New insights into 3-(aminomethyl)naphthoquinones: Evaluation of cytotoxicity, electrochemical behavior and search for structure–activity correlation

Article abstract of DOI:10.1016/j.bmcl.2016.06.027

Herein we describe the structure–activity relationship of a large library of Mannich bases (MBs) synthesized from 2-hydroxy-1,4-naphthoquinone. In general, the compounds have shown high to moderate activity against the HL-60 (promyelocytic leukaemia) cell

Full text of DOI:10.1016/j.bmcl.2016.06.027

Accepted Manuscript
New insights into 3-(aminomethyl)naphthoquinones: evaluation of cytotoxicity,
electrochemical behavior and search for structure-activity correlation
Gustavo B. da Silva, Amanda P. Neves, Maria D. Vargas, José D.B. Marinho-
Filho, Letícia V. Costa-Lotufo
PII:
S0960-894X(16)30638-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.06.027
BMCL 23980
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 April 2016
8 June 2016
9 June 2016
Please cite this article as: da Silva, G.B., Neves, A.P., Vargas, M.D., Marinho-Filho, J.D.B., Costa-Lotufo, L.V.,
New insights into 3-(aminomethyl)naphthoquinones: evaluation of cytotoxicity, electrochemical behavior and
search for structure-activity correlation, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/
10.1016/j.bmcl.2016.06.027
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Bioorganic & Medicinal Chemistry Letters
New insights into 3-(aminomethyl)naphthoquinones: evaluation of cytotoxicity,
electrochemical behavior and search for structure-activity correlation
Gustavo B. da Silvaa,, Amanda P. Nevesa,b, Maria D. Vargasa,, José D. B. Marinho-Filhoc,d and Letícia V.
Costa-Lotufoc,e
a Instituto de Química, Universidade Federal Fluminense, Campus do Valonguinho, Outeiro São João Batista s/n, Centro, Niterói-RJ 24020-150, Brazil.
b Departamento de Química, Universidade Federal Rural do Rio de Janeiro, Campus de Seropédica, BR-465 km 7, Seropédica-RJ 23890-000, Brazil.
c Departamento de Fisiologia e Farmacologia, Centro de Ciências da Saúde, Universidade Federal do Ceará, Rua Coronel Nunes de Mello 1127, Rodolfo
Teófilo, Fortaleza-CE 60430-270, Brazil.
d Curso de medicina, Universidade Federal do Piauí-Campus Ministro Reis Velloso, Rua Capitão Claro, 382, Centro, Parnaíba-PI 64200-500, Brazil.
e Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo-SP 05508-900, Brazil.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Herein we describe the structure-activity relationship of a large library of Mannich bases (MBs)
synthesized from 2-hydroxy-1,4-naphthoquinone. In general, the compounds have shown high to
moderate activity against the HL-60 (promyelocytic leukaemia) cell line with IC50 = 1.1-19.2
M. Our results suggest that the nature of the aryl moiety introduced in the structure of MBs by
the aldehyde component is crucial to the cytotoxicity, and although the group originated from
the primary amine has a lesser influence, aromatic ones were found to suppress the activity.
Thus, MBs derived from salicylaldehydes or 2-pyridinecarboxaldehyde and aliphatic amines are
the most active compounds. A satisfactory correlation of the EpIIc vs. IC50 (M) in
dimethylsulfoxide was observed. The most cytotoxic MBs (Series a-c, derived from
salicylaldehydes) showed the least negative EpIIc values. Noteworthy, however, Series d (derived
from 2-pyridinecarboxaldehyde) did not follow this correlation. They exhibited both the lowest
IC50 and the most negative EpIIc values, thus suggesting that other factors also influence the
cytotoxicity of the MBs, such as lipophilicity, electronic distribution and hydrogen bonding.
Keywords:
cyclic voltammetry
cytotoxicity
drug design
Mannich bases
structure-activity relationship
© 2016 Elsevier Ltd. All rights reserved.
Quinones are known for their wide range of
We have reported the bactericidal11 and antiviral12,13
profiles of novel MBs, which have shown very good
pharmacological
properties.1
Naphthoquinones
and
anthraquinones, for instance, are active against parasites,2
bacteria and fungi,3 and their antitumor properties4,5 have
attracted increasing research interest. These compounds
have been shown to act via oxidative stress, topoisomerases
inhibition and DNA alkylation or intercalation, eventually
causing strand breaks.5,6
activities.
Furthermore,
MBs
derived from
2-
pyridinecarboxaldehyde exhibited moderate to high
activities against some tumor cell lines.14 Their respective
platinum(II) and platinum(IV) complexes were also
evaluated and in some cases they were more active than
cisplatin, one of the most commonly used drugs in
chemotherapy.14,15 It was also found that the MBs were more
active than their respective platinum(II) complexes against
most cell lines, even though the latter were found to interact
strongly with DNA and induce DNA strand breaks in vitro.16
The higher cytotoxicity of the MBs has been proposed to be
due to deamination with formation of an ortho-quinone
methide, which may cause DNA strand breaks and cell
death.16
3-(Aminomethyl)-2-hydroxy-1,4-naphthoquinones known
as Mannich bases (MBs), constitute an interesting class of
naphthoquinones that were first synthesized in the 40s by
Leffer and co-workers who also described their antimalarial
activity.7 They are obtained by the condensation reaction of
2-hydroxy-1,4-naphthoquinone (lawsone), a non-enolizable
aldehyde and
a
primary or secondary amine.7,8
Methodologies for the synthesis of MBs derived from
anilines and heterocyclic amines have also been reported
using metal ions as catalysts.9,10
Continuing our efforts to obtain other MB derivatives with
improved cytotoxicities, we have synthesized a series of novel 3-
(R-amino-(R')-methyl)-2-hydroxy-1,4-naphthoquinones
and
———
 Corresponding author. Tel.: +55-21-2629-2225; e-mail: mdvargas@vm.uff.br
 Corresponding author. Tel.: +55-21-2629-2185; e-mail: gustavobezerrads@gmail.com

