (dd,
1
J = 7.3, 1.7 Hz, 1H), 7.78–7.68 (m, 2H), 7.61 (dd, J = 8.6, 5.4 Hz, 2H), 7.17 (t, J = 8.6 Hz, 2H), 6.35 (s, 1H).

Molecules 2018, 23, 83
9 of 16
13C-NMR (100 MHz, CDCl3)
δ
: 182.9, 181.6, 165.3, 162.8, 156.8, 139.26 (d, J = 8.3 Hz), 134.4, 133.4, 132.8,
132.3, 131.6, 126.86 (d, J = 13.7 Hz), 119.24 (d, J = 3.6 Hz), 117.84 (d, J = 21.8 Hz).
2-Hydroxy-3-methylnaphthalene-1,4-dione [49 menadione, ): (1.0 g; 5.8 mmol) was dissolved in 10 mL
]
(
6
methanol and chilled on an ice bath. A solution of 0.2 g of anhydrous Na2CO3 and 1 mL of 30% H2O2 in
◦
5 mL of water were added slowly with the reaction mixture maintained at 0 C. Then 100 mL of water
were added and 2-methyl-1,4-naphthoquinone oxide precipitated as colourless crystals, which were
collected by filtration and dried. The solid was treated with 5 mL concentrated H2SO4 and the mixture
was allowed to stand for 10 min. Subsequent addition of 20 mL water resulted in a yellow precipitate
which was filtered, dried in vacuum and purified by column chromatography (EtOAc/hexane 1:4).
The product was obtained in 78% yield as yellow needles; m.p. (◦C) = 178.2–179.1; IR (solid, cm−1
ν
)
: 3332 (s), 1657 (s), 1276 (m), 726 (s); HRMS (EI+): 188.0467 [M]+. Cald. for [C11H8O3]: 188.0473;
1H-NMR (400 MHz, CDCl3)
δ: 8.13 (dd, J = 7.6, 1.2 Hz, 1H), 8.08 (dd, J = 7.6, 1.2 Hz, 1H), 7.75 (td,
J = 7.5, 1.3 Hz, 1H), 7.68 (td, J = 7.5, 1.3 Hz, 1H), 7.33 (s, 1H), 2.11 (s, 3H). 13C-NMR (100 MHz, CDCl3)
δ: 185.0, 181.2, 153.1, 134.8, 132.9, 132.9, 129.4, 126.7, 126.1, 120.5, 8.7.
2-Methoxy-3-methylnaphthalene-1,4-dione (
(188.2 mg, 1 mmol) in CHCl3 (30 mL) were added Ag2O (463.5 mg, 2.0 mmol) and iodomethane
(125.0 L, 2 mmol). The reaction was refluxed for 48 h, filtered through a pad of Celite and the
7): To a solution of 2-hydroxy-3-methylnaphthalene-1,4-dione
µ
solvent was removed under reduced pressure. The residue was purified via column chromatography
(EtOAc/hexane 1:5). The product was obtained in 62% yield as a yellow solid; m.p. (◦C) = 99.3–100.7;
IR (solid, cm−1 : 2953 (w), 1674 (s), 1269 (m), 720 (s); HRMS (EI+): 202.0627 [M]+. Cald. for
) ν
[C12H10O3]: 202.0630; 1H-NMR (400 MHz, CDCl3)
δ
: 8.20–7.89 (m, 2H), 7.84–7.58 (m, 2H), 4.12 (s, 3H),
2.09 (s, 3H). 13C-NMR (100 MHz, CDCl3)
126.1, 61.0, 9.2.
δ: 185.7, 181.2, 157.8, 133.7, 133.2, 132.0, 131.69, 131.5, 126.1,
2-(Bromomethyl)-3-methoxynaphthalene-1,4-dione: 2-(Bromomethyl)-3-methoxynaphthalene-1,4-dione
was prepared as described in reference [50]. To a stirred solution of 2-methoxy-3-methyl-
1,4-naphthoquinone (7) (1.0 g, 5 mmol) in CCl4 (30 mL) were added NBS (900 mg, 5.0 mmol) and
benzoyl peroxide (0.5 g, 2.1 mmol). The mixture was stirred under white light irradiation (60 W) at
◦
80 C for 12 h. The solvent was then removed in vacuo and the residue was dissolved in CH2Cl2 (60 mL)
and washed with H2O (4
purified by column chromatography (EtOAc/hexane 1:4). The product was obtained in 76% yield as a
yellow solid; m.p. (◦C) = 117.4–118.7; IR (solid, cm−1 : 2953 (w), 1677 (s), 1217 (s), 723 (s); 1H-NMR
×
30 mL). The organic layer was dried with Na2SO4, filtered, evaporated and
)
ν
(400 MHz, CDCl3) δ: 8.12 (dd, J = 6.8, 2.2 Hz, 1H), 8.06 (dd, J = 6.8, 2.2 Hz, 1H), 7.78–7.70 (m, 2H), 4.48
(s, 2H), 4.35 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ: 182.7, 181.3, 158.1, 134.3, 133.6, 131.6, 131.5, 129.1,
126.5, 126.4, 61.7, 20.0.
2-(Azidomethyl)-3-methoxynaphthalene-1,4-dione (8): To a stirred solution of 2-(bromomethyl)-3-
methoxynaphthalene-1,4-dione (281.1 mg, 1 mmol) in DMF (5 mL) was added NaN3 (195.0 mg,
3 mmol). The reaction was allowed to stir for 20 min and quenched with H2O (15 mL). Then, the
mixture was extracted with ethyl acetate (30 mL), and the organic phase was separated and dried
with Na2SO4. The solvent was removed under vacuum and the residue was purified via column
chromatography (EtOAc/Hexane 1:5). The product was obtained in 100% yield as a dark yellow
solid; m.p. (◦C) = 69.1–70.0; IR (solid, cm−1
)
ν
: 2957 (w), 2100 (s), 1677 (s), 1273 (s), 730 (s); MS
(ESI+): 244.1 [M + H]+. Cald. for [C12H10 N3O3]+: 244.1; H-NMR (400 MHz, CDCl3)
δ: 8.05 (dd,
1
J = 6.4, 2.5 Hz, 1H), 8.01 (dd, J = 6.4, 2.5 Hz, 1H), 7.75–7.66 (m, 2H), 4.30 (s, 2H), 4.25 (s, 3H). 13C-NMR
(100 MHz, CDCl3) δ: 184.0, 181.4, 158.9, 134.3, 133.6, 131.5, 131.4, 126.4, 126.0, 61.9, 42.7.
