Long-chain alkyltriazoles as antitumor agents: Synthesis, physicochemical properties, and biological and computational evaluation

Article abstract of DOI:10.1007/s00044-014-1137-3

A series of novel long-chain alkyltriazoles were prepared from commercial diols in a rapid process with good yields. The compounds were evaluated in vitro for their anticancer potential against two human cancer cell lines: colon carcinoma (RKO) and uterine carcinoma (HeLa). The results of colorimetric MTT assays showed that six of fourteen compounds tested decreased cell viability in these cell lines. Compounds 5e and 6a were the most active against RKO cells, with IC₅₀ values of 16.70 and 14.57 μM, respectively. The same compounds, 5e and 6a, were the most active in HeLa cells as well, with IC₅₀ values of 11.05 and 12.77 μM, respectively. In addition, compound 5e was found to induce apoptosis in RKO cells, as assessed by TUNEL assay. The results suggest that compound 5e may be a promising prototype anticancer agent.

Full text of DOI:10.1007/s00044-014-1137-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2015) 24:430–441
DOI 10.1007/s00044-014-1137-3
ORIGINAL RESEARCH
Long-chain alkyltriazoles as antitumor agents: synthesis,
physicochemical properties, and biological and computational
evaluation
´
Vanessa Silva Gontijo Michael Eder Oliveira Rafael Jose Resende
•
•
•
´
Amanda Luisa Fonseca Renata Rachide Nunes Moacyr Comar Junior
•
•
•
´
•
Alex Gutterres Taranto Natalia Machado Pereira Oliveira Torres
•
•
Gustavo Henrique Ribeiro Viana Luciana Maria Silva Rosemeire Brondi Alves
•
•
•
Fernando Pilla Varotti Rossimiriam Pereira Freitas
Received: 27 March 2014 / Accepted: 25 June 2014 / Published online: 15 July 2014
Ó Springer Science+Business Media New York 2014
Abstract A series of novel long-chain alkyltriazoles were
prepared from commercial diols in a rapid process with
good yields. The compounds were evaluated in vitro for
their anticancer potential against two human cancer cell
lines: colon carcinoma (RKO) and uterine carcinoma
(HeLa). The results of colorimetric MTT assays showed
that six of fourteen compounds tested decreased cell via-
bility in these cell lines. Compounds 5e and 6a were the
most active against RKO cells, with IC50 values of 16.70
and 14.57 lM, respectively. The same compounds, 5e and
6a, were the most active in HeLa cells as well, with IC50
values of 11.05 and 12.77 lM, respectively. In addition,
compound 5e was found to induce apoptosis in RKO cells,
as assessed by TUNEL assay. The results suggest that
compound 5e may be a promising prototype anticancer
agent.
Keywords Alkyltriazoles ꢀ Antitumoral ꢀ
Click chemistry ꢀ Heterocycles
Introduction
Cancer is the second leading cause of death in the world. Most
of the anticancer drugs currently available for cancer treat-
ment have well-established shortcomings, such as poor effi-
ciency and selectivity, and high toxicity. Therefore, the
identification of potent, selective, and less toxic anticancer
agents remains an important and challenging goal of medici-
´
nal chemistry (Hilario et al., 2011; Correale et al., 2011).
Single long-chain alkylphospholipids (APLs) are a rela-
tively new class of structurally related antitumor agents that,
unlike conventional chemotherapeutic drugs, induce apop-
tosis in tumor cells by acting on cell membranes rather than
on DNA. APLs accumulate in the cell and interfere with
lipid-dependent survival signaling pathways, notably the
PI3K-Akt and Raf-Erk1/2 pathways, and de novo
phospholipid biosynthesis (Blitterswijk and Verheij, 2012).
Alkyllysophospholipids and alkylphosphocholines (APCs)
are two classes of APL ether lipids that could be potential
anticancer agents. Miltefosine, perifosine, erucylphosph-
ocholine, and erufosine (Fig. 1) are APCs, which are derived
from alkyllysophospholipids by the removal of the glycerol
group. In the APC edelfosine, however, the glycerol back-
bone is maintained. Hexadecylphosphocholine (1) is a lipid
analog that exerts antiproliferative activity against a broad
spectrum of established tumor cell lines (Blitterswijk and
Verheij, 2012; Wieder et al., 1998). Studies on cytotoxic
APLs revealed that a long alkyl chain and a polar group are
essential for antitumor activity (Rakotomanga et al., 2007).
In the last decade, a large number of studies have
reported the synthesis and biological screening of several
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-014-1137-3) contains supplementary
material, which is available to authorized users.
V. S. Gontijo ꢀ N. M. P. O. Torres ꢀ R. B. Alves ꢀ
R. P. Freitas (&)
Departamento de Quımica, ICEx, UFMG, Av. Pres. Antonio
Carlos 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil
e-mail: rossimiriam@pq.cnpq.br
´
ˆ
´
M. E. Oliveira ꢀ R. J. Resende ꢀ A. L. Fonseca ꢀ
´
R. R. Nunes ꢀ M. C. Junior ꢀ A. G. Taranto ꢀ
G. H. R. Viana ꢀ F. P. Varotti (&)
Universidade Federal de Sa˜o Joa˜o del-Rei, Campus Centro-
´
Oeste, Av. Sebastia˜o Gonc¸alves Coelho, 400, Divinopolis,
MG 35501-296, Brazil
e-mail: varotti@ufsj.edu.br
L. M. Silva
´
Laboratorio de Biologia Celular, Fundac¸a˜o Ezequiel Dias,
Belo Horizonte, MG 30535-380, Brazil
123

Med Chem Res (2015) 24:430–441
431
CH3
CH3
CH3
H3C
CH3
O
CH3
CH3
N
O
H3C
N
CH3
H3C
N
CH3
H3C
N
CH3
H3C
N
CH2
H3C
N CH3
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
P
CH2
O
P
O
P
O
O
P
O
P
O
O
O
O
O
O
P
O
O
O
O
O
O
O
O
O
O
CH2
CH2
O
HO CH
H2C
HO CH
CH2
O
O
C
O
CH3
CH3
Perifosine
Miltefosine
H3C
H3C
H3C
LysoPC
H3C
Erucylphosphocholine
(ErPC)
Edelfosine
Erufosine
(ErPC3)
Fig. 1 Structures of natural lysophosphatidylcholine and some synthetic alkyl-phospholipid (APL) analogs. (Adapted of Blitterswijk and
Verheij, 2012)
APC compounds (Ungera and Eibl, 1991; Van der Luit
et al., 2007; Vink et al., 2007). Although they are struc-
turally simple, the purification of these highly polar com-
pounds is very difficult, time-consuming, expensive, and
frequently results in low yields.
heterocycles are resistant to metabolic degradation and can
interact with biological structures in several noncovalent
ways (Deiters et al., 2003; Wang et al., 2003; Dirks et al.,
2005; Kosiova et al., 2007; Santos et al., 2008). Finally,
they have a large dipole moment and are capable of
hydrogen bonding, which could allow them to act as a
polar head group.
