11a-N-tosyl-5-carbapterocarpans: Synthesis, antineoplastic evaluation and in silico prediction of ADMETox properties

Article abstract of DOI:10.1016/j.bioorg.2018.07.004

11a-N-tosyl-5-carbapterocarpans (5a–c and 6a–c), 9-N-tosyl-4,4a,9,9a-tetrahydro-3H-carbazole (7), 11a-N-tosyl-5-carbapterocarpen (8) analogues of LQB-223 (4a), were synthesized through palladium catalyzed azaarylation of substituted dihydronaphtalenes (14a–c) and cyclohexadiene (15), respectively, with N-tosyl-o-iodoaniline (11). In order to understand the role of the N-tosyl moiety for the pharmacological activity, the azacarbapterocarpen (9) was also synthesized by Fischer indol reaction. The structural requirements at the A and D-rings for the antineoplastic activity toward human leukemias and breast cancer cells were evaluated as well. Substitutions on the A-ring of 4a and analogues alter the effect on different breast cancer subtypes. On the other hand, A-ring is not essential for antileukemic activity since compound 7, which does not contain the A-ring, showed efficacy with high selectivity indices for drug-resistant leukemias. On the other hand, substitutions on the D-ring of 4a for fluorine or iodine did not improve the antileukemic activity. In silico studies concerning Lipinskís rule of five, ADMET properties and drug scores of those compounds were performed, indicating good physicochemical properties for all compounds, in special for compound 7.

Full text of DOI:10.1016/j.bioorg.2018.07.004

BioorganicChemistry80(2018)585–590
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
11a-N-tosyl-5-carbapterocarpans: Synthesis, antineoplastic evaluation and
in silico prediction of ADMETox properties
Joseane A. Mendesa,1, Eduardo J. Salustianob,c,1, Carulini de S. Piresd, Thaís Oliveirae,
Julio C.F. Barcellosf, Jhonny M.C. Cifuentesa, Paulo R.R. Costaf, Magdalena N. Rennód,⁎
,
Camilla D. Buarquea,⁎
a
Departamento de Química, Pontifícia Universidade Católica do Rio de Janeiro, Rua Marquês de São Vicente, 225, Gávea, Rio de Janeiro, RJ 22435-900, Brazil
Laboratório de Imunologia Tumoral, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Bloco H sala 003, Universidade Federal do Rio de
b
Janeiro, RJ 21941-590, Brazil
c
Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Bloco C sala C1-042, Universidade Federal do Rio de Janeiro, RJ
21941-590, Brazil
d
Laboratório de Modelagem Molecular e Pesquisa em Ciências Farmacêuticas, Núcleo em Ecologia e Desenvolvimento Sócio-Ambiental de Macaé, Universidade Federal do
Rio de Janeiro Campus Macaé Professor Aloísio Teixeira, Macaé, RJ 27965-045, Brazil
e
Laboratório de Bioquímica e Biologia Molecular do Câncer, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Bloco C sala E1-022,
Universidade Federal do Rio de Janeiro, RJ 21941-590, Brazil
f
Laboratório de Química Bioorgânica, Instituto de Pesquisas de Produtos Naturais, Centro de Ciências da Saúde, Bloco H, Universidade Federal do Rio de Janeiro, RJ
21941-590, Brazil
A R T I C L E I N F O
A B S T R A C T
InChIKeys:
11a-N-tosyl-5-carbapterocarpans (5a–c and 6a–c), 9-N-tosyl-4,4a,9,9a-tetrahydro-3H-carbazole (7), 11a-N-
tosyl-5-carbapterocarpen (8) analogues of LQB-223 (4a), were synthesized through palladium catalyzed
azaarylation of substituted dihydronaphtalenes (14a–c) and cyclohexadiene (15), respectively, with N-tosyl-o-
iodoaniline (11). In order to understand the role of the N-tosyl moiety for the pharmacological activity, the
azacarbapterocarpen (9) was also synthesized by Fischer indol reaction. The structural requirements at the A and
D-rings for the antineoplastic activity toward human leukemias and breast cancer cells were evaluated as well.