3.1.2. General Procedure for the Synthesis of Triazoles
The corresponding alkynes (1.1 mmol) were reacted with 2-(azidomethyl)-3-methoxy-naphthalene-
1,4-dione (8) (243.2 mg, 1 mmol) or (3R,4S)-4-azido-3-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[h]

Molecules 2018, 23, 83
10 of 16
chromene-5,6-dione (18) (362.2 mg, 1 mmol) in 12 mL of CH2Cl2/H2O (1:1) using CuSO4.5H2O (9.3 mg,
0.04 mmol) and sodium ascorbate (22 mg, 0.11 mmol) as the catalytic system. The mixture was stirred at
room temperature and monitored by TLC until total consumption of starting material. The mixture was
extracted with CH2Cl2, dried with Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by column chromatography on silica gel using a gradient mixture of hexane/ethyl
acetate with increasing polarity up to 100% ethyl acetate as eluent.
2-Methoxy-3-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione (
1.1 mmol) was used. The product was obtained in 96% yield as a dark yellow solid; m.p. (◦C) =
103.8–104.7; IR (solid, cm−1 : 2921 (m), 1671 (s), 1263 (m), 763 (s); HRMS (ESI+): 346.1160 [M + H]+.
Cald. for [C20H16N3O3]+: 346.1186; 1H-NMR (400 MHz, CDCl3)
: 8.09–7.99 (m, 2H), 7.95 (s, 1H), 7.79
(d, J = 7.4 Hz, 2H), 7.75–7.64 (m, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 5.55 (s, 2H), 4.30 (s,
3H). 13C-NMR (100 MHz, CDCl3)
: 184.0, 181.3, 159.4, 147.5, 134.4, 133.8, 131.5, 131.3, 130.7, 128.7,
9): Ethynylbenzene (112.3 mg,
)
ν
δ
δ
128.0, 126.5, 126.4, 125.7, 125.1, 120.8, 62.1, 42.3, 29.7.
2-Methoxy-3-((4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione (10): 1-Ethynyl-4-nitrobenzene
(161.8 mg, 1.1 mmol) was used. The product was obtained in 83% yield as a bright yellow solid;
m.p. (◦C) = 205.8–206.7; IR (solid, cm−1
) ν: 3134 (w), 2924 (w), 1667 (s), 1338 (m), 756 (w); HRMS
(ESI+): 391.1010 [M + H]+. Cald. for [C20H15N4O5]+: 391.1037; 1H-NMR (400 MHz, CDCl3) δ: 8.26 (d,
J = 8.5 Hz, 2H), 8.14 (s, 1H), 8.09 (t, J = 6.5 Hz, 2H), 7.99 (d, J = 8.5 Hz, 2H), 7.81–7.70 (m, 2H), 5.62 (s,
2H), 4.37 (s, 3H). 13C–NMR (100 MHz, CDCl3)
δ: 184.1, 181.3, 159.5, 147.3, 136.9, 134.6, 133.9, 131.5,
131.2, 126.7, 126.4, 126.1, 124.4, 124.2, 122.4, 62.3, 42.6, 29.7.
2-Methoxy-3-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione (11): 1-Ethynyl-4-
methoxybenzene (145.4 mg, 1.1 mmol) was used. The product was obtained in 74% yield as an yellow
solid; m.p. (◦C) = 149.3–150.7; IR (solid, cm−1 : 3088 (w), 1671 (s), 1266 (m), 720 (w); HRMS (ESI+):
) ν
376.1370 [M + H]+. Cald. for [C21H18N3O4]+: 376.1292; 1H-NMR (400 MHz, CDCl3)
2H), 7.91 (s, 1H), 7.76–7.66 (m, 4H), 7.19 (d, J = 7.9 Hz, 2H), 5.55 (s, 2H), 4.31 (s, 3H), 2.35 (s, 3H).
13C-NMR (100 MHz, CDCl3)
: 184.1, 181.3, 159.4, 147.6, 137.8, 134.4, 133.7, 131.5, 131.3, 129.4, 127.9,
δ: 8.12–7.98 (m,
δ
126.5, 126.4, 125.6, 125.2, 120.4, 62.1, 42.2, 21.2.
2-Methoxy-3-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione (12): 1-Ethynyl-4-methylbenzene
◦
(127.8 mg, 1.1 mmol) was used. The product was obtained in 70% yield as an yellow solid; m.p. ( C) =
123.1–124.5; IR (solid, cm−1
)
ν
: 3112 (w), 1644 (s), 1217 (m), 819 (s); HRMS (ESI+): 360.134 [M + H]+.
: 8.09–8.00 (m, 2H), 7.86 (s, 1H),
7.78–7.65 (m, 4H), 6.90 (d, J = 8.7 Hz, 2H), 5.54 (s, 2H), 4.30 (s, 3H), 3.81 (s, 3H). 13C-NMR (100 MHz,
Cald. for [C21H18N3O3]+: 360.1343; H-NMR (400 MHz, CDCl3)
δ
1
CDCl3) : 184.1, 181.3, 159.5, 159.4, 147.4, 134.4, 133.7, 131.5, 131.3, 127.0, 126.5, 126.4, 125.2, 123.4, 120.0,
δ
114.2, 62.1, 55.3, 42.2.
2-((4-(4-Bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-methoxynaphthalene-1,4-dione (13): 1-Bromo-4-
ethynylbenzene (199.1 mg, 1.1 mmol) was used. The product was obtained in 50% yield as an
orange solid; m.p. (◦C) = 174.1–175.0; IR (solid, cm−1
)
ν
: 2914 (w), 1674 (s), 1213 (m), 822 (s); HRMS
(ESI+): 425.9820 [M+2]+. Cald. for [C20H16BrN3O3]+: 425.0364; 1H-NMR (400 MHz, CDCl3)
: 8.15–8.01
(m, 2H), 7.96 (s, 1H), 7.79–7.71 (m, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 5.58 (s, 2H), 4.34
(s, 3H). 13C-NMR (100 MHz, CDCl3)
: 184.1, 181.3, 159.4, 146.6, 134.5, 133.8, 131.9, 131.5, 131.3, 129.6,
δ
δ
127.2, 126.6, 126.4, 124.9, 121.9, 120.9, 62.2, 42.4.