compared their cytotoxic activity against melanoma (MDA-MB-
435), promyelocytic leukaemia (HL-60), colorectal
the literature.18 The compounds were formulated based on
elemental analysis and their structures, confirmed by
spectroscopic data (see Experimental, Supplementary data).
adenocarcinoma (HCT-8) and glioblastoma (SF-295) with those
of analogous compounds reported previously.14 To look for
possible correlations between their redox properties and cytotoxic
activities, the electrochemical behavior of these molecules was
evaluated in DMSO, a non-aqueous aprotic solvent, which has
been suggested to mimic the cell membrane environment.17
The 1H NMR spectra show similar profiles. Hydrogens H5-H8
are observed in the  8.0-7.0 range as dd or ddd for H5 and H8,
and as td for H6 and H7. A singlet attributed to H11 is also
observed around  6.0-5.5, except for compounds of Series i
where this singlet is around  4.0. The aromatic hydrogens (H13-
H17) are observed in the expected region and were attributed to
the respective hydrogens of the aryl or pyridyl groups based on
coupling constant values (J) and 1H-1H COSY experiments.11 The
aliphatic peaks are the most shielded signals at  4.0-1.0. The
spectra of the MBs containing Boc-protected amines exhibit a
singlet attributed to the three methyl groups, at  1.41-1.48. The
13C (APT) NMR spectra show all the expected peaks (see
Supplementary data).
The synthesis of the MBs was carried out following a
procedure described previously and illustrated in Fig. 1A.11
Except for MBs 4a, 5a, 8a, 4b, 5b, 4c, 5c, 4d-8d, 9e, 5g, 4h and
5h the compounds are novel. The MBs were isolated as
analytically pure orange powders with yields ranging from 33-
94%. They are all stable in the solid state, but undergo slow
decomposition in solution (MeOH, EtOH, CHCl3 and DMSO)
when left for long periods of time. This process is probably
related to the deamination of the MBs, extensively discussed in
Figure 1. (A) General procedure for the preparation of 3-(R-amino-(R')-methyl)-2-hydroxy-1,4-naphthoquinones and (B) structures of
the synthesized MBs (Series a-i).