Substitutions on the A-ring of 4a and analogues alter the effect on different breast cancer subtypes. On the other
hand, A-ring is not essential for antileukemic activity since compound 7, which does not contain the A-ring,
showed efficacy with high selectivity indices for drug-resistant leukemias. On the other hand, substitutions on
the D-ring of 4a for fluorine or iodine did not improve the antileukemic activity. In silico studies concerning
Lipinskís rule of five, ADMET properties and drug scores of those compounds were performed, indicating good
physicochemical properties for all compounds, in special for compound 7.
AABHTRGBALOPLD-OFNKIYASSA-N
CSYLMVCMPNCBMW-NFBKMPQASA-N
UUNISZPPBPZRLP-NFBKMPQASA-N
CMRUDJCDJDEHFQ-FYYLOGMGSA-N
CMRUDJCDJDEHFQ-FYYLOGMGSA-
NKeywords:
Cancer
Multidrug resistant phenotype (MDR)
N-tosyl-carbapterocarpans
Molecular descriptors
Druglikeness
1. Introduction
[a]carbazole as 3, which inhibited the growth of breast cancer tumors
in rats [4] due to their affinity to estrogen receptors [5]. The 11a-N-
Pterocarpans, the second most abundant sub-class of isoflavonoids
and its derivatives are interesting sources of bioactive compounds [1].
For example, medicarpin (1), a pterocarpan isolated from Medicago
sativa, presents antimitotic effects on sea urchin eggs [2] (Fig. 1). The
11a-aza-pterocarpan (2), recently isolated from roots of black locust
(Robinia pseudoacacia) is the first example of a natural aza-pterocarpan.
This compound was synthesized by Dejon et al. and showed moderate
antineoplastic activity on HL-60 leukemia cell lines [3]. Von Angerer
and co-workers reported the synthesis of some 6,11-dihydro-5H-benzo
tosyl-5-carbapterocarpan LQB-223 (4a) was previously designed and
prepared as racemate by our group, as part of a research aiming to the
synthesis of new antineoplastic and antiparasitic drug candidates
(Fig. 1). This compound presented antineoplastic activity towards
multidrug resistant (MDR) leukemias and breast cancer cells [6–8],
leishmanicidal properties in vitro [6], as well as in vitro and in vivo
antimalarial activities [9]. The potential of 4a as an antineoplastic
prompted us to prepare derivatives for these studies. In this paper we
report the synthesis of compounds 4–9 designed to evaluate, along with
⁎
Corresponding authors.
E-mail addresses: mnrenno@macae.ufrj.br (M.N. Rennó), camilla-buarque@puc-rio.br (C.D. Buarque).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.bioorg.2018.07.004
Received 6 May 2018; Received in revised form 28 June 2018; Accepted 1 July 2018
Availableonline17July2018
0045-2068/©2018ElsevierInc.Allrightsreserved.

J.A. Mendes et al.
BioorganicChemistry80(2018)585–590
Fig. 1. Pterocapan, Aza-pterocarpan and 6,11-dihydro-5H-benzo[a]carbazole derivatives.
compound 4a, the effect of substitutions at A and D-rings on the cyto-
toxicity against models of human leukemias (K562, Lucena-1 and FEPS)
and breast cancers (MCF-7 and MDA-MB-231) presenting diverse phe-
notypes of drug resistance. Additionally, ADMET properties were pre-
dicted in silico. Since the exchange of the N-tosyl group for mesyl or
benzoyl groups led to a drastic reduction in cytotoxic effect [7], we
decided to further investigate the role of tosyl group for the toxicity
exerted by the aza-carbapterocarpan derivatives.
dihydronaphthalene and N-tosyl-4-fluoro-o-iodoaniline (11b), pre-
viously prepared in good yield (86%) by reaction of tosyl chloride and
4-fluoro-o-iodoaniline (10b) employing similar conditions as to obtain
11a. Compound 4c was obtained in 88% yield by the reaction of
compound 4a with N-iodosuccinimide (NIS) catalyzed by FeCl3 in di-
chloromethane (Scheme 2) [14].