2-Methoxy-3-((4-((phenylselanyl)methyl)-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione (14): Phenyl
(prop-2-yn-1-yl)selane (214.6 mg, 1.1 mmol) was used. The product was obtained in 50% yield as
an bright yellow solid; m.p. (◦C) = 69–71; IR (solid, cm−1
)
ν
: 2921 (w), 1679, 1645 (s), 964, 734 (m);
HRMS (ESI+): 440.0520 [M + H]+. Cald. for [C21H18N3O3Se]+: 440.0508; 1H-NMR (400 MHz, CDCl3)
8.09–8.03 (m, 2H), 7.77–7.71 (m, 2H), 7.43 (dd, J = 7.8, 1.6 Hz, 2H), 7.37 (s, 1H), 7.18–7.10 (m, 3H), 5.43
(s, 2H), 4.24 (s, 3H), 4.14 (s, 2H). 13C-NMR (100 MHz, CDCl3)
: 183.8, 181.3, 159.2, 145.2, 134.5, 133.8,
133.3, 131.5, 131.3, 129.9, 129.0, 127.3, 126.5, 126.4, 125.0, 122.8, 62.0, 42.1, 20.6.
δ
:
δ

Molecules 2018, 23, 83
11 of 16
2-Methoxy-3-((4-(((4-methoxyphenyl)selanyl)methyl)-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione (15):
(4-Methoxyphenyl)(prop-2-yn-1-yl)selane (247.7 mg, 1.1 mmol) was used. The product was obtained
in 70% yield as a dark yellow oil; IR (oil, cm-1) : 2957 (w), 1677 (s), 1243 (m), 726 (s); MS (ESI+):
ν
440.0 [M + H]+. Cald. for [C21H18 N3O3Se]+: 440.0; 1H-NMR (400 MHz, CDCl3)
7.77–7.70 (m, 2H), 7.37 (s, 1H), 7.34 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 5.43 (s, 2H), 4.26 (s, 3H),
4.04 (s, 2H), 3.73 (s, 3H). 13C-NMR (100 MHz, CDCl3)
: 183.9, 181.4, 159.6, 159.3, 145.5, 136.3, 134.5,
δ: 8.08–8.03 (m, 2H),
δ
133.8, 131.5, 131.3, 126.6, 126.4, 125.0, 122.8, 119.7, 114.8, 62.1, 55.27, 42.2, 21.6.
3-Bromo-4-(4-(((4-chlorophenyl)selanyl)methyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-3,4-dihydro-2H-benzo[h]
chromene-5,6-dione (17): (4-Chlorophenyl)(prop-2-yn-1-yl)selane (252.5 mg, 1.1 mmol) was used. The
product was obtained in 25% yield as a yellow powder. m.p. (◦C) = 185.3–187.1, IR (solid, cm−1
)
ν
: 1656 (s), 782 (w), HRMS (EI+): 591.9556 [M]+. Cald. for [C16H10SeO2]: 591.9536; 1H-NMR (400 MHz,
CDCl3) : 8.10 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.74 (t, J = 7.2 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H),
7.54 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 5.56 (d, J = 9.2 Hz, 1H), 4.90 (d, J = 9.1 Hz,
1H), 4.12 (s, 2H), 1.75 (s, 3H), 1.64 (s, 3H). 13C-NMR (100 MHz, CDCl3)
: 177.8, 176.4, 162.6, 135.7,
δ
δ
135.2, 134.0, 132.3, 130.6, 130.5, 129.2, 129.2, 127.3, 125.2, 125.0, 110.4, 83.4, 58.9, 54.5, 27.5, 21.0, 20.5.
3-Bromo-4-(4-(((4-fluorophenyl)selanyl)methyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-3,4-dihydro-2H-benzo[h]
chromene-5,6-dione (18): (4-Fluorophenyl)(prop-2-yn-1-yl)selane (234.4 mg, 1.1 mmol) was used. The
product was obtained in 43% yield as an orange powder. m.p. (◦C) = 187.1–190.0, IR (solid, cm−1
) ν:
1660 (s), 1214 (w), HRMS (EI+): 575.9885 [M]+. Cald. for [C16H10SeO2]: 575.9837; 1H-NMR (400 MHz,
CDCl3) : 8.08 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.62 (t, J = 7.5 Hz
δ
,
1H), 7.52 (s, 1H), 7.36 (s, 1H), 7.46 (dd, J = 8.4, 5.6 Hz, 2H), 6.95 (t, J = 8.7 Hz, 2H), 5.57 (d, J = 9.1
Hz, 1H), 4.90 (d, J = 9.1 Hz, 1H), 4.09 (s, 2H), 1.75 (s, 3H), 1.64 (s, 3H). 13C-NMR (100 MHz, CDCl3)
δ
: 178.0, 176.6, 164.2, 162.8, 161.7, 144.6, 137.2 (d, J = 8.0 Hz), 135.4, 132.5, 130.8, 130.7, 129.4, 125.3 (d,
J = 32.7 Hz), 123,8 (d, J = 3.4 Hz) 116.5 (d, J = 21.4 Hz), 110.6, 83.7, 59.1, 54.8, 27.7, 21.6, 20.7.
3-Bromo-4-(4-(((4-methoxyphenyl)selanyl)methyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-3,4-dihydro-2H-benzo[h]
chromene-5,6-dione (19): (4-Methoxyphenyl)(prop-2-yn-1-yl)selane (247.6 mg, 1.1 mmol) was used. The
product was obtained in 76% yield as an orange powder. m.p. (◦C) = 113.5–114.6, IR (solid, cm−1
) ν:
1654 (s), 1246 (w), HRMS (EI+): 588.0093 [M]+. Cald. for [C16H10SeO2]: 588.0032, 1H-NMR (400 MHz,
CDCl3) : 8.11 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H),
7.74 (d, J = 9.4 Hz, 3H), 6.81 (d, J = 8.5 Hz, 2H), 5.58 (d, J = 9.0 Hz, 1H), 4.93 (d, J = 9.0 Hz, 1H), 4.06 (s,
2H), 3.79 (s, 3H), 1.75 (s, 3H), 1.66 (s, 3H). 13C-NMR (100 MHz, CDCl3)
: 178.1, 176.6, 162.8, 159.9,
δ
δ
144.9, 137.2, 135.4, 132.5, 130.8, 130.7, 129.2, 125.5, 124.9, 119.3, 115.0, 110.5, 83.6, 58.9, 55.4, 54.8, 21.8,
21.0, 14.4.