Similarly the IR spectra exhibit the expected bands for the
synthesized MBs19 (see Supplementary data). The UV-Vis
spectra show the same pattern for all compounds, with three
bands, 1 = 270-280 nm, 2 = 330-340 nm and 3 = 460-470 nm,
attributed, respectively, to * transitions of the benzene and
naphthoquinone rings, naphthoquinone* transition and
carbonyl groups n* transition.20-22
against MDA-MB-435 and HL-60 cell lines (Table 1).
Although the benzyl and furfuryl derivatives of Series d also
present high activity, a noticeable increase in activity with
the length of the R chain (n-butyl < n-heptyl ~ n-decyl) is
observed against HCT-8, SF-295 and HL-60 cell lines.
Previous work suggested a correlation with increased uptake
associated with higher lipophilicity.16 Finally, changing the
alkyl chain (n-butyl, 3-chloropropyl and 3-(N-Boc-amino)-
propyl) does not lead to appreciable changes in the activity.
The cytotoxicity of the MBs was investigated and
compared to the data described previously for compounds
4d-8d 14
.
Aiming to improve their solubility in water, some
Conversion of the MBs into their hydrochlorides (MBs.HCl)
does not result in increased cytotoxicity in the cases of inactive
MBs (e.g. Series g and h, Tables S1-S4). Among the MBs that
present good to moderate activity, e.g. those containing R =
benzyl (compounds 4a-c), no improvement is noted for their
hydrochlorides. However, in few cases marked enhancement of
cytotoxicity is observed upon conversion into the MBs.HCl.
E.g., 9e (derived from benzaldehyde and R = pyridin-2-ylmethyl)
is inactive against all cell lines except for HCT-8 (IC50 = 14.3 ±
0.7 mol L-1), whereas 9e.HCl is active against all cell lines with
IC50 values varying from 3.4 to 13.5 mol L-1. For MBs derived
from 2-hydroxybenzaldehydes and R = furfuryl (8a) and butyl
(5b-c), appreciable enhancement of cytotoxicity is noted for
8a.HCl, 5b.HCl and 5c.HCl. As suggested earlier by our group,
the cytotoxicity of lawsone derived MBs may be associated with
their ability to undergo deamination18,23 in the biological medium
(pH 7.4) and form ortho-quinone methide species,16 whose toxic
effects are known (e.g. through covalent modification of proteins
and/or DNA). In phenolic derivatives, the deamination process is
known to take place via a pre-equilibrium with formation of the
zwitterion.24 It is possible that the deamination rate of MBs.HCl
is altered by the protonation.
MBs
(4a
,
5a 8a 4b 5b 4c 5c 9e 5g 4h and 5h
,
,
,
,
,
,
,
,
)
11,23 were
converted into their hydrochloride forms upon treatment
with acetyl chloride. The MBs.HCl were obtained in
quantitative yields and formulated based on elemental
analysis data. Nevertheless they were not soluble enough in
water and therefore the cytotoxicity assays of all compounds
were undertaken in 1% DMSO (DMSO concentration did
not exceed 1% in the highest drug concentration solution,
see Experimental, Supplementary data).
All MBs described in Fig. 1 have been tested, but only
those that have shown cytotoxic activity (IC50 < 40 
mol L-
1) against the tested tumor cell lines are shown in Table 1,
which also contains compounds 4d-8d14 for comparison.
The results show that the activity of the MBs is mostly
dependent on the nature of the substituent on C11. Thus, the
MBs derived from benzaldehyde
hydroxybenzaldehyde (Series f), 2,4-dichorobenzaldehyde
Series ), 4-nitrobenzaldehyde Series and
(
Series
e), 3-
(
g
(
h)
formaldehyde (Series i) are inactive.
In general, MBs of Series
a
(derived from 2-
hydroxybenzaldehyde)
and
d
(derived from 2-
As naphthoquinone derivatives are redox active
molecules and in principle the mechanism of cytotoxicity
could be associated with their redox processes,1 the
electrochemical behavior of the MBs was studied by cyclic
voltammetry. Measurements were carried out in DMSO,
which has been proposed to mimic the cell membrane
environment.17 The cyclic voltammograms (CVs) of
compounds 4d-8d and 9e were previously reported in
MeOH and MeCN.14,15,23 However, because the nature of the
solvent is known to strongly affect the electrochemical
behavior of the MBs,25 these compounds were also studied
in DMSO.
pyridinecarboxaldehyde) are the most active. Furthermore, the
highest activities are associated with aliphatic substituents R on
the nitrogen atom, whereas the presence of aromatic substituents
(R = C6H5, 4-Me-C6H4, 4-OMe-C6H4) leads to inactive MBs
(10d-12d).
On the whole the compounds in Table 1 are active against
all cell lines except for 4d-8d (Series d, derived from 2-
pyridinecarboxaldehyde) that are not active against MDA-
MB-435. However, these MBs present the highest activity
against the other cell lines, with IC50 ranging from 1.0 to
12.5
hydroxybenzaldehyde (Series a
the four cell lines, and in these cases, with the lowest IC50
values against HL-60 (ranging from 1.1 to 19.2
mol L-1).