As it could be seen in Table 1, compounds 4a and 8 presented si-
milar biological activity against the cell lines studied in this work. In
order to understand the role of the N-tosyl moiety we decided to syn-
thesize compound 9 (Fig. 1), which lacks the tosyl group, using the
classic Fischer indol synthesis [15]. Compound 9 is known as an anti-
fungal [15] and anticancer agent with immunoregulatory properties
[16], and this framework is present in some derivatives with anticancer
and antiestrogen activities as described in Fig. 1 [4,5].
2. Chemistry
As previously described, compounds 4a, 5a–c and 7 were prepared
in moderate to good yields by a palladium-catalyzed azaarylation of
substituted dihydronaphthalenes (14a–c) or cyclohexadiene (15) by N-
tosyl-o-iodoaniline (11a) using 10 mol% of Pd(OAc)2, 1.2 eq. of Ag2CO3
in PEG-400 at 130 °C or in refluxing acetone (Scheme 1, conditions iii or
iv) [10]. Compounds 5a–c were subsequently purified using flash
chromatography followed by recrystallization with methanol, resulting
in yields up to 55%. In this work, PEG was also used at 220 °C (con-
dition vi) in order to obtain 11a-N-tosyl-5-carbapterocarpen (8). In this
case, a mixture of products 4 and 8 was obtained in which the com-
pound 8 was obtained in 30% yield. The dihydronaphthalenes (14a–c)
were prepared in excellent yields by reduction of commercially avail-
able tetralones (12a–c) followed by water elimination in the resulting
alcohols 13a–c [11]. N-tosyl-o-iodoaniline (11a) was prepared in good
yields (88%) by the reaction of tosyl chloride and o-iodoaniline (10a) in
solution of pyridine/dichloromethane (10% v/v) [12]. Aiming to
achieve the synthesis of new analogues for biological assays analogues
for biological assays, these compounds were submitted to O-demethy-
lation in the presence of five equivalents of BBr3 in an inert atmosphere
leading to 6a–c in almost quantitative yields (88–98%) [13].
3. Results and discussion
3.1. Cytotoxicity towards neoplastic cells
All compounds were evaluated for their effect against a panel of
human cell lines with diverse phenotypes of drug resistance and the
results compared with those obtained for 4a. For breast cancers, MCF-7
is a model of an invasive, endocrine therapy-sensitive breast ductal
carcinoma, estrogen and progesterone receptors positive and Her2/neu
overexpression negative. MDA-MB-231 cell line is an invasive, endo-
crine therapy-resistant breast ductal carcinoma, p53 mutant and ne-
gative for estrogen, progesterone and Her2/Neu receptors. For leuke-
mias, K562 is representative of a chronic myeloid leukemia from
erythroid origin with constitutive BCR/ABL tyrosine kinase activity,
whereas Lucena-1 and FEPS are multidrug resistant (MDR) cell lines
selected by either vincristine or the anthracycline daunorubicin (DNR)
exposure [17,18]. The latter was employed as a standard due to being
widely used in many chemotherapy regimens, including for cancers
Aza-carbapterocarpan 4b was synthesized in moderate yields (56%)
by palladium-catalyzed Aza-Heck arylation in PEG 400 between
586

J.A. Mendes et al.
BioorganicChemistry80(2018)585–590
Scheme 1. Synthesis of compounds 5a-d, 6a–c, 7 and 8.
Scheme 2. Synthesis of compounds 4b and 4c.
587

J.A. Mendes et al.
BioorganicChemistry80(2018)585–590
Table 1
Antineoplastic effect (IC50) of 4, 5, 6, 7, 8, 9 and daunorubicin (DNR) on the cell viability of human breast cancer and chronic myeloid leukemia cells.