4-(4-((Benzylselanyl)methyl)-1H-1,2,3-triazol-1-yl)-3-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[h]-chromene-
5,6-dione (20): Benzyl(prop-2-yn-1-yl)selane (230.1 mg, 1.1 mmol) was used. The product was obtained
in 52% yield as a yellow powder. m.p. (◦C) = 112.2–115.6, IR (solid, cm−1
)
ν
: 1656 (s), HRMS (EI+):
: 8.10 (d, J = 7.6 Hz, 1H),
7.90 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.0 Hz
2H), 7.06 (d, J = 7.7 Hz, 2H), 5.56 (d, J = 8.9 Hz, 1H), 4.92 (d, J = 8.9 Hz, 1H), 4.10 (d, J = 4.1 Hz, 2H),
2.30 (s, 3H), 1.72 (s, 3H), 1.65 (s, 3H). 13C-NMR (100 MHz, CDCl3)
: 178.1, 176.7, 162.9, 145.7, 139.2,
572.0089 [M]+. Cald. for [C16H10SeO2]: 572.0083; 1H-NMR (400 MHz, CDCl3)
δ
,
δ
135.5, 132.6, 130.9, 130.8, 129.4, 129.4, 128.8, 126.9, 125.5, 125.2, 110.6, 83.7, 59.1, 54.8, 27.7, 21.0, 16.0.
3-Bromo-2,2-dimethyl-4-(4-((p-tolylselanyl)methyl)-1H-1,2,3-triazol-1-yl)-3,4-dihydro-2H-benzo[h]-chromene-
5,6-dione (21): Prop-2-yn-1-yl(p-tolyl)selane (230.1 mg, 1.1 mmol) was used. The product was obtained
in 26% yield as a yellow powder. m.p. (◦C) = 114.1–116.6, IR (solid, cm−1
)
ν
: 1656 (s), HRMS (EI+):
: 8.08 (d, J = 7.5 Hz,
572.0062 [M]+. Cald. for [C16H10SeO2]: 572.0083; 1H-NMR (400 MHz, CDCl3)
δ
1H), 7.91 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.69 (s, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.35–7.24 (m,
4H), 7.18 (t, J = 7.0 Hz, 1H), 5.64 (d, J = 8.9 Hz, 1H), 4.96 (d, J = 8.9 Hz, 1H), 3.81 (s, 2H), 3.75 (s, 2H),

Molecules 2018, 23, 83
12 of 16
1.75 (s, 3H), 1.67 (s, 3H). 13C-NMR (100 MHz, CDCl3)
δ
: 178.0, 176.7, 162.8, 144.9, 137.9, 135.4, 134.8,
132.5, 130.9, 130.8, 130.1, 129.4, 125.8, 125.5, 125.1, 110.5, 83.6, 59.1, 54.6, 27.6, 21.3, 21.2, 21.0.
3-Bromo-2,2-dimethyl-4-(4-((thiophen-2-ylselanyl)methyl)-1H-1,2,3-triazol-1-yl)-3,4-dihydro-2H-benzo[h]
chromene-5,6-dione (22): 2-(Prop-2-yn-1-ylselanyl)thiophene (221.3 mg, 1.1 mmol) was used.
The product was obtained in 47% yield as a yellow powder. m.p. (◦C) = 104.3–108.6, IR (solid, cm−1
ν
)
: 1656 (s), 710 (w), HRMS (EI+): 563.9529 [M]+. Cald. for [C16H10SeO2]: 563.9490; 1H-NMR (400 MHz,
CDCl3) δ: 8.10 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 7.2 Hz,
1H), 7.43 (s, 1H), 7.37 (d, J = 5.3 Hz, 1H), 7.11 (d, J = 4.2 Hz, 1H), 6.95 (dd, J = 5.2, 3.5 Hz, 1H), 5.58 (d,
J = 9.0 Hz, 1H), 4.94 (d, J = 9.0 Hz, 1H), 4.05 (s, 2H), 1.75 (s, 3H), 1.65 (s, 3H). 13C-NMR (100 MHz,
CDCl3) δ: 178.0, 176.6, 162.9, 144.2, 137.2, 135.4, 132.5, 131.7, 130.8, 130.7, 129.4, 128.4, 125.5, 125.2,
123.0, 110.6, 83.6, 59.2, 54.6, 27.7, 24.0, 20.9.
3-Bromo-4-(4-((butylselanyl)methyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-
5,6-dione (23): Butyl(prop-2-yn-1-yl)selane (192.6 mg, 1.1 mmol) was used. The product was obtained
◦
−1
) ν
in 31% yield as a yellow powder. m.p. ( C) = 123.1–124.4, IR (solid, cm
: 2914 (s), 1670 (s), 782 (w),
HRMS (EI+): 538.0343 [M]+. Cald. for [C16H10SeO2]: 538.0239; 1H-NMR (400 MHz, CDCl3) δ: 8.07 (d,
J = 7.6 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.79 (s, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 5.65
(d, J = 9.0 Hz, 1H), 4.96 (d, J = 9.0 Hz, 1H), 3.83 (d, J = 3.1 Hz, 2H), 2.57 (d, J = 7.3 Hz, 2H), 1.76 (s,
3H), 1.67 (s, 3H), 1.61 (dd, J = 15.0, 7.5 Hz, 2H), 1.37 (dd, J = 14.4, 7.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H).
13C-NMR (100 MHz, CDCl3)
δ: 178.0, 162.8, 145.7, 135.4, 130.9, 130.7, 129.3, 125.5, 125.1, 110.6, 83.6,
59.1, 54.8, 32.4, 27.6, 24.2, 23.1, 20.9, 15.4, 13.8.