1,2,3-Triazoles are a very important class of synthetic
heterocycles that have received widespread attention in
recent years because of their broad range of pharmaco-
logical properties and easy synthetic accessibility by click
chemistry. They are found in various bioactive molecules,
including antifungal (Aher et al., 2009), antibacterial
(Demaray et al., 2008; Wang et al., 2010), antiallergic
(Buckle et al., 1983), anti-HIV (Whiting et al., 2006; Giffin
et al., 2008), antitubercular (Costa et al., 2006; Patpi et al.,
2012), and anti-inflammatory agents (Simone et al., 2011).
In addition, the synthesis of different 1,2,3-triazoles with
anticancer activity has also been increasingly noted (Alam
et al., 2013; Praveena et al., 2014; Kurumurthy et al.,
2014). Triazoles are often considered bioisosteres of amide
functionalities in bioactive compounds due to similarities
in spatial structure and electronic effect. Furthermore, these
Considering the potential anticancer activity of APCs
and the speculation that their activity is linked to the pre-
sence of a hydrophobic tail attached to a hydrophilic polar
head group, we focused our attention on synthesizing
simpler potentially antitumoral compounds containing a
1,2,3-triazole ring and alkyl chains with different lengths
and functionalizations. These compounds can be prepared
using a 1,3-dipolar cycloaddition reaction between an
alkyne and an azide (Struthers et al., 2010). This cycliza-
tion reaction, developed in the early 1960s by Huisgen
(1961), became highly popular when Sharpless (Rostovtesv
et al., 2002) and Meldal (Tornøe et al., 2002) separately
reported its Cu(I)-catalyzed version (Scheme 1). The
reaction is now known as the Cu-catalyzed azide–alkine
123

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Med Chem Res (2015) 24:430–441
( )
( )
( )
i
ii
n
n
n
HO
N3
HO
OH
HO
Br
3a, n=6, 48%
3b, n=9, 85%
3c, n=12, 80%
1a, n=6
1b, n=9
1c, n=12
2a, n=6, 87%
2b, n=9, 87%
2c, n=12, 65%
R
N
iii
N
5a, X=OMs, n=1, R=-(CH2)3OH (46%)
5b, X=OMs, n=1, R=-COOCH2CH3 (60%)
5c, X=OMs, n=4, R=-(CH2)3OH (92%)
5d, X=OMs, n=4, R=-COOCH2CH3 (92%)
5e, X=OMs, n=7, R=-(CH2)3OH (52%)
5f, X=OMs, n=7, R=-(CH2)2COOH (81%)
5g, X=OMs, n=7, R=-COOCH2CH3 (93%)
5h, X=OMs, n=7, R=-CH2OH (56%)
5i, X=F, n=4, R=-(CH2)3OH (48%)
N
( )
n
v
X
N3
n
4a, X= OMs, n=6, 37%
4b, X= OMs, n=9, 90%
4c, X= F, n= 9, 47%
4d, X= OMs, n=12, 84%
4e, X= F, n=12, 49%
iv
iv
5j, X=F, n=7, R=-(CH2)3OH (46%)
X
Scheme 1 Reagents and conditions: (i) HBr (48 %), toluene, 110 °C,
24 h, 65–87 %; (ii) NaN3, DMSO, rt, 24 h, 48–85 %; (iii) CH2Cl2,
mesyl chloride, triethylamine, rt, 24 h, 37–90 %; (iv) KF/18-crown-6,
DMSO, 110 °C, 24 h, 47–49 %; (v) NaAsc (20 mol%), CuSO4ꢀ5H2O
(8 mol%), alkyne: pent-4-yn-1-ol, ethyl propiolate, 4-pentynoic acid,
or propargyl alcohol, CH2Cl2:H2O (1:1), rt., 24 h, 46–93 %
cycloaddition (CuAAC) (Amblard et al., 2009; Meldal and
Tornoe, 2008) or click reaction. Sharpless strongly defen-
ded its use in drug discovery, reasoning that, in this field,
all searches must be restricted to molecules that are easy to
make (Kolb et al., 2001). In addition to synthesizing al-
kyltriazoles, we also evaluated the antitumoral activity
in vitro of the new compounds against two human cancer
cell lines: colon carcinoma (RKO-AS451) cells and uterine
carcinoma (HeLa).
ionization coupled to time-of-flight (Solvent: MeOH). The
progress of the reactions was monitored by TLC on Merck
silica plates (GF254). Column chromatography was per-
formed over silica gel 60, 70–230 mesh (Merck).
Synthesis
General procedure for the synthesis of methanesulfonate
alkylazides (4a, 4b, and 4d)
To a stirred solution of 1,6-hexanodiol 1a (1.00 equiv.), 1,9-
nonanediol 1b (1.00 equiv.), or 1,12-dodecanediol 1c (1.00
equiv.), in 30 mL of toluene was added HBr 48 % (2.00
equiv.). The reaction was stirred at 110 °C for 24 h. The
solvent was removed under reduced pressure, and the residue
was purified by column chromatography over silica gel,
eluting with hexane/EtOAc 9:1, to yield pure haloalcohol
2a–c. These compounds were transformed into their corre-
spondingazidoalcohols 3a–c bySN2 substitution (Scheme 1).