mol L-1.14 The large majority of MBs derived from 2-
,
b and c) are active against
In general the CVs of the MBs in DMSO exhibit three main
processes (see Fig. 2A). The first one is assigned to the reduction
of 3-(aminomethyl)-2-hydroxy-1,4-naphthoquinone (NQOH)
into the respective semiquinone – NQOH.- (irreversible process
Ic/Ia), which can deprotonate a NQOH molecule, affording a

The presence of a methyl substituent in para position with
respect to the OH group (Series c) had no appreciable effect
on the activity compared with analogous compounds of
Series a. On the other hand, a Br substituent in the same
position (Series b) leads to marked decrease in the activity
(Tables S1-S4). The position of the hydroxyl group on the
phenyl ring is crucial, as the MBs derived from 3-
hydroxybenzaldehyde (Series f) are mostly inactive. These
results are in accordance with previous studies on the
.
protonated semiquinone (NQOH2 ), which in turn can be reduced
-
to a protonated cathecol – CATOH2 (irreversible process –
Ic*/Ia*). Finally, the quasi-reversible process IIc/IIa is
attributed to the redox processes of the naphthoquinonate (NQO-)
generated from the autoprotonation (Fig. 3).26,27 An additional
process (IIIc/IIIa) is observed in the CVs of the MBs derived
from 4-nitrobenzaldehyde (1-6h) and is attributed to the
reduction/oxidation of the nitro group.28 Differently, the CVs of
the MBs derived from 2- and 3-hydroxybenzaldehydes (Series a-
c and f, e.g., see Fig. 2B) exhibit an additional redox process
(IIc*/IIa*), which showed dependence on the scan rate and is
associated to the presence of the OH group (possibly involving
hydrogen bonding or deprotonation processes).25,29
cytotoxicity of some of the compounds of Series a, b, c, e, g
and
h against MDBK (Madin-Darby Bovine Kidney
Epithelial) cells.12
Because the MBs of Series a and
d present the largest
number of active compounds, a possible correlation between
activity and nature of the substituent R was examined. In
Series a, benzyl (4a) and furfuryl (8a) derivatives were by
far the most active ones (IC50 from 1.1 to 20.2

mol L-1)