3-Bromo-2,2-dimethyl-4-(4-((phenylthio)methyl)-1H-1,2,3-triazol-1-yl)-3,4-dihydro-2H-benzo[h]chromene-
5,6-dione (24): Phenyl(prop-2-yn-1-yl)sulfane (◦163.0 mg, 1.1 mmol) was used. The product was
−1
obtained in 47% yield as a yellow powder. m.p. ( C) = 119.5–121.4, IR (solid, cm
)
ν
: 1656 (s), 754 (w),
HRMS (EI+): 510.0859 [M]+. Cald. for [C16H10SeO2]: 510.0482; 1H-NMR (400 MHz, CDCl3) δ: 8.09 (d,
J = 8.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 8.2 Hz, 1H), 7.65–7.59 (m, 2H), 7.34 (d, J = 7.4 Hz,
2H), 7.29–7.24 (m, 2H), 7.18 (t, J = 7.3 Hz, 1H), 5.58 (d, J = 9.0 Hz, 1H), 4.89 (d, J = 9.0 Hz, 1H), 4.21
(d, J = 7.2 Hz, 2H), 1.71 (s, 3H), 1.63 (s, 3H). 13C-NMR (100 MHz, CDCl3)
δ: 178.0, 176.6, 162.9, 144.1,
135.4, 135.3, 132.5, 130.9, 130.8, 130.7, 129.4, 129.2, 128.4, 127.0, 125.5, 125.5, 110.5, 83.6, 59.2, 54.6, 29.5,
27.6, 20.9.
3.1.3. Activity Against Cancer Cell Lines
Compounds were evaluated for antitumor activity in cell culture in vitro using several human
cancer cell lines obtained from the National Cancer Institute, NCI (Bethesda, MD, USA). The L929
cells (mouse fibroblast L cells NCTC clone 929) employed in this study as a control cell line, were
obtained from the American Type Culture Collection (Manassas, VA, USA). All cancer cell lines were
maintained in RPMI 1640 medium. The L929 cells were cultivated under standard conditions in
DMEM with Earle’s salts. All culture media were supplemented with 10% (cancer and L929 cells)
◦
fetal bovine serum, 2 mM L-glutamine, 100 IU/mL penicillin, 100
µ
g/mL streptomycin at 37 C
with 5% CO2. In cytotoxicity experiments, cells were plated in 96-well plates (0.1
×
106 (SF295);
0.7 × 105 (HCT-116); 0.5
×
105 (NCIH-460), 0.1
×
106 (PC3 and L929). All compounds tested were
dissolved in DMSO. The final concentration of DMSO in the culture medium was kept constant (0.1%,
v/v). Doxorubicin (0.001–1.10 µM) was used as the positive control, and negative control groups
received the same amount of vehicle (DMSO). The cell viability was determined by reduction of
the yellow dye 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT) to a purple
formazan product as described by Mosmann [58]. At the end of the incubation time (72 h), the plates
were centrifuged and the medium was replaced by fresh medium (200
MTT. After 3 h, the MTT formazan product was dissolved in DMSO (150
µ
L) containing 0.5 mg/mL
µL) and the absorbance was
measured using a multiplate reader (Spectra Count, Packard, ON, Canada). The impact of compounds

Molecules 2018, 23, 83
13 of 16
on cell proliferation was quantified as the percentage of control absorbance of the reduced dye at
550 nm. All cell culture based studies were performed in triplicate. All cells were mycoplasma-free.
4. Conclusions
We have demonstrated in previous reports that the strategy of conjoining two redox centers,
namely a quinoidal moiety and the atom of selenium or sulfur, represents a promising avenue to
prepare new compounds with antitumor activity. Here, we have prepared and assayed 24 such
compounds against five cancer cell lines and have identified several such quinone-selenium
hybrid molecules with moderate to high activity. Notably, in the past quinone-based triazole
chalcogenium-containing agents were considered as potent antitumor derivatives, with IC50 values
below 1 µM, and we have now added a new class of naphthoquinonoid compounds with improved
cytotoxicity against cancer cells. These compounds provide a lead for the further development of
redox active and often catalytic molecules based on natural products which eventually may be able to
distinguish between cancer and normal cells by modulating the specific pre-existing differences in
redox state which for a number of reasons is often found between those cells.
Acknowledgments: This research was funded by grants from the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq 305385/2014-3, PVE 401193/2014-4, 477346/2013-8 and Edital Universal
MCTI/CNPq NO. 01/2016), FAPEMIG (APQ-02478-14), and Programa Pesquisador Mineiro (PPM-00638-16),
INCT-Catálise and CAPES. C. Jacob and E.N. da Silva Júnior would especially like to thank to CAPES/DAAD
99999.008126/2015-01.
Author Contributions: Eufrânio N. da Silva Júnior, Claudia Pessoa, Antonio L. Braga and Claus Jacob
conceived and designed the experiments; Guilherme A. M. Jardim, Eduardo H. G. da Cruz, Wagner O. Valença,
Daisy J. B. Lima, Bruno C. Cavalcanti and Jamal Rafique performed the experiments; Eufrânio N. da Silva Júnior
and Claus Jacob analyzed the data; Eufrânio N. da Silva Júnior, Claudia Pessoa, Antonio L. Braga and
Claus Jacob contributed reagents/materials/analysis tools; Guilherme A. M. Jardim, Claus Jacob and
Eufrânio N. da Silva Júnior wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
The following abbreviations are used in this manuscript:
ROS
IC50
Reactive Oxygen Species
Half Maximal Inhibitory Concentration
CuAAC Copper(I) Catalyzed Azide-Alkyne Cycloaddition
NBS
DMF
CI
N-bromosuccinimide
Dimethylformamide
Confidence Interval
Micromole
µM
NMR
EtOAc
DMSO
Nuclear Magnetic Resonance
Ethyl Acetate
Dimethyl sulfoxide
References
1.
2.
3.
Stewart, B.W.; Wild, C.P. World Cancer Report; IARC Publications: Lyon, France, 2014.
World Health Organization (WHO). Guide to Cancer Early Diagnosis; WHO: Geneva, Switzerland, 2017.