A stock solution of 0.5 M NaN3 in DMSO was prepared by
stirring the solution for 24 h at room temperature. To a
100-mL round-bottom flask equipped with a magnetic stir bar
was added a 0.5 M solution of NaN3 in DMSO at room tem-
perature. To this solution was added the bromoalcohol 2a
(1.00 equiv.), 2b (1.00 equiv.), or 2c (1.00 equiv.), and the
mixturewasstirredfor 24 h atroomtemperature. Thereaction
was quenched with H2O (50 mL) and stirred until it cooled to
room temperature. The mixture was extracted with Et2O
Methods and materials
General
Reagents and solvents were purchased as reagent grade and
used without further purification. All melting points were
measured on Fisher–Jonhs and are uncorrected. IR spectra
were recorded on Perkin-Elmer Spectrum One SP-IR
Spectrometer. 1H and 13C NMR spectra were recorded on a
Bruker AVANCE DRX 200 MHz spectrometer using TMS
as an internal standard. The results are presented as
chemical shift d in ppm, number of protons, multiplicity,
J values in Hertz (Hz), proton position, and carbon posi-
tion. Multiplicities are abbreviated as follows: s (singlet), d
(doublet), t (triplet), m (multiplet), and qn (quintet). High
resolution mass spectra were recorded on ESI-MS—Bruker
Daltonics Micro TOF mass spectrometer with electrospray
123

Med Chem Res (2015) 24:430–441
433
(3 9 30 mL), and the resulting extracts were washed with
H2O (3 9 50 mL) and brine (50 mL). The organic layer was
dried (Na2SO4) and filtered, and the residue obtained was
purified by column chromatography over silica gel, eluting
with hexane/EtOAc 9:1, to yield pure alkyl azidoalcohols 3a–
c. A solution of the azidoalcohol 3a (1.00 equiv.), 3b (1.00
equiv.), or 3c (1.00 equiv.) in CH2Cl2 (50 mL) was cooled to
0 °C. Et3N (2.00 equiv.) and methanesulfonyl chloride (2.00
equiv.) was added. The reaction mixture was stirred for 24 h
and then allowed to reach room temperature. The reaction
mixture was poured into crushed ice (70 mL) and was then
extracted with methylene chloride (3 9 30 mL). The organic
layer was dried (Na2SO4), filtered, and evaporated under
reduced pressure. The residue obtained was purified by col-
umn chromatography over silica gel, eluting with hexane/
EtOAc 9:1, to yield highly purified halo alcohol pure meth-
anesulfonate alkylazides compounds 4a, 4b, and 4d.
ascorbate (0.20 equiv.), and alkyne (pent-4-yn-1-ol, propargyl
alcohol, 4-pentynoic acid, or ethyl propiolate (1.00 equiv.).
The reaction mixture was vigorously stirred at room temper-
ature for 24 h. After completion ofthe reaction, 5 mLofwater
were added, followed by extraction with dichloromethane
(3 9 8 mL). The resulting organic layer was washed three
times with a 25 % EDTA solution buffered with NH4Cl at pH
9.5. The organic layer was dried with Na2SO4 and the solvent
was removed under reduced pressure. The crude product was
purified by column chromatography over silica gel, eluting
with dichloromethane, dichloromethane:EtOAc (8:2 v/v; 5:5
v/v; 2:8 v/v), EtOAC and EtOAc/MeOH (8:2 v/v; 5:5 v/v; 2:8
v/v), to give pure compounds 5a–j.
6-(4-(3-Hydroxypropyl)-1H-1,2,3-triazol-1-yl)hexyl meth-
anesulfonate (5a) Yellow oil, 46 %; IR (neat) mmax 3276,
2916, 2850, 1331, 1162, 1052–848 cm-1; 1H NMR (CDCl3,
200 MHz): d = 1.24–1.96 (10H, m, 59 CH2), 2.79 (2H, t,
J = 6.0 Hz, –CH2–Ctriazole), 2.98 (3H, s, –CH3SO2), 3.66
(2H, t, J = 6.0 Hz, –CH2–Ntriazole), 4.18 (2H, t, J = 6.0 Hz,
–CH2OH), 4.30 (2H, t, J = 6.0 Hz, –CH2OMs), 7.33 (1H, s,
–C=CHtriazole); 13C NMR (CDCl3, 50 MHz): d = 21.5, 24.4,
25.4, 28.4, 29.6 and 31.8 (69 CH2), 36.9 (–CH3SO2), 49.6
(–CH2–Ntriazole), 60.8(–CH2OH), 69.9 (–CH2OMs), 121.1
(–C=CHtriazole), 147.2 (–C=Ctriazole); HRESIMS m/z
[M?H]?: 306.1350 C12H24N3O4S (calcd. 306.1487).
General procedure for the synthesis of alkylfluoro (4c
and 4e)
To a stirred solution of 9-azidononyl methanesulfonate 4b
(1.00 equiv.) or 12-azidododecyl methanesulfonate 4d (1.00
equiv.) in 4 mL of anhydrous DMSO was added KF (2.00
equiv.) and 18-crown-6 (2.00 equiv.). The reaction was
mainteined at 110 °C for 24 h. The solvent was removed
under reduced pressure, and the residue was purified by
column chromatography over silica gel, eluting with hexane/
EtOAc 9:1, to yield pure alkylfluoro 4c and 4e.
6-(4-(Ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl methane-
sulfonate (5b) Yellow–white solid, 60 %; m.p. =
70–72 °C; IR (neat) mmax 2945, 2915, 2869, 1728, 1344,
1
1-Azido-9-fluorononane (4c) Yellow oil, 49 %; IR (neat)
max 2929, 2857, 2091 cm-1; 1H NMR (CDCl3, 200 MHz):
1197, 1097–957, 1166, 1156, 1097, 915 cm-1; H NMR
m
(CDCl3, 200 MHz): d = 1.30–1.38 (7H, m, –OCH2CH3 and
29 CH2), 1.68 (2H, qn, J = 6.0 Hz, –CH2CH2Ntriazole), 1.90
(2H, qn, J = 6.0 Hz, –CH2CH2OMs), 2.95 (3H, s,
–CH3SO2), 4.15 (2H, t, J = 6.0 Hz, –CH2OMs), 4.26–4.42
(4H, m, –CH2–Ntriazole and –OCH2CH3), 8.08 (1H, s, –C=
CHtriazole); 13C NMR (CDCl3, 50 MHz): d = 14.2
(–OCH2CH3), 24.7, 25.6, 28.7 and 29.8 (49 CH2), 37.2
(–CH3SO2), 50.3 (–CH2–Ntriazole), 61.1 (–OCH2CH3), 69.7
(–CH2OMs), 127.3 (–C = CHtriazole), 140.1 (–C=Ctriazole),
160.6 (–CO); HRESIMS m/z [M?H]?: 320.1138
C12H22N3O5S (calcd. 320.1280).
d = 1.20–1.49 (12H, m, 69 CH2), 1.52–1.81 (2H, m,
–CH2CH2F), 3.26 (2H, t, J = 6.0 Hz, –CH2N3), 4.43(2H, td,
J = 6.0, 48.0 Hz, –CH2F). 13C NMR (CDCl3, 50 MHz):
d = 25.2 (–CH2CH2N3), 26.8 (–CH2CH2F), 29.0, 29.2, 29.
3, 29.5 (49 CH2), 30.6 (d, J = 19.0, –CH2CH2F), 51.6
(–CH2N3), 84.3 (d, J = 163.0, –CH2F).