Table 1. Selected data of IC50 values of MBs in mol L-1 after 72 h of incubation.
MB
R
R’
MDA-MB-435
30.1 ± 8.0
26.3 ± 4.6
37.8 ± 2.8
18.9 ± 0.8
25.6 ± 9.6
33.3 ± 2.7
30.9 ± 3.5
20.2 ± 2.4
>40
HCT-8
SF-295
HL-60
1a
3-chloropropyl
2-(N-Boc-amino)ethyl
3-(N-Boc-amino)propyl
benzyl
2-hydroxyphenyl
2-hydroxyphenyl
2-hydroxyphenyl
2-hydroxyphenyl
2-hydroxyphenyl
2-hydroxyphenyl
2-hydroxyphenyl
2-hydroxyphenyl
5-bromo-2-hydroxyphenyl
5-bromo-2-hydroxyphenyl
5-methyl-2-hydroxyphenyl
5-methyl-2-hydroxyphenyl
2-pyridyl
17.7 ± 2.3
10.8 ± 7.0
22.7 ± 6.2
15.6 ± 3.6
20.5 ± 3.6
19.7 ± 6.3
32.2 ± 2.3
14.4 ± 2.3
>40
17.5 ± 5.3
15.9 ± 2.0
26.0 ± 3.2
23.1 ± 0.2
33.3 ± 7.6
18.9 ± 1.9
23.1 ± 2.2
23.4 ± 3.7
28.8 ± 5.1
17.4 ± 0.4
8.5 ± 0.6
29.6 ± 7.1
1.3 ± 0.1a
9.5 ± 0.2a
1.0 ± 0.4a
1.7 ± 0.6a
3.3 ± 2.3a
>40
8.1 ± 2.6
19.2 ± 1.1
17.2 ± 1.6
3.9 ± 1.2
6.5 ± 0.4
7.7 ± 3.0
12.2 ± 1.5
1.1 ± 0.1
8.4 ± 3.3
8.4 ± 0.2
7.2 ± 1.1
6.0 ± 1.1
4.8 ± 1.3a
>40a
2a
3a
4a
5a
n-butyl
6a
n-heptyl
7a
n-decyl
8a
furfuryl
1b
3-chloropropyl
benzyl
4b
25.2 ± 4.6
15.8 ± 2.8
26.5 ± 5.7
>40a
14.9 ± 2.3
11.3 ± 2.7
17.0 ± 4.5
2.2 ± 0.1a
12.5 ± 0.8a
1.6 ± 0.6a
1.7 ± 0.2a
4.4 ± 1.2a
14.3 ± 0.7
25.8 ± 5.6
21.2 ± 5.6
>40
4c
benzyl
5c
n-butyl
4d
benzyl
5d
n-butyl
2-pyridyl
>40a
6d
n-heptyl
2-pyridyl
>40a
1.8 ± 0.2a
3.8 ± 1.3a
5.8 ± 0.6a
>40
7d
n-decyl
2-pyridyl
23.3 ± 3.9a
>40a
8d
furfuryl
2-pyridyl
9e
pyridin-2-ylmethyl
n-decyl
phenyl
>40
7f
3-hydroxyphenyl
2,4-dichlorophenyl
2,4-dichlorophenyl
2-hydroxyphenyl
2-hydroxyphenyl
5-bromo-2-hydroxyphenyl
5-bromo-2-hydroxyphenyl
5-methyl-2-hydroxyphenyl
5-methyl-2-hydroxyphenyl
phenyl
31.1 ± 4.7
16.2 ± 3.4
>40
>40
11.9 ± 0.7
N.D.
3g
3-(N-Boc-amino)propyl
n-heptyl
>40
6g
>40
4.5 ± 0.5
4.6 ± 0.8
1.2 ± 0.4
4.9 ± 0.5
6.2 ± 1.3
N.D.
4a.HCl
8a.HCl
4b.HCl
5b.HCl
4c.HCl
5c.HCl
9e.HCl
benzyl
18.3 ± 1.1
2.9 ± 0.2
>40
14.4 ± 2.5
3.0 ± 0.8
15.9 ± 10.2
12.5 ± 0.9
12.1 ± 2.0
5.6 ± 1.3
6.3 ± 2.2
0.05 ± 0.03
11.6 ± 2.4
1.8 ± 0.5
10.7 ± 0.9
21.4 ± 13.9
14.4 ± 2.8
5.5 ± 1.3
13.5 ± 2.7
0.39 ± 0.05
furfuryl
benzyl
n-butyl
23.9 ± 15.2
18.7 ± 2.9
11.0 ± 4.2
3.6 ± 0.9
0.83 ± 0.03
benzyl
n-butyl
1.6 ± 0.4
5.4 ± 0.6
0.03 ± 0.01
pyridin-2-ylmethyl
Doxorubicin
* Experiments were performed in triplicate and data are presented as mean IC50 value ± standard deviation of the mean of 3.
aThese data were previously reported in reference 14.
Figure 2. CVs of compounds (A) 1d and (B) 1a at scan rate of 0.200 V s-1.