World Health Organization. Global Health Observatory: The Data Repository; World Health Organization:
Geneva, Switzerland, 2017.
4.
5.
Barbounaki-Konstantakou, E. Chemotherapy; Beta Medical Arts: Athens, Greece, 1989.
Epstein, R.J. Maintenance therapy to suppress micrometastasis: The new challenge for adjuvant cancer
treatment. Clin. Cancer Res. 2005, 11, 5337–5341. [CrossRef] [PubMed]
6.
Rampling, R.; James, A.; Papanastassiou, V. The present and future management of malignant brain tumours:
Surgery, radiotherapy, chemotherapy. J. Neurol. Neurosurg. Psychiatry 2004, 75, 24–30. [CrossRef]

Molecules 2018, 23, 83
14 of 16
7.
8.
Scudamore, K.A.; Atkin, P.M.; Buckle, A.E. Natural occurrence of the naphthoquinone mycotoxins,
xanthomegnin, viomellein and vioxanthin in cereals and animal feldstuffs. J. Stored Prod. Res. 1986
22, 81–84. [CrossRef]
,
Machado, T.B.; Pinto, A.V.; Pinto, M.C.F.R.; Leal, I.C.R.; Silva, M.G.; Amaral, A.C.F.; Kuster, R.M.; Netto-dos
Santos, K.R. In vitro activity of Brazilian medicinal plants, naturally occurring naphthoquinones and their
analogues, against methicillin-resistant Staphylococcus aureus. Int. J. Antimicrob. Agents 2003, 21, 279–284.
[CrossRef]
9.
Lester, R.L.; White, D.C.; Smith, S.L. The 2-Desmethyl vitamin K2’s. A new group of naphthoquinones
isolated from Hemophilus parainfluenzae. Biochemistry 1964, 3, 949–954. [CrossRef] [PubMed]
10. Huang, L.J.; Chang, F.C.; Lee, K.H.; Wang, J.P.; Teng, C.M.; Kuo, S.C. Synthesis and antiplatelet,
antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone
and related compounds. Bioorg. Med. Chem. 1998, 6, 2261–2269. [CrossRef]
11. Tandon, V.K.; Chhor, R.B.; Singh, R.V.; Rai, S.; Yadav, D.B. Design, synthesis and evaluation of novel
1,4-naphthoquinone derivatives as antifungal and anticancer agents. Bioorg. Med. Chem. Lett. 2004, 14,
1079–1083. [CrossRef] [PubMed]
12. Ilina, T.V.; Semenova, E.A.; Pronyaeva, T.R.; Pokrovskii, A.G.; Nechepurenko, I.V.; Shults, E.E.; Andreeva, O.I.;
Kochetkov, S.N.; Tolstikov, G.A. Inhibition of HIV-1 reverse transcriptase by aryl-substituted naphtho- and
anthraquinones. Dokl. Biochem. Biophys. 2002, 382, 56–59. [CrossRef] [PubMed]
13. Huang, S.T.; Kuo, H.S.; Hsiao, C.L.; Lin, Y.L. Efficient synthesis of ‘redox-switched’ naphthoquinone
thiol-crown ethers and their biological activity evaluation. Bioorg. Med. Chem. 2002, 10, 1947–1952. [CrossRef]
14. Lien, J.C.; Huang, L.J.; Wang, J.P.; Teng, C.M.; Lee, K.H.; Kuo, S.C. Synthesis and antiplatelet,
antiinflammatory and antiallergic activities of 2,3-disubstituted 1,4-naphthoquinones. Chem. Pharm. Bull.
1996, 44, 1181–1187. [CrossRef] [PubMed]
15. Ting, C.Y.; Hsu, C.T.; Hsu, H.T.; Su, J.S.; Chen, T.Y.; Tarn, W.Y.; Kuo, Y.H.; Whang-Peng, J.; Liu, L.F.; Hwang, J.
Isodiospyrin as a novel human DNA topoisomerase I inhibitor. Biochem. Pharmacol. 2003, 66, 1981–1991.
[CrossRef] [PubMed]
16. Wurm, G.; Schwandt, S. Methylated 2-aryl-1,4-naphthoquinone derivatives with diminished antioxidative
activity. Pharmazie 2003, 58, 531–538. [PubMed]
17. Song, G.Y.; Kim, Y.; You, Y.J.; Cho, H.; Kim, S.H.; Sok, D.E.; Ahn, B.Z. Naphthazarin derivatives
(VI): Synthesis, inhibitory effect on DNA topoisomerase-I and antiproliferative activity of 2- or
6-(1-oxyiminoalkyl)-5,8-dimethoxy-1,4-naphthoquinones. Arch. Pharm. 2000, 333, 87–92. [CrossRef]
18. De Castro, S.L.; Emery, F.S.; da Silva Júnior, E.N. Synthesis of quinoidal molecules: Strategies towards
bioactive compounds with an emphasis on lapachones. Eur. J. Med. Chem. 2013, 69, 678–700. [CrossRef]
[PubMed]
19. Kovacic, P.; Somanathan, R. Recent developments in the mechanism of anticancer agents based on electron
transfer, reactive oxygen species and oxidative stress. Anticancer Agents Med. Chem. 2011, 11, 658–668.
[CrossRef] [PubMed]
20. Sunassee, S.N.; Veale, C.G.L.; Shunmoogam-Gounden, N.; Osoniyi, O.; Hendricks, D.T.; Caira, M.R.;
la Mare, J.A.; Edkins, A.L.; Pinto, A.V.; da Silva Júnior, E.N.; et al. Cytotoxicity of lapachol, β-lapachone and
related synthetic 1,4-naphthoquinones against oesophageal cancer cells. Eur. J. Med. Chem. 2013, 62, 98–110.