Compound
MDA-MB-231
MCF-7
K562
Lucena-1
FEPS
4a
4b
4c
5a
5b
5c
6a
6b
6c
7
31.71
NA
NA
> 40
8.29
27.06
22.08
> 40
4.88
12.17
33.37
> 40
104.20
3.68
17.96
NA
NA
27.45
5.93
34.56
26.57
10.39
16.97
> 40
> 40
> 40
27.40
5.76
3.67
2.90
0.65a
1.26
5.46
1.66
0.40
2.51
1.78
0.76
2.75
0.87
0.88
2.49
0.14a
3.30
4.48
0.28
0.28
0.02
1.62
0.60
3.76
1.35
1.47
7.35
115.59
2.12
14.05
3.92
11.16
2.58
7.90
7.39
2.90
8.83
1.68
0.73a
2.89
0.40
0.70
0.44
2.06
1.11
0.76
0.74
0.62
0.92
8.16
15.95
23.53
11.29
2.91
8.09
11.27
2.87
13.31
1.85
1.93
> 40
108.53
28.30
14.35
12.75
4.54
10.05
6.55
3.56
26.46
4.14
2.08
7.31
5.77
3.58
6.13
8.25
3.99
3.90
1.18
1.18
3.98
8
9
2.18
34.73
799.67
2.89
25.28
> 1200
DNRb
8.73
4.93
13.26
Results are reported as IC50 values
SD in μM. Data represent means obtained from three independent experiments, with each concentration tested in triplicate.
Assays were performed as described in the Experimental Section [20].
a
IC50 obtained from our previous work [7]. NA = Not analyzed.
For daunorubicin (DNR) only, results are reported as IC50 values
b
SD in nM.
from both breast and blood origins [19]. The effect of the various
compounds on our cell panel, as measured by their IC50 values, are
summarized in Table 1.
this observation. Compound 6c, however, was more active on MDA-
MB-231 and FEPS. As for DNR, anthracyclines induce toxicity by a dual
mechanism, inhibition of DNA topoisomerase II and ROS generation
[19]. Resistance to this drug depends on the level of expression of ABC
proteins [28], a fact that reflected on its IC50 for the various cells
evaluated in this work.
Concerning breast cancer, compounds 5b, 6c and 7 presented
higher cytotoxicity to the MDA-MB-231 cell line whereas 5b and 6b
were the most active against MCF-7. Compounds 5c and 6a were
equipotent on both breast cancer cells. The presence of the A-ring with
oxygenated groups in position 3 of the aza-carbapterocarpan was as-
sociated with toxicity on MCF-7 cells, although such correlation was not
valid for MDA-MB-231 since removal of the A-ring on 7 did not di-
minish the cytotoxicity. Nevertheless, compound 5b was the most po-
tent on breast cancer cells, deserving further studies. The aza-carbap-
terocarpen 8 acted in a comparable fashion as 4a, which is consistent
with their structural similarity, and the removal of N-tosyl in 9 dras-
tically reduced the activity towards breast cancer. Concerning leuke-
mias, all compounds, except for compound 9, were active on K562,
Lucena-1 and FEPS, being 5b, 6b, 7 and 8 the most active. These data
suggest a correlation with the oxygenation pattern at the A-ring as well
as the presence of N-tosyl reinforcing what we have indicated before for
LQB-223 (4a) [7]. Accordingly, this is proven by the synthesis of
compound 9, since removal of the N-tosyl group abrogated its cyto-
toxicity showing the highest IC50 toward all cell types. Furthermore, the
A-ring was not essential for the antileukemic activity considering the
results of compound 7. The fluoro- (4b) or iodo-(4c) substitution of D-
ring did not improve the antileukemic activity. Due to increased level of
antioxidants, resistant cells usually have lower reactive oxygen species
(ROS) levels compared to their sensitive counterparts [21]. Chronic
myeloid leukemias such as K562 are tolerant to oxidative stress, and the
MDR counterpart Lucena-1 is described as even more resistant due to
overexpression of catalase and glutathione [18,22]. ROS levels are re-
ported to be lower in MDA-MB-231 than in MCF-7 [23], and since
glutathione is also present in high levels in the latter [24], our results
suggest that compounds 4a, 5b and 6b act regardless of resistance to
oxidative stress. In addition, these compounds manifested similar ef-
fects on cells expressing varying degrees of ATP-binding cassette pro-