1-Azido-12-fluorododecane (4e) Yellow oil, 47 %; IR
(neat) mmax 2929, 2857, 2091 cm-1 1H NMR (CDCl3,
;
200 MHz): d = 1.19–1.44 (18H, m, 99 CH2), 1.52–1.80
(2H, m, –CH2CH2F), 3.26 (2H, t, J = 6.0 Hz, –CH2N3,).
4.44 (2H, t, J = 6.0 Hz, –CH2F); 13C NMR (CDCl3,
50 MHz): d = 25.3 (–CH2CH2N3), 26.9 (–CH2CH2F),
29.0, 29.3, 29.4, 29.7 (79 –CH2), 30.6 (d, J = 19.5 Hz,
–CH2CH2F), 51.7 (–CH2N3), 84.5 (d, J = 156.5 Hz, –CH2F).
9-(4-3-Hydroxypropyl)-1H-1,2,3-triazol-1-yl)nonyl methane-
sulfonate (5c) White solid, 39 %; m.p. = 64–66 °C; IR
(neat) mmax 3276, 2919, 2851, 1332, 1164, 1059–848 cm-1
;
1H NMR (CDCl3, 200 MHz): d = 1.02–1.45 (10H, m, 59
CH2), 1.57–1.71 (m, –CH2CH2Ntriazole), 1.70–1.99 (4H, m,
–CH2CH2OMs and –CH2CH2OH), 2.76 (2H, t, J = 6.0
Hz, –CH2–Ctriazole), 2.94 (3H, s, –CH3SO2), 3.63 (2H, t,
J = 6.0 Hz, –CH2OH), 4.15 (2H, t, J = 6.0 Hz,
–CH2OMs), 4.24 (2H, t, J = 6.0 Hz, –CH2–Ntriazole), 7.24
(1H, s, –C=CHtriazole); 13C NMR (CDCl3, 50 MHz): d =
General procedure for the synthesis of alkyltriazoles (5a–j)
The azide compound (4a–e) (1.00 equiv.) was added to a
10-mL round-bottom flask containing 1 mL of dichloro-
methane, 1 mL of water, CuSO4ꢀ5H2O (0.08 equiv.), sodium
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Med Chem Res (2015) 24:430–441
12-(4-(Ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)dodecyl
methanesulfonate (5g) White solid, 93 %; m.p. =
78–80 °C; IR (neat) mmax 2916, 2850, 1717, 1341, 1226,
21.8, 24.9, 25.9, 28.5, 28.9, 29.8 and 31.9 (99 CH2), 36.9
(–CH3SO2), 49.5 (–CH2–Ntriazole), 61.4 (–CH2OH), 70.1
(–CH2OMs), 120.7 (–C=Ctriazole), 147.4 (–C=Ctriazole);
HRESIMS m/z [M?H]?: 348.1834 C15H30N3O4S (calcd.
348.1957).
1207, 1168, 1046–943, 848 cm-1 1H NMR (CDCl3,
;
200 MHz): d = 1.20–1.30 (16H, m, 89 CH2), 1.41 (2H, t,
J = 6.0 Hz, –OCH2CH3), 1.74 (2H, qn, J = 6.0 Hz,
–CH2CH2OMs), 1.87–1.98 (2H, m, –CH2CH2Ntriazole),
2.97 (3H, s, –CH3OMs), 4.18 (2H, t, J = 6.0 Hz,
–CH2–Ntriazole), 4.39–4.45 (4H, m, –CH2OMs and
–OCH2CH3), 8.05 (1H, s, –C=CHtriazole); 13C NMR (CDCl3,
50 MHz): d = 14.2 (–OCH2CH3), 25.2, 26.2, 29.0, 29.2,
29.5, 29.8 and 30.3 (89 CH2), 37.0 (–CH3OMs), 50.8
(–CH2–Ntriazole), 61.5 (–OCH2CH3), 70.4 (–CH2OMs),
127.2 (–C=CHtriazole), 140.1 (–C=Ctriazole), 160.7 (–CO);
HRESIMS m/z [M?H]?: 404.2464 C18H34N3O5S (calcd.
404.2219).
9-(4-(Ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)nonyl methane-
sulfonate (5d) Yellow solid, 92 %; m.p. = 72–74 °C; IR
(neat) mmax 2936, 2912, 2852, 1713, 1352, 1215, 1168,
1051–979 cm-1; 1H NMR (CDCl3, 200 MHz): d = 1.14–1.
33 (10H, m, 59 CH2), 1.39 (2H, t, J = 6.0 Hz, –OCH2CH3),
1.71 (2H, qn, J = 6.0, –CH2CH2OMs,), 1.81–1.99 (2H, m,
–CH2CH2Ntriazole), 2.90 (3H, s, –CH3SO2), 4.19 (2H, t, J =
6.0 Hz, –CH2OMs), 4.30–4.50 (2H, m, –CH2–Ntriazole), 8.08
(1H, s, –C=CHtriazole); 13C NMR (CDCl3, 50 MHz): d =
13.7 (–OCH2CH3), 24.9, 26.3, 28.6, 29.0 and 29.8 (59 CH2),
37.4 (–CH3OMs), 49.9 (–CH2–Ntriazole), 60.9 (–OCH2CH3),
69.7 (–CH2OMs), 127.3 (–C=CHtriazole), 140.2 (–C=Ctriazole),
160.6 (–CO); HRESIMS m/z [M?H]?: 362.1861 C15H28
N3O5S (calcd. 362.1749).
12-(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)dodecyl meth-
anesulfonate (5h) Yellow solid, 56 %; m.p. = 86–88 °C;
IR (neat) mmax 3117, 3023, 2916, 2850, 1331, 1162, 1120,
1052–951 cm-1; 1H NMR (CDCl3, 200 MHz): d = 1.16–1.
38 (16H, m, 89 CH2), 1.62–1.88 (4H, m, CH2CH2OMs and
CH2CH2Ntriazole), 2.95 (3H, s, –CH3OMs), 4.16 (2H, t, J =
6.0 Hz, –CH2OMs), 4.27 (2H, t, J = 6.0 Hz, –CH2–Ntriazole),
4.70 (2H, s, –CH2OH), 7.54 (1H, s, –C=CHtriazole); 13C NMR
(CDCl3, 50 MHz): d = 25.4, 26.3, 28.8, 28.9, 29.2, 30.1 and
31.2(109CH2), 37.2(–CH3OMs), 50.3(–CH2–Ntriazole),55.9
(–CH2OH), 70.3 (–CH2OMs), 121.8 (–C=CHtriazole), 147.8
(–C=Ctriazole); HRESIMS m/z [M?H]?: 362.2047 C16H32
N3O4S (calcd. 362.2113).