Figure 3. Redox behavior for MBs in aprotic solvents.
Attempts have been made to establish a correlation
between the first reduction potential (EpIc) and the
molluscicidal activity (LD50 and LD90 values) of 2-hydroxy-
naphthoquinones.17 However, it is known that in these cases,
including the MBs, autoprotonation strongly affects the
previously associated with high uptake.16 The MBs of Series
derived from formaldehyde, also present negative EpIIc
values (from –1.853 to –1.888 V) and no activity. Thus, in
these series a satisfactory correlation was encountered
between activity and EpIIc values and follows similar
tendency to that previously reported for other 2-
hydroxynaphthoquinones.30
i
kinetics of the first reduction/oxidation process (Ic/Ia),
leading to irreversibility.30 Thus, in terms of correlation with
biological data, reversible or quasi-reversible processes,
such as IIc/IIa were shown to be more suitable choices. For
example, in another series of 2-hydroxynaphthoquinones, a
correlation was found between strong inhibitory effect on
the fertilization of sea urchin eggs (LD50) and highest
reduction potentials and similarly, low activity was related
with the lowest reduction potentials.30
According to the data shown in Table S5 the EpIIc values
for the MBs vary from –1.652 to –1.960 V and depend far
more on the nature of the substituent on C11 than that on the
nitrogen atom. E.g., EpIIc values for compounds derived from
3-(chloropropyl)amine and containing different substituents
on C11 (1a,b,d-i, see Fig. 1) vary as much as 227 mV,
whereas in one series, for instance, that of compounds
derived from 2-hydroxybenzaldehyde 1a-8a, the EpIIc values
vary only by 66 mV.
Plots of the second reduction process (EpIIc) for all MBs vs
IC50 values against the four cell lines were obtained (Fig. 4 and
Fig S1). Because the best correlation was observed for the HL-60
cell line, against which the compounds have exhibited the highest
activities (Fig. 4), this plot will be further discussed.
Figure 4. Correlation of the EpIIc (V vs FcH+/FcH) of the
MBs and the IC50 (
mol L-1) against HL-60 cell line.
Of the MBs derived from substituted benzaldehydes,
those containing the R’ = 2-hydroxyphenyl substituent
The MBs derived from 2-pyridinecarboxaldehyde, however,
appear as a separate group in the plot, with the lowest IC50 values
(from 1.8 to 5.8 mol L-1, except for one case) and EpIIc values
ranging from –1.854 to –1.888 V). These results indicate that
EpIIc values alone do not allow safe prediction of the activity of
this class of compounds. Other factors, such as nature of the
substituents on C11 and on the nitrogen atom also seem to play
important effects on the activity.
(
Series a-c) show the least negative EpIIc values ranging
from –1.652 to –1.765 V and are also the most active (IC50
from 1.1 to 19.2
mol L-1), except for the 5-bromo-2-

hydroxybenzaldehyde derivatives 5b-7b that are inactive.
Furthermore, the presence of other substituents on the
phenyl ring (Series e-h) leads to the most negative EpIIc
values (from –1.812 to –1.960 V) and exhibit low
cytotoxicity (IC50 > 40 
mol L-1), except for compounds 7f
In summary, from the structural modifications performed on
the naphthoquinone Mannich bases (MBs) it was found that their
activity depends mostly on the substituent on C11. The ones
and 6g that contain the longest aliphatic carbon chains on
the nitrogen atom (n-decyl and n-heptyl, respectively),