teins, a feature associated to MDR [25]. ABCB1 genomic region is re-
ported to be 5 and 30-fold amplified, respectively, in Lucena-1 and
FEPS cells over K562 [26], leading to high levels of protein expression
and to an increase in its activity [17]. FEPS, MDA-MB-231 and MCF-7
express functional ABCC1 [17,27], indicating that 4a, 5b and 6b were
active in the presence of those active transporters. The prototype
compound 4a was previously demonstrated to be similarly effective on
MCF-7 DoxR, an ABCB1-overexpressing cell line derived from MCF-7
after exposure to the DNR analogue doxorubicin [8], adding depth to
3.2. Effect on non-neoplastic cells and calculation of selectivity indices
For drugs to be successfully used in the chemotherapeutic practice,
it is important to assess their toxicity on healthy cells. To accomplish
this, we employed cells from breast and blood origins. As a model of
non-neoplastic breast cells we used MCF-10A, a human epithelial cell
line derived from benign breast tissue that does not express the estrogen
receptor [29], whereas fresh human peripheral blood mononuclear cells
(PBMC) were employed as controls for leukemias. Both cells were sti-
mulated to proliferate, the first with epidermal growth factor and in-
sulin, and the latter with phytohemagglutinin. The cytotoxicity exerted
by the most potent compounds on the corresponding models of normal
cells, as measured by their IC50 values, are reported in Table 2.
Results in Table 3 indicate that selectivity indices (SI) were, in
general, higher to leukemias than to breast cancer cells, mainly for
compounds 4a, 5b and 6b. Compound 4a was previously demonstrated
to be selective to leukemia cells, not affecting normal proliferating
murine lymphocytes [7]. This profile was maintained on human PBMC
and a similar outcome was observed for 5b, 6c and 7. For breast cells, in
Table 2
Cytotoxicity of 4a, 5b, 6b, 6c, 7 and daunorubicin (DNR) on models of non-
neoplastic breast cells and peripheral blood mononuclear cells (PBMC).
Compound
MCF-10A
PBMC
4a
6.15
21.94
33.83
NA
NA
70.46
1.80
6.85
5.90
> 30
> 40
23.83
> 40
> 40
28.67
5b
6b
6c
4.03
4.19
7
DNRa
8.45
PBMC and MCF-10A: Results are reported as IC50 values
represent means obtained from three independent experiments, with each
concentration tested in triplicate. Assays were performed as described in the
SD in μM. Data
Experimental Section. NA = Not analyzed.
a
For DNR only, results are reported as IC50 values
SD in nM.
588

J.A. Mendes et al.
BioorganicChemistry80(2018)585–590
Table 4
Physicochemical parameters of the compounds and DNR.
Table 3
Selectivity indices (SI) of 4a, 5b, 6b, 6c, 7 and daunorubicin (DNR).
Compound MCF-10A/
MDA-MB-231
MCF-10A/
MCF-7
PBMC/
K562
PBMC/LUC PBMC/
FEPS
Compound miLogP nON nOHNH MW TPSA
nrotb nviolations
4a
4b
4c
5a
5b
5c
6a
6b
6c
7
5.27
5.41
6.33
5.28
5.30
5.30
5.21
4.77
4.77
4.33
5.36
3.93
0.90
3
3
3
4
4
4
4
4
4
3
3
1
11
0
0
0
0
0
0
1
1
1
0
0
1
6
375.49 37.38
393.48 37.38
501.39 37.38
405.52 46.61
405.52 46.61
405.52 46.61
391.49 57.61
391.49 57.61
391.49 57.61
325.43 37.38
373.48 39.08
219.29 15.79
527.53 185.85
2
2
2
3
3
3
2
2
2
2
2
0
4
1
1
2
1
1
1
1
0
0
0
1
0
3
4a
5b
6b
6c
7
DNR
0.19
2.65
0.85
NA
NA
0.68
0.34
3.70
3.26
NA
NA
2.57
10.34
13.75
8.30
3.00
21.62
0.26
12.04
8.81
6.69
1.51
9.66
0.04
14.15
15.50
8.22
4.53
23.81
0.02
Selectivity indices (SI) were calculated as a ratio of the IC50 in non-neoplastic
cells (PBMC or MCF-10A, Table 2) to the IC50 in the corresponding neoplastic
cell (breast cancer or leukemias, Table 1). When IC50 was expressed on Tables 1
or 2 as being higher than a concentration (e.g. > 30), this value, 30 μM, was
used for the SI calculation (e.g. SI of 4 towards K562: IC50 PBMC/IC50
K562 = 30/2.90 = 10.34). NA = Not analyzed.