12-(4-(3-Hydroxypropyl)-1H-1,2,3-triazol-1-yl)dodecyl
methanesulfonate (5e) White solid, 52 %; m.p. =
80–82 °C; IR (neat) mmax 3389, 2916, 2850, 1332, 1163,
1045, 956 cm-1
;
1H NMR (CDCl3, 200 MHz): d =
1.25–1.44 (16H, m, 29 CH2), 1.75 (2H, qn, J = 6.0 Hz,
–CH2CH2OMs), 1.84–1.99 (4H, –CH2CH2Ntriazole and
–CH2CH2OH), 2.84 (2H, t, J = 6.0 Hz, –CH2–Ctriazole),
3.01 (3H, s, –CH3OMs,), 3.71 (2H, t, J = 6.0 Hz,
–CH2OH), 4.22 (2H, t, J = 6.0 Hz, –CH2–Ntriazole), 4.31
(2H, t, J = 6.0 Hz, –CH2OMs), 7.74 (1H, s, –C=CHtriazole);
13C NMR (CDCl3, 50 MHz): d = 21.2 (–CH2(CH2)2OMs),
24.8, 25.9, 28.5, 28.6, 28.8, 29.0, 29.8 and 31.9 (119 CH2),
35.5 (–CH3OMs), 49.8 (–CH2–Ntriazole), 60.5(–CH2OH), 70.
2 (–CH2OMs), 121.7 (–C=CHtriazole), 150.1 (–C=Ctriazole);
HRESIMS m/z [M?H]?: 390.2572 C18H34N3O5S (calcd.
390.2426).
3-(1-(9-Fluorononyl)-1H-1,2,3-triazol-1-yl)propan-1-ol (5i)
White solid, 48 %; m.p. = 62–64 °C; IR (neat) mmax 3312,
2913, 2848, 1050 cm-1;1H NMR (CDCl3, 200 MHz): d =
1.29–1.40 (10H, m, 59 CH2), 1.68 (2H, qnd, J = 2.0 Hz,
J = 24.0 Hz, –CH2CH2F,), 1.83–1.98 (4H, m, –CH2
CH2OH and CH2CH2Ntriazole), 2.83 (2H, t, J = 8.0 Hz,
–CH2–Ctriazole), 3.66–3.74 (2H, m, –CH2OH), 4.31 (2H, t,
J = 8.0 Hz, –CH2–Ntriazole), 4.43 (2H, td, J = 8.0 Hz,
J = 48.0 Hz, –CH2F), 7.54 (1H, s, –C=CHtriazole); 13C
NMR (CDCl3, 50 MHz): d = 21.85 (–CH2(CH2)2F), 24.9,
26.3, 28.7, 28.9, 29.0 and 30.1 (69 CH2), 30.22 (d, J =
13.5 Hz, –CH2F), 33.3 (HOCH2CH2–Ctriazole), 51.5
(–CH2–Ntriazole), 62.8 (–CH2OH), 85.4 (d, J = 163.0 Hz,
–CH2F),122.0(–C=CHtriazole),148.0(–C=Ctriazole);HRESIMS
m/z [M?H]?: 272.1973 C14H27FN3O (calcd. 272.2138).
3-(1-(12-Methanesulfonoyldodecyl)-1H-1,2,3-triazol-1-yl)
propanoic acid (5f) Yellow solid, 81 %; IR (neat) mmax
1
2916, 2850, 1729, 1331, 1163, 1052–952, 850 cm-1; H
(CDCl3, 200 MHz): d = 1.18–1.26 (16H, m, 89 CH2),
1.50–1.69 (4H, m, –CH2CH2Ntriazole and –CH2CH2OMs),
2.19–2.50 (4H, m, CH2CH2COOH), 3.19 (2H, t, J =
6.0 Hz, –CH2–Ntriazole), 4.15 (2H, t, J = 6.0 Hz, –CH2OMs),
7.98 (1H, s, –C=CHtriazole); 13C NMR (CDCl3, 50 MHz):
d = 25.3 (–CH2(CH2)2OMs), 26.6, 28.5, 28.7, 28.9, 29.0 and
29.4 (119 CH2), 33.2 (–CH2COOH), 37.1 (–CH3OMs), 51.0
(–CH2–Ntriazole), 70.3 (–CH2OMs), 115.6 (–C=CHtriazole),
136.3 (–C=Ctriazole), 178.9 (–CO); HRESIMS m/z [M?H]?:
404.2464 C18H34N3O5S (calcd. 404.2219).
3-(1-(12-Fluorododecyl)-1H-1,2,3-triazol-1-yl)propano-1-
ol (5j) White solid, 46 %; m.p. = 88–90 °C; IR (neat)
mmax 3321, 2917, 2846, 1006 cm-1;1H NMR (CDCl3,
200 MHz): d = 1.21–1.44 (16H, m, 29 CH2), 1.56–2.05
(6H, 39 CH2), 2.86 (2H, t, J = 6.0 Hz, –CH2–Ctriazole),
3.70 (2H, t, J = 6.0 Hz, –CH2OH), 4.32 (2H, t, J =
123

Med Chem Res (2015) 24:430–441
435
Ethyl-1-(9-iodononyl)-1H-1,2,3-triazole-4-carboxylate
(6c) White solid, 97 %; m.p. = 90–92 °C; IR (neat) mmax
2919, 2848, 1723, 1216, 1197, 1164 cm-1;1H NMR
(CDCl3, 200 MHz): d = 1.22–1.28 (10H, m, 59 CH2),
1.41 (3H, t, J = 6.0 Hz, –OCH2CH3), 1.71–1.96 (4H, m,
–CH2CH2Ntriazole and –CH2CH2I), 3.18 (2H, t, J = 6.0 Hz,
–CH2I), 4.30–4.51 (4H, m, –CH2–Ntriazole and –OCH2
CH3), 8.07 (1H, s, –C=CHtriazole); 13C NMR (CDCl3,
50 MHz): d = 7.37 (–CH2I), 14.5 (–OCH2CH3), 26.5,
28.7, 29.1, 29.6, 30.3, 30.6 and 33.3 (79 CH2), 50.6
(–CH2–Ntriazole), 61.8 (–CH2OH), 127.4 (–C=CHtriazole),
140.5 (–C=Ctriazole), 160.8 (–CO); HRESIMS m/z
[M?H]?: 394.1123 C14H25IN3O2 (calcd. 394.0991).