[CrossRef] [PubMed]
21. Srinivas, P.; Gopinath, G.; Banerji, A.; Dinakar, A.; Srinivas, G. Plumbagin induces reactive oxygen species,
which mediate apoptosis in human cervical cancer cells. Mol. Carcinog. 2004, 40, 201–211. [CrossRef]
[PubMed]
22. Papageorgiou, V.S.; Assimopoulou, A.N.; Couladouros, E.A.; Hepworth, D.; Nicolau, K.C. The Chemistry
and biology of alkannin, shikonin, and related naphthazarin natural products. Angew. Chem. Int. Ed. 1999
38, 270–300. [CrossRef]
,
23. Li, C.J.; Li, Y.Z.; Pinto, A.V.; Pardee, A.B. Potent inhibition of tumor survival in vivo by β-lapachone plus
taxol: Combining drugs imposes different artificial checkpoints. Proc. Natl. Acad. Sci. USA 1999, 96,
13369–13374. [CrossRef] [PubMed]
24. Lee, J.I.; Choi, D.Y.; Chung, H.S.; Seo, H.G.; Woo, H.J.; Choi, B.T.; Choi, Y.H. β-lapachone induces growth
inhibition and apoptosis in bladder cancer cells by modulation of Bcl-2 family and activation of caspases.
Exp. Oncol. 2006, 28, 30–35. [PubMed]

Molecules 2018, 23, 83
15 of 16
25. Li, Y.Z.; Sun, X.G.; Lamont, J.T.; Pardee, A.B.; Li, C.J. Selective killing of cancer cells by
β-lapachone: Direct
checkpoint activation as a strategy against cancer. Proc. Natl. Acad. Sci. USA 2003, 100, 2674–2678. [CrossRef]
[PubMed]
26. Cragg, G.M.; Grothaus, P.G.; Newman, D.J. Impact of natural products on developing new anti-cancer agents.
Chem. Rev. 2009, 109, 3012–3043. [CrossRef] [PubMed]
27. da Silva Júnior, E.N.; Guimarães, T.T.; Menna-Barreto, R.F.S.; Pinto, M.C.F.R.; de Simone, C.A.; Pessoa, C.;
Cavalcanti, B.C.; Sabino, J.R.; Andrade, C.K.Z.; Goulart, M.O.F.; et al. The evaluation of quinonoid
compounds against Trypanosoma cruzi: Synthesis of imidazolic anthraquinones, nor-β-lapachone derivatives
and β-lapachone-based 1,2,3-triazoles. Bioorg. Med. Chem. 2010, 18, 3224–3230. [CrossRef] [PubMed]
28. Szatrowski, T.P.; Nathan, C.F. Production of large amounts of hydrogen peroxide by human tumor cells.
Cancer Res. 1991, 51, 794–798. [PubMed]
29. Verrax, J.; Beck, R.; Dejeans, N.; Glorieux, C.; Sid, B.; Pedrosa, R.C.; Benites, J.; Vásquez, D.; Valderrama, J.A.;
Calderon, P.B. Redox-active quinones and ascorbate: An innovative cancer therapy that exploits the
vulnerability of cancer cells to oxidative stress. Anticancer Agents Med. Chem. 2011, 11, 213–221. [CrossRef]
[PubMed]
30. Trachootham, D.; Alexandre, J.; Huang, P. Targeting cancer cells by ROS-mediated mechanisms: A radical
therapeutic approach? Nat. Rev. Drug Discov. 2009, 8, 579–591. [CrossRef] [PubMed]
31. Jamier, V.; Ba, L.A.; Jacob, C. Selenium- and tellurium-containing multifunctional redox agents as biochemical
redox modulators with selective cytotoxicity. Chem. Eur. J. 2010, 16, 10920–10928. [CrossRef] [PubMed]
32. Doering, M.; Ba, L.A.; Lilienthal, N.; Nicco, C.; Scherer, C.; Abbas, M.; Zada, A.A.P.; Coriat, R.; Burkholz, T.;
Wessjohann, L.; et al. Synthesis and selective anticancer activity of organochalcogen based redox catalysts.
J. Med. Chem. 2010, 53, 6954–6963. [CrossRef] [PubMed]
33. Mecklenburg, S.; Shaaban, S.; Ba, L.A.; Burkholz, T.; Schneider, T.; Diesel, B.; Kiemer, A.K.; Roseler, A.;
Becker, K.; Reichrath, J.; et al. Exploring synthetic avenues for the effective synthesis of selenium- and
tellurium-containing multifunctional redox agents. Org. Biomol. Chem. 2009, 7, 4753–4762. [CrossRef]
[PubMed]
˙
34. Kieliszek, M.; Lipinski, B.; Błazejak, S. Application of sodium selenite in prevention and treatment of cancers.
Cells 2017, 6, 39. [CrossRef] [PubMed]
˙
35. Kieliszek, M.; Błazejak, S. Current knowledge on the importance of selenium in food for living organisms:
A review. Molecules 2016, 21, 609. [CrossRef] [PubMed]
˙
36. Kieliszek, M.; Błazejak, S. Selenium: Significance, and outlook for supplementation. Nutrition 2013, 29,
713–718. [CrossRef] [PubMed]
37. Vieira, A.A.; Brandão, I.R.; Valença, W.O.; de Simone, C.A.; Cavalcanti, B.C.; Pessoa, C.; Carneiro, T.R.;
Braga, A.L.; da Silva Júnior, E.N. Hybrid compounds with two redox centres: Modular synthesis of
chalcogen-containing lapachones and studies on their antitumor activity. Eur. J. Med. Chem. 2015, 101,
254–265. [CrossRef] [PubMed]
38. Da Cruz, E.H.G.; Silvers, M.A.; Jardim, G.A.M.; Resende, J.M.; Cavalcanti, B.C.; Bomfim, I.S.; Pessoa, C.;
de Simone, C.A.; Botteselle, G.V.; Braga, A.L.; et al. Synthesis and antitumor activity of selenium-containing
quinone-based triazoles possessing two redox centres, and their mechanistic insights. Eur. J. Med. Chem.