8
9
DNR
miLogP: octanol/water partition coefficient; nON: number of hydrogen bond
acceptors; nOHNH: number of hydrogen bond donors; MW: Molecular weight,
TPSA: Topological Polar Surface Area; nrotb: Number of Rotatable Bonds;
nviolations: number of violations from Lipinski’s rule.
contrast, 4a reduced the viability of non-tumor MCF-10A in lower IC50
than in tumor cells. Conversely, the non-neoplastic breast human cell
line HB4a was resistant to the action of 4a in another work [8], sug-
gesting that the SI for breast cancer could vary depending on the sub-
types of both the tumor and the normal cell. This is especially true for
5b, that despite presenting lower IC50 than 6b on MCF-10A, it was more
effective toward breast cancer cells. Results toward normal blood cells
indicate that substitutions in the A-ring were associated with loss of
selectivity. In this regard, removal of the A-ring in 7 led to the highest
SI of all compounds for K562 and FEPS cells. Overall, results on models
of normal cells indicate 5b and 7, respectively, as interesting drug
candidates for breast cancer and leukemias.
positively correlated to ABCC1-mediated drug efflux, in a way that
xenobiotics with low values of this descriptor present low affinity for
this transporter as well [35]. This is in accordance to the IC50 values on
cells such as FEPS (Table 1), whose ABCC1 activity has been well de-
scribed [17]. For the Lipinskís rule, all compounds presented para-
meters for good oral bioavailability, except DNR and compound 4c.
Our study correlated in silico physicochemical properties (drugli-
keness and drug scores), to potential toxicity risks, such as mutageni-
city, tumorigenicity, irritating effects and reproductive effects.
Prediction of toxicity risks showed that the structure with the lowest
risk of undesirable effects is compound 7, which would likely not
manifest risks of tumorigenicity, mutagenicity, irritant nor reproductive
effects. However, all other synthetic compounds presented high risk for
reproductive effect, though compounds 8 and 9 were predicted to
present tumorigenic effects. Results suggest that these risks may be
linked to the presence of the aromatic A-ring in all substances and its
absence in compound 7 (Table 4). The standard drug DNR was pre-
dicted to manifest both reproductive and irritant effects. A high drug
score suggest that the structure is a promising lead for future devel-
opment of an efficient drug, and all compounds were in the range of
0.0693–0.3208, while the positive control presented 0.1889. Ad-
ditionally, DNR presented the highest druglikeness value in relation to
the compounds, and this drug is commercially available as an injectable
pharmaceutical formulation (see Table 5).
3.3. Admetox predictions
In order to describe the potential for good oral bioavailability and to
evaluate the druglikeness and drug score values of the synthesized
compounds, physicochemical properties were predicted in silico and
compared with the descriptors obtained for daunorubicin (DNR). The
physicochemical and toxicological descriptors were calculated using
the Molinspiration Cheminformatics version 2016.10 server (http://
www.molinspiration.com) and OSIRIS Property Explorer (https://
www.organic-chemistry.org/prog/peo/) using DataWarrior version
4.7.2 software (http://www.openmolecules.org/datawarrior/) [30,31]
The Lipinskís ‘rule of five’ descriptors were analyzed, which describes
physicochemical properties of a compound required to estimate im-
portant pharmacokinetic parameters, such as absorption or permeation
of the molecule, distribution, metabolism and excretion, being those
parameters associated with permeability and solubility [32]. For the
Lipinski’s rule the compounds 4(a,b), 5(a–c), 6a and 8 presented only
one violation. Additionally, compounds 6b, 6c, 7 and 9 did not violate
any criteria. These results showed that the compounds have structures
that would present good absorption properties, therefore permeability
across the cell membrane, and good theoretical oral bioavailability.