6.0 Hz, –CH2–Ntriazole), 4.55 (2H, td, J = 6.0 Hz, J =
46.0 Hz, –CH2F), 7.34 (1H, s, –C=CHtriazole); 13C NMR
(CDCl3, 50 MHz): d = 21.7 (–CH2(CH2)2F), 25.2, 26.6,
29.6, 29.0 and 30.4 (99 CH2), 30.5 (d, J = 19.0 Hz,
–CH2F), 32.2 (HOCH2CH2CH2triazole), 49.8 (–CH2–Ntriazole),
61.1 (–CH2OH), 84.2 (d, J = 179.5 Hz, –CH2F), 121.0 (–C=
CHtriazole), 147.3 (–C=Ctriazole); HRESIMS m/z [M?H]?:
314.2458 C17H33FN3O (calcd. 314.2608).
General procedure for the synthesis of 6a–d
To a solution of compounds 5c, 5d, 5e, or 5g (1.00 equiv.)
in acetone (5 mL), was added sodium iodide (2.00 equiv.).
The mixture was heated at reflux for 24 h. Afterward the
reaction mixture was diluted with water and extracted with
dichloromethane (3 9 15 mL). The organic extracts were
combined and dried (Na2SO4), and the solvent was
removed under reduced pressure. The residue obtained was
purified by column chromatography over silica gel, eluting
with mixtures of EtOAc/MeOH (100:0; 80:20, and 0:100),
to give pure compounds 6a–d.
Ethyl-1-(12-iodododecyl)-1H-1,2,3-triazole-4-carboxylate
(6d) Yellow solid, 90 %; m.p. = 80–82 °C. IR (neat)
1
mmax 2919, 2848, 1723, 1224, 1207, 1164, 777 cm-1; H
NMR (CDCl3, 200 MHz): d = 1.15–1.39 (16H, m, 89
CH2), 1.41 (3H, t, J = 6.0 Hz, –OCH2CH3), 1.81 (2H, t,
J = 6.0 Hz, –CH2CH2I), 1.95 (2H, qn, J = 6.0 Hz,
–CH2CH2Ntriazole), 3.18 (2H, t, J = 6.0 Hz, –CH2I), 4.47
(4H, m, –CH2–Ntriazole and –OCH2CH3), 8.06 (1H, s, –C=
CHtriazole); 13C–NMR (50 MHz, CDCl3): 6.9 (–CH2I), 14.3
(–OCH2CH3), 26.3, 28.3, 28.8, 29.1, 30.1, 30.4 and 33.4
(69 CH2), 50.9 (–CH2–Ntriazole), 61.1 (–CH2OH), 127.2
(–C=CHtriazole), 140.09 (–C=Ctriazole), 160.8 (CO);
HRESIMS m/z [M?H]?: 436.1419 C17H31IN3O2 (calcd.
436.1461).
3-(1-(9-Iodononyl)-1H-1,2,3-triazol-4-yl)propan-1-ol
(6a) Yellow solid, 84 %; m.p. = 88–90 °C; IR (neat)
m
max 3350, 2924, 2851 cm-1;1H NMR (CDCl3, 200 MHz):
d = 1.24–1.34 (10H, m, 59 CH2), 1.74–1.94 (6H, m,
–CH2CH2Ntriazole, –CH2CH2OH and –CH2CH2I), 2.80 (2H,
t, J = 6.0 Hz, –CH2Ctriazole), 3.17 (2H, t, J = 6.0 Hz,
–CH2I), 3.67 (2H, t, J = 6.0 Hz, –CH2OH), 4.29 (2H, t,
Biological assays
J = 6.0 Hz, –CH2Ntriazole), 7.31 (1H, s, –C=CHtriazole); 13
C
NMR (CDCl3, 50 MHz): d = 7.5 (–CH2I), 22.0 (–CH2
(CH2)3I), 26.6, 28.5, 29.00, 29.3, 30.4, 32.2, 33.6 (89
CH2), 50.7 (–CH2–Ntriazole), 61.6 (–CH2OH), 121.0 (–C=
CHtriazole), 147.6 (–C=Ctriazole); HRESIMS m/z [M?H]?:
380.1170 C14H27IN3O (calcd. 380.1199).
Cytotoxicity assay
The cytotoxicity of the compounds was assessed with the
human cell lines RKO (colon carcinoma ATCC# CRL-2577),
uterine carcinoma (HeLa), and lung fibroblast (WI-26VA4)
cells, using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-
nyltetrazolium bromide) (Sigma, St. Louis, MO, USA) color-
imetric method. Briefly, the cells were plated in 96-well plates
(1 9 105 cells/well) and incubated for 24 h at 37 Æ C in a humid
atmosphere with 5 % CO2 to adhesion. After this period, the
wells were washed with culture medium (EMEM ? 10 %
inactivated fetal calf serum ? 2 mM L-glutamine) and incu-
bated with the compounds at different concentrations
(0.01–500 lM). Control with etoposide (Sigma-Aldrich, St.
Louis, MO) used as reference anticancer drug, was performed
in parallel. After the incubation, the plates were treated with
MTT. The reading was performed using a SpectraMax M5e
microplate reader (Molecular Devices, Sunnyvale, CA, USA)
at 550 nm. Cytotoxicity was scored as the percentage reduction
3-(1-(12-Iodododecyl)-1H-1,2,3-triazol-4-yl)propan-1-ol
(6b) Yellow solid, 73 %; m.p. = 84–86 °C; IR (neat)
m
max 3308, 2917, 2848 cm-1; 1H NMR (CDCl3, 200 MHz):
d = 1.12–1.46 (16H, m, 89 CH2), 1.62–2.04 (6H, m,
–CH2CH2Ntriazole, –CH2CH2OH and –CH2CH2I), 2.83 (2H,
t, J = 6.0 Hz, –CH2–Ctriazole), 3.18 (2H, t, J = 6.0 Hz,
–CH2I), 3.70 (2H, t, J = 6.0 Hz, –CH2OH), 4.30 (2H, t,
J = 6.0 Hz, –CH2–Ntriazole), 7.31 (1H, s, –C=CHtriazole);
13C NMR (CDCl3, 50 MHz): d = 7.34 (–CH2I), 21.91
(–CH2(CH2)3I), 26.3, 28.3, 28.8, 29.2, 29.3, 30.2, 30.3,
31.9 and 34.0 (99 CH2), 49.9 (–CH2–Ntriazole), 61.3
(–CH2OH), 120.8 (–C=CHtriazole), 147.4 (–C=Ctriazole);
HRESIMS m/z [M?H]?: 422.1637 C17H33IN3O (calcd.