Matson, E. J.; Moore, E. E.; Moore, M. B.; Rapala, R. T.; Zaugg, H. E. J.
Am. Chem. Soc. 1948, 70, 3151.
containing a 2-pyridyl group have exhibited the highest activities
(IC50 from 1.0 to 12.5 mol L-1), except for the melanoma cell
line, thus indicating that this group plays an important role in
cytotoxicity. The presence of a hydroxyl group in position 2 of
the phenyl substituent on C11 (derived from 2-
hydroxybenzaldehyde) is also important for the cytotoxicity,
leading to compounds with moderate to high activities.
Differently, other substituents on C11, such as C6H5 (Series e), 3-
OH-C6H4 (Series f), 2,4-Cl-C6H4 (Series g), 4-NO2-C6H4 (Series
h) and H (Series i) mostly resulted in inactive compounds. The
nature of the R substituent on the nitrogen atom also has
important consequences in the activity of the MBs. Aromatic
substituents (R = C6H5, 4-Me-C6H4 or 4-OMe-C6H4) gave
completely inactive MBs, thus indicating that cytotoxicity is
associated with aliphatic substituents R, especially the benzyl and
furfuryl groups that led to the most active MBs. Besides,
increasing the length of the alkyl chain on the nitrogen atom also
resulted in increased activities (n-butyl << n-heptyl ~ n-decyl),
which may be attributed to the greater cellular accumulation of
these derivatives. Conversion of the MBs into their
hydrochlorides (MBs.HCl) may result in improvement of
cytotoxicity, especially of the MBs with good to moderate
activities. Finally, a satisfactory correlation was encountered
between cytotoxicity (IC50 values for HL-60 cell line) and the
second reduction potential (EpIIc values) of the naphthoquinone
9. Dabiri, M.; Tisseh, Z. N.; Bazgir, A. Dyes Pigm. 2011, 89, 63.
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Santos, R. B.; Romão, W.; Greco, S. J. Tetrahedron Lett. 2014, 55, 4373.
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D.; Paixão, I. C. N. P. Arch. Virol. 2014, 159, 1827.
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MBs,
except
for
Series
d
(derived
from
2-
pyridinecarboxaldehyde). Those with the least negative EpIIc
values (Series a-c derived from 2-hydroxybenzaldehyde) are also
the most active, which could suggest that the ease of reduction of
the MBs may play a role in their activities. However, MBs of
Series d exhibited the lowest IC50 values and yet also the most
negative EpIIc values, thus indicating that other factors also
influence the cytotoxicity of the MBs, amongst which
lipophilicity, electronic distribution and hydrogen bonding as a
result of the nature of the substituents on C11 and on the nitrogen
atom.
Acknowledgments
The authors thank the Brazilian agencies 'National Council for
Scientific and Technological Development (CNPq)', 'Brazilian
Federal Agency for Support and Evaluation of Graduate
Education (CAPES)' and 'Rio de Janeiro Research Foundation
(FAPERJ)' for financial support. Pronex-FAPERJ (grant number
E-26/110.574/2010) is acknowledged. G. B. S. (136200/2009-5)
and M. D. V. (306136/2011-2) thank for their CNPq grants.
28. Squella, J. A.; Bollo, S.; Nuñes-Vergara, L. J. Curr. Org. Chem. 2005, 9,
565.
29. Frontana, C.; González, I. J. Electroanal. Chem. 2007, 603, 155.
30. Solorio-Alvarado, C. R.; Peña-Cabrera, E.; Garcia-Soto, J.; López-
Godínez, J.; González, F. J.; Álvarez-Hernández, A. Arkivoc 2009, 2,
239.
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Graphical Abstract
New insights into 3-(aminomethyl)-
naphthoquinones: evaluation of cytotoxicity,
electrochemical behavior and search for
structure-activity correlation
Gustavo B. da Silva, Amanda P. Neves, Maria D. Vargas, José D. B. Marinho-Filho, Letícia V. Costa-Lotufo