2016, 122, 1–16. [CrossRef] [PubMed]
39. Roudesly, F.; oble, J.; Poli, G. Metal-catalyzed C-H activation/functionalization: The fundamentals. J. Mol.
Catal. A Chem. 2017, 426, 275–296. [CrossRef]
40. Gensch, T.; Hopkinson, M.N.; Glorius, F.; Wencel-Delord, J. Mild metal-catalyzed C–H activation: Examples
and concepts. Chem. Soc. Rev. 2106, 45, 2900–2936. [CrossRef] [PubMed]
41. Hartwig, J.F. Evolution of C–H bond functionalization from methane to methodology. J. Am. Chem. Soc.
2016, 138, 2–24. [CrossRef] [PubMed]
42. Bahia, S.B.B.B.; Reis, W.J.; Jardim, G.A.M.; Souto, F.T.; De Simone, C.A.; Gatto, C.C.; Menna-Barreto, R.F.S.;
De Castro, S.L.; Cavalcanti, B.C.; Pessoa, C.; et al. Molecular hybridization as a powerful tool towards
multitarget quinoidal systems: Synthesis, trypanocidal and antitumor activities of naphthoquinone-based
5-iodo-1,4-disubstituted-, 1,4- and 1,5-disubstituted-1,2,3-triazoles. Med. Chem. Commun. 2016, 7, 1555–1563.
[CrossRef]

Molecules 2018, 23, 83
16 of 16
43. Jardim, G.A.M.; Calado, H.D.R.; Cury, L.A.; da Silva Júnior, E.N. Synthesis of a phenazine-based 1,2,3-triazole
from naturally occurring naphthoquinone designed as a probe for Cd ions. Eur. J. Org. Chem. 2015, 38,
703–709. [CrossRef]
44. Jardim, G.A.M.; Reis, W.J.; Ribeiro, M.F.; Ottoni, F.M.; Alves, R.J.; Silva, T.L.; Goulart, M.O.F.; Braga, A.L.;
Menna-Barreto, R.F.S.; Salomão, K.; et al. On the investigation of hybrid quinones: Synthesis, electrochemical
studies and evaluation of trypanocidal Activity. RSC Adv. 2015, 5, 78047–78060. [CrossRef]
45. Cruz, E.H.G.; Carvalho, P.H.P.R.; Correa, J.R.; Silva, D.A.C.; Diogo, E.B.T.; Souza Filho, J.D.; Coelho, B.;
Pessoa, C.; Oliveira, H.C.B.; Guido, B.C.; et al. Design, synthesis and application of fluorescent
2,1,3-benzothiadiazole-triazole-linked biologically active lapachone derivatives. New J. Chem. 2014, 38,
2569–2580. [CrossRef]
46. Jardim, G.A.M.; da Silva Júnior, E.N.; Bower, J.F. Overcoming naphthoquinone deactivation:
Rhodium-catalyzed C-5 selective C–H iodination as a gateway to functionalized derivatives. Chem. Sci. 2016
,
7, 3780–3784. [CrossRef]
47. Jardim, G.A.M.; Bower, J.F.; da Silva Júnior, E.N. Rh-Catalyzed Reactions of 1,4-Benzoquinones with
Electrophiles: C-H Iodination, Bromination, and Phenylselenation. Org. Lett. 2016, 18, 4454–4457. [CrossRef]
[PubMed]
48. Jardim, G.A.M.; Silva, T.L.; Goulart, M.O.F.; de Simone, C.A.; Barbosa, J.M.C.; Salomão, K.; de Castro, S.L.;
Bower, J.F.; da Silva Júnior, E.N. Rhodium-catalyzed C-H bond activation for the synthesis of quinonoid
compounds: Significant Anti-Trypanosoma cruzi activities and electrochemical studies of functionalized
quinones. Eur. J. Med. Chem. 2017, 136, 406–419. [CrossRef] [PubMed]
49. Kathawate, L.; Gejji, S.P.; Yeole, S.D.; Verma, P.L.; Puranik, V.G.; Salunke-Gawali, S. The first
naphthosemiquinone complex of K+ with vitamin K3 analog: Experiment and density functional theory.
J. Mol. Struct. 2015, 1088, 56–63. [CrossRef]
50. Biyogo, A.M.; Khoumeri, O.; Terme, T.; Curti, C.; Vanelle, P. Synthesis of new 2,4-disubstituted
2,3-dihydrobenzo[g]indol-5-ones by an SRN1 strategy. Synthesis 2015, 47, 2647–2653. [CrossRef]
51. Sharpless, K.B.; Fokin, V.V.; Green, L.G.; Rostovtsev, V.V. A stepwise Hüisgen cycloaddition process:
Copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes. Angew. Chem. Int. Ed. 2002, 41,
2596–2599.
52. Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Click chemistry for drug development and diverse
chemical-biology applications. Chem. Rev. 2013, 113, 4905–4979. [CrossRef] [PubMed]
53. Kacprzak, K.; Skiera, I.; Piasecka, M.; Paryzek, Z. Alkaloids and isoprenoids modification by
copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (Click Chemistry): Toward new functions and
molecular architectures. Chem. Rev. 2016, 116, 5689–5743. [CrossRef] [PubMed]
54. Iha, R.K.; Wooley, K.L.; Nystro, A.M.; Burke, D.J.; Kade, M.J.; Hawker, C.J. Applications of orthogonal
“click” chemistries in the synthesis of functional soft materials. Chem. Rev. 2009, 109, 5620–5686. [CrossRef]
[PubMed]
55. Maarseveen, J.H.; Hiemstra, H.; Bock, V.D. CuI-catalyzed alkyne-azide “click” cycloadditions from a
mechanistic and synthetic perspective. Eur. J. Org. Chem. 2006, 1, 51–68.
56. Pinto, C.N.; Dantas, A.P.; De Moura, K.C.G.; Emery, F.S.; Polequevitch, P.F.; Pinto, M.C.F.R.; De Castro, S.L.;
Pinto, A.V. Chemical Reactivity Studies with Naphthoquinones from Tabebuia with Anti-trypanosomal
Efficacy. Arzneimittelforschung 2000, 50, 1120–1128. [CrossRef] [PubMed]
57. Pinto, A.V.; Pinto, C.N.; Pinto, M.C.; Rita, R.S.; Pezzella, C.A.C.; de Castro, S.L. Trypanocidal activity of
synthetic heterocyclic derivatives of active quinones from Tabebuia sp. Arzneimittelforschung 1997, 47, 74–79.
[PubMed]
58. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and
cytotoxicity assays. J. Immunol. Methods 1983, 65, 55–63. [CrossRef]
Sample Availability: Samples of all compounds are available from the C. Jacob (c.jacob@mx.uni-saarland.de) and
E. N. da Silva Júnior (eufranio@ufmg.br) laboratories.
©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).