422.1668).
´
in absorbance versus untreated control cultures (Hilario et al.,
2011). All experiments were performed in triplicate. The
123

436
Med Chem Res (2015) 24:430–441
results were expressed as the mean of the IC50 (the lethal drug
concentration that reduced cell viability by 50 %).
defined as a cube with the geometric center in the crys-
tallographic ligand sufficiently to accommodate the whole
˚
binding site and with spaced points of 1 A. Hence, all
DNA Nick-End labeling by the TUNEL method
and immunofluorescence
ligands were docked against molecular target using Auto-
Dock Vina 1.1.2. The search algorithm used was Iterated
Local Search Global Optimizer for global optimization. In
this process, a succession of steps with a mutation and local
optimization (the method of Broyden–Fletcher–Goldfarb–
Shanno [BFGS]) were conducted, and each step followed
the Metropolis criterion (Trott and Olson, 2010).
Apoptotic cell death was measured using the APO-BrdU
TUNEL assay kit (Invitrogen, CA, USA). Briefly, the
effect of the compound 5e and etoposide on DNA frag-
mentation was determined using RKO cells. The cells were
incubated with the compounds during 48 h as described
above, and fixed using a solution of ice-cold 70 % ethanol.
The cells were then counterstained with 5-Bromo-20-
deoxyuridine 50-triphosphate (BrdUTP) in the presence of
the terminal deoxynucleotidyl transferase (TdT) and
stained with Anti-BrdU monoclonal antibody PRB-1 Alexa
Fluor 488 conjugate, as previous described (Pereira et al.,
2012). The loaded cells were visualized by fluorescence
microscopy using a Zeiss Axiovert 200.
Statistical analysis
The average of IC50 was compared using Tukey’s test.
Differences between the values were evaluated with Origin
6.0. A p value of 0.05 was considered to be statistically
significant.
Results and discussion
Virtual screening
The synthesis of new long-chain alkyltriazole compounds is
depicted in Scheme 1. The mesylate compounds (4a–e) were
prepared using 1,6-hexanodiol (1a), 1,9-nonanediol (1b), or
All ligands were built and optimized using GaussView
(Frisch et al., 2009) and Parametric Method 6 (PM6)
(Stewart, 2007) implemented in Gaussian 09W (Carregal
et al., 2012), respectively. Next, the inverse virtual
screening approach was used to identify the molecular
target of each ligand present in Our Own Molecular Tar-
gets Data Bank (OOMT) (Carregal et al., 2013), OOMT is
a data bank with 34 molecular targets from Protein Data
Bank (PDB) (Berman et al., 2013), and built by compar-
ative homology modeling, which was parameterized for
screening studies by redocked of respective crystallo-
graphic ligand (Nunes et al., 2013). The parameterization
of OOMT includes the construction of grid box, which was
´
1,12-dodecanediol (1c) as starting materials (Hilario et al.,
2011; Chong et al., 2000). These diols were converted in
their monobrominated derivatives by treatment with hydro-
bromic acid. The haloalcohols obtained were transformed
into azido alcohols by SN2 substitution. The azide com-
pounds were transformed in their corresponding mesylates
by reaction with mesyl chloride in alkaline conditions.
Compounds 4b and 4d were treated with KF/18-crown-6 in
dimethylsulfoxide to yield 4c and 4e. To obtain the alkyl-
triazoles 5a–j, a solution of commercially available alkynes
(pent-4-yn-1-ol, propargyl alcohol, 4-pentynoic acid, or
R
N
( )
N
i
n
MsO
N
N
N
N
5c, n=9, R=-(CH2)3OH
R
5d, n=9, R=-COOCH2CH3
5e, n=12, R=-(CH2)3OH
5g, n=12, R=-COOCH2CH3
6a, n=4, R=-(CH2)3OH (90%)
6b, n=7, R=-(CH2)3OH (64%)
6c, n=4, R=-COOCH2CH3 (97%)
6d, n=7, R=-COOCH2CH3 (73%)
I
Scheme 2 Reagents and conditions: (i) NaI, acetone, reflux, 24 h
123

Med Chem Res (2015) 24:430–441
437
ethyl propiolate) and alkylazides (4a–e) in dichloromethane
was treated with a solution of copper sulfate pentahydrate
(8 mol%) and sodium ascorbate (20 mol%) in water. The
reaction mixture was stirred for 24 h at room temperature,
exclusively producing high yields of the 1,4-disubstituted
1,2,3-triazoles (5a–j).
active compounds, i.e., 5e, was selected for further investi-
gation of its cytotoxic mode of action.
Apoptosis via cytotoxicity is considered an efficient
strategy for the identification of potential antitumor drugs
Table 2 Physicochemical properties of miltefosine and the alkyl-
triazole compounds 5a–j and 6a–d
We synthesized four additional novel long-chain alkyl-
triazoles that contained an iodine atom (Scheme 2).
All synthesized compounds were evaluated in vitro for
their anticancer potential against two human cancer cell
lines (colon carcinoma RKO and uterine carcinoma HeLa).
The compounds were also tested on a non-cancerous
human cell line (lung fibroblast WI-26VA4) to determine
the selectivity index. Colorimetric MTT assays determined
that compounds 5e and 6a presented potent antitumor
activity in vitro (Table 1). Against RKO cells, compounds
5e and 6a showed IC50 values of 16.70 and 14.57 lM,
respectively. These same compounds presented similar
IC50 values (11.05 and 12.77 lM, respectively) against the
HeLa cell line. The cytotoxicity of compounds 5e and 6a
was comparable to that of etoposide, an anticancer agent
(Correale et al., 2011).