However, the positive control DNR and compound 4c showed at least
three and two violations, including acceptor, donor hydrogen, mole-
cular weight and miLogP, respectively. The data for other physico-
chemical parameters such as Topological Polar Surface Area (TPSA)
and number of rotatable bonds is presented in Table 4. The TPSA
methodology described by Ertl et al. using published data of various
types of drug transport properties shown to be a very good descriptor to
characterize drug absorption, including intestinal absorption, bioa-
vailability, blood-brain barrier penetration, and Caco-2 cell perme-
ability [33]. Compounds that present TPSA values equal to or less than
140 Å2 and fewer rotatable bonds would show good potential for oral
bioavailability [34]. The results indicate that all compounds presented
lower TPSA values than 140 Å2 and lower number of rotatable bonds
when compared to DNR (Table 4). Furthermore, TPSA has been
Table 5
In silico predicted druglikeness, drug score and toxicity risks of the synthesized
compounds and DNR.
Compound
Druglikeness
Drug score
Toxicity risksa (high)
4a
4b
4c
5a
5b
5c
6a
6b
6c
7
−4.7053
−6.505
0.1435
0.1304
0.0942
0.1402
0.1402
0.1402
0.1565
0.1565
0.1565
0.3208
0.0693
0.1761
0.1889
Reproductive
Reproductive
Reproductive
Reproductive
Reproductive
Reproductive
Reproductive
Reproductive
Reproductive
None
Reproductive tumorigenic
Reproductive tumorigenic
Reproductive irritant
−4.6745
−4.4787
−4.4811
−4.4811
−4.778
−4.8167
−4.8167
−8.8552
−4.5446
−0.4097
6.1633
8
9
DNR
a
Mutagenicity, tumorigenicity, irritating effects, reproductive effects.
589

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BioorganicChemistry80(2018)585–590
4. Conclusion
[9] W.A. Cortopassi, J. Penna-Coutinho, A.C. Aguiar, A.S. Pimentel, C.D. Buarque,
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In conclusion, the new 11a-N-tosyl-5-carbapterocarpans present effi-
cacy on different neoplastic cell subtypes in accordance with the presence
or absence of the A-ring as well as the pattern of substitution at A-ring. The
N-tosyl group is essential for the antineoplastic activity to manifest.
Compounds 5b and 7 showed to be the best candidates for treating the
majority of the cancer cell lines studied in this work, with higher potencies
and the best selectivity indices for leukemia cell lines. The A-ring was
important for targeting breast cancer cells, and the position of methoxyl or
hydroxyl groups altered the efficacy on subtypes of these tumors.
Furthermore, our results confirmed the structural importance of the N-
tosyl moiety for the design of more effective N-tosyl-carbapterocarpan
drug candidates, since its removal in 9 abolished the effect on both cancer
cell types studied in this work. In addition, compounds 5b, 6b, 7 and 8
exerted toxicity in similar levels to cells with diverse phenotypes com-
monly associated with resistance to chemotherapy.
In silico studies suggest that the compounds present descriptors for
good oral bioavailability, low or absent toxicity risks and drug score
values comparable with the one for daunorubicin. Further investiga-
tions will be carried out aiming to clarify the mechanism of action
exerted by the most promising compounds. Results obtained in this
work propose the 11a-N-tosyl-5-carbapterocarpans, notably compound
7, as antineoplastic drug candidates effective on drug-resistant cancer
subtypes, with reasonable selectivity indices and interesting physico-
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Acknowledgements
We are grateful for the financial support from Conselho Nacional de
Pesquisa e Desenvolvimento Científico e Tecnológico (CNPq), Instituto
Nacional de Ciência e Tecnologia (INCT) para o Controle do Câncer,
Coordenação de Aperfeiçoamento Pessoal de Nível Superior (CAPES)
and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do
Rio de Janeiro (FAPERJ).
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Appendix A. Supplementary material
Supplementary data associated with this article can be found, in the
online version, at https://doi.org/10.1016/j.bioorg.2018.07.004. These
data include MOL files and InChiKeys of the most important compounds
described in this article.
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