Compounds
cLog P
MW
HBD
HBA
Miltefosine
6.0
407.56
305.39
319.37
347.47
361.45
389.55
403.53
403.53
361.5
0
1
0
1
0
1
1
0
1
1
1
1
1
0
0
4
4
5
4
5
4
5
5
4
2
2
1
1
2
2
5a
5b
5c
5d
5e
5f
0.59
1.24
1.67
2.32
2.74
2.36
3.57
2.12
2.70
3.77
3.37
4.45
3.86
4.93
5g
5h
5i
271.37
313.45
379.28
421.36
393.26
435.34
5j
6a
6b
6c
6d
The physicochemical properties of miltefosine and all the
alkyltriazole compounds synthesized in this study are shown
in Table 2. All new alkyltriazoles showed a desirable profile
for an oral drug (Leeson and Springthorpe, 2007). Based on
IC50 values and physicochemical properties, one of the most
MW molecular weight, HDB hydrogen-bond donors, HBA hydrogen-
bond acceptors
Table 1 In vitro cytotoxic activity of the alkyltriazole compounds against human colon carcinoma (RKO) cells, uterine carcinoma (HeLa) cells,
and lung fibroblast (WI-26VA4) cells
Compounds
IC50 (lM) SDa
SI
HeLa
RKO
WI
WI/HeLa
WI/RKO
Miltefosine
13.80 4.2
210.10 5.18
202.18 0.31
24.48 5.20
37.10 3.90
11.05 3.70
35.95 7.38
208.17 25.12
21.87 0.78
84.25 9.92
25.82 9.19
12.77 1.16
145.33 13.22
52.22 12.74
26.61 2.20
11.35 2.73
[100
ND
ND
ND
5a
397.90 6.54
198.23 18.02
182.03 28.4
20.49 5.80
16.70 3.40
99.94 0.89
180.16 5.92
19.87 4.22
307.21 8.77
90.82 0.83
14.57 2.18
138.16 10.10
199.01 26.30
62.23 2.55
10.66 2.23
489.15 4.02
339.34 27.86
ND
2.33
1.67
ND
1.23
1.71
ND
5b
5c
5d
ND
ND
ND
5e
ND
ND
ND
5f
39.45 10.42
490.41 4.03
36.54 3.21
184.43 1.51
80.48 12.66
21.40 3.36
27.68 4.08
253.82 59.95
71.84 14.10
4.30 1.34
1.09
2.35
1.67
2.19
3.11
1.67
0.19
4.87
2.70
0.39
0.39
2.72
1.84
0.60
1.13
1.47
0.20
2.27
1.15
0.40
5g
5h
5i
5j
6a
6b
6c
6d
Etoposide
ND not determined, SI selectivity index
a
Values are average Standard Deviation
123

438
Med Chem Res (2015) 24:430–441
Fig. 2 Apoptosis in human colon carcinoma (RKO) cells. Cells were
incubated (48 h) with compound 5e in different concentrations.
(a) control of life, (b) etoposide at 1 lM, and 5e (c) 1 lM, (d) 10 lM,
and (e) 100 lM. The arrow indicates cell death by apoptosis (green).
Viable cells are stained red. Scale bar: 20 lm (Color figure online)
Table 3 Docking results between miltefosine and alkyltriazoles al-
kyltriazole compounds 5a–j and 6a–d against the molecular targets
Galectin-1 and ERK1 carried out by Autodock Vina
(Essack et al., 2011). To investigate the possible apoptosis-
inducing action of these compounds, specific DNA frag-
ments on RKO cells were detected by a TUNEL assay
using compound 5e and etoposide, an apoptosis-inducing
drug (Liu et al., 2011). The results presented here indicate
that compound 5e promoted apoptosis in RKO cells
(Fig. 2), reducing the number of viable cells in a concen-
tration-dependent manner (Fig. 2a–e). The mechanism by
which long-chain APLs trigger apoptosis is, as yet, unclear.
APLs interact with signaling proteins, membrane lipids,
or lipid microdomains (Strassheim et al., 2000; Samadder
et al., 2003; Kondapaka et al., 2003). The ability of cells to
proliferate or initiate apoptosis relies on signaling path-
ways that produce anti- or pro-apoptotic signals (Ruiter
et al., 1999; Dineva et al., 2012). Anti-apoptotic pathways
can comprise the Ras–Raf–MAPK/ERK proliferative
pathway (Ruiter et al., 2002). Other targets, such as
transmembrane proteins, are also involved in the apoptosis
process. In this context, galectins (galactoside-binding
glycoproteins) were shown to modulate many functions in
cell survival, including proliferation and metastasis (Vla-
doiu et al., 2014). In an attempt to understand the mode of
action of the compounds synthesized in this work, we
performed a virtual screening against 34 potential antitu-
mor targets. All synthesized compounds exhibited the best
docking scores against galectin-1 (PDB: 1W6M) and
ERK1 (PDB: 2ZOQ) (Table 3). The compound 5e, an
apoptosis inducer, showed a better binding energy for
galectin-1 (-4.4 kcal mol-1) and ERK-1 (-6.2 kcal -
mol-1) than miltefosine, used as reference compound.
Figure 3 shows 3D and 2D diagrams of the intermolecular
interactions between 5e and galectin-1 and ERK1.
Compounds
Binding Energy (kcal mol-1
)
Galectin-1 (PDB: 1W6M)
ERK1 (PDB: 2ZOQ)
Miltefosine
-3.3
-4.3
-4.4
-4.4
-4.5
-4.1
-3.7
-3.8
-4.0
-4.7
-4.5
-4.7
-4.5
-4.0
-4.7
-5.7
-5.7
-6.0
-6.2
-6.0
-5.7
-5.6
-5.7
-6.2
-6.4
-6.3
-5.9
-6.3
-6.1
-5.9
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
6a
6b
6c
6d
Conclusions
In conclusion, this preliminary investigation demonstrates
that very simple long-chain alkyltriazoles may be a
promising class of substances with cytotoxic activity, and
that this activity can be modified significantly by classical
chemical modifications. Among the synthesized com-
pounds, 5e was the most active, could represent a prom-
ising template for developing a new class of antitumor
123

Med Chem Res (2015) 24:430–441
439
Fig. 3 3D and 2D diagrams of the intermolecular interactions
between 5e and galectin-1 and ERK1. a 3D diagram of 5e and
galectin-1 (PDB: 1W6M). b Intermolecular interactions between 5e
and galectin-1 (PDB: 1W6M): electrostatic interactions, hydrogen
bonds (ASN A:1046), and van der Waals interactions (ASP A:1123)
with the mesyl group. The triazole ring and hydroxyl group form
electrostatic interactions and hydrogen bonds (ASN A:1061). c 3D
diagram of 5e and ERK1 (PDB: 2ZOQ). d Intermolecular interactions
between 5e and ERK1 (PDB: 2ZOQ): the triazole ring forms
electrostatic interactions and hydrogen bonds (LYS A:131), electro-
static interactions (SER A:170 e LYS A:168), and van der Waals
interactions (ASP A:128)
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J Quantum Chem
agents, and deserves further investigation of derived
scaffolds.
Acknowledgments The authors thank Fundac¸a˜o de Amparo a
Pesquisa do Estado de Minas Gerais (FAPEMIG) and Conselho
´
Nacional de Desenvolvimento Cientıfico e Tecnologico (CNPq) for
financial support. We further thank Pro-Reitoria de Pesquisa (UFMG)
´
´
for the financial aid to publish the results.
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