Synthesis and SAR study of novel anticancer and antimicrobial naphthoquinone amide derivatives

Article abstract of DOI:10.1016/j.bmcl.2014.04.080

A series of novel naphthoquinone amide derivatives of the bioactive quinones, plumbagin, juglone, menadione and lawsone, with various amino acids were synthesized. The compounds were characterized by ¹H NMR, ¹³C NMR, Mass, IR and ele

Full text of DOI:10.1016/j.bmcl.2014.04.080

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR study of novel anticancer and antimicrobial
naphthoquinone amide derivatives
a
b
b
b
Thonthula Sreelatha a, , Subramani Kandhasamy , Raghu Dinesh , Suresh Shruthy , Sinha Shweta ,
⇑
Doble Mukesh b, Devarajan Karunagaran b, Ravichandran Balaji c, Narayanasamy Mathivanan c,
Paramasivan Thirumalai Perumal a,
⇑
a Organic Chemistry Division, Central Leather Research Institute (CSIR), Chennai 600 020, India
b Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600 036, India
c Biocontrol and Microbial Metabolites Lab, Centre for Advanced Studies in Botany, University of Madras, Maraimalai Campus, Guindy, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel naphthoquinone amide derivatives of the bioactive quinones, plumbagin, juglone,
menadione and lawsone, with various amino acids were synthesized. The compounds were characterized
by 1H NMR, 13C NMR, Mass, IR and elemental analysis. All the compounds were evaluated for their anti-
cancer activity against HeLa and SAS cancer cell lines and 3D-QSAR indicated the presence of electron
donating group near sulphur enhanced the activity against HeLa cells. Among the derivatives synthesized,
Received 27 November 2013
Revised 8 April 2014
Accepted 21 April 2014
Available online xxxx
compounds 11f, 10a, 10b and 10g were the most active with IC50 values of 16, 12, 14 and 24.5 lM,
Keywords:
Plumbago zeylanica
Juglans regia
Lawsonia inermis
Menadione
Amide derivatives
Anticancer
respectively. The analogues were also screened for antimicrobial activity against two human bacterial
pathogens, the Gram-positive Methicillin resistant Staphylococcus aureus (MRSA) and the Gram-negative
Pseudomonas aeruginosa and a human yeast pathogen, Fluconazole resistant Candida albicans (FRCA).
Among the synthesized compounds, 8g, 10g and 11g exhibited maximum antibacterial activity towards
MRSA and antifungal activity against FRCA in well diffusion method.
Ó 2014 Elsevier Ltd. All rights reserved.
Antimicrobial activity
Cancer is one of the deadliest diseases affecting mankind.
Although a number of chemotherapeutic agents are available, most
of them also kill the normal cells that divide rapidly and cause sev-
eral side effects such as immunosuppression, inflammation of the
digestive tract lining and hair loss.1 The search for anticancer drugs
with increased potency and lower toxicity continues. In the quest
for new bioactive molecules the isolation from medicinal plants
as well as synthesis of their analogues is being explored. Some of
the well-established anticancer drugs such as taxol,2 camptothe-
cin3 and vinca alkaloids4 are derived from plants. Our ongoing
research programme focuses on the isolation of novel bioactive
molecules from Indian medicinal plants for cancer therapy and
synthesis of their analogues to enhance their activity. Plumbago
zeylanica, Juglans regia and Lawsonia inermis have been chosen for
the study. Plumbagin, juglone and lawsone along with menadi-
one-bioactive quinones have been selected for the study.
occurring quinones such as psychorubrin,5 lapachol,6 menadione,7
cribrostatin8 and thymoquinone9 (Fig. 2) have antineoplastic
activity with IC50 values of 0.04–25 lM against various cancer cell
lines. One of our target compounds, plumbagin is considered to be
a natural anticancer agent and induces potent cytotoxicity in
MCF-7 human breast cancer cells via reactive oxygen species
(ROS) generation.10
There are several mechanisms by which cytotoxic quinone
containing compounds induce cell death. Quinone containing com-
pounds exert cytotoxicity by radical formation through electron
transport with a vital role for the quinone ring.11 In the absence
of oxygen, anthracyclins (e.g., daunorubicin, valrubicin) have the
potency to generate aglycone free radicals that produce DNA and
RNA single and double strand breaks. Free oxygen radicals can
damage intra as well as extracellular macromolecules (lipids and
proteins). Quinone moieties can also be cytotoxic by binding to
membranes thus altering their functions.12
As a part of our ongoing research program in designing novel
cytotoxic analogues of bioactive compounds quinones, plumbagin
1a, juglone 1b, lawsone 1c and menadione 1d (Fig. 3) four series
of 28 synthetic 1,4-naphthoquinone amides were synthesized. In
this structure–activity relationship study we have studied the
Several quinone based chemotherapeutic drugs such as
Mitomycin C, Mitoxantrone, Daunorubicin and Valrubicin (Fig. 1),
are used in treating breast, lung and ovarian cancers. Naturally
⇑
Corresponding authors. Tel.: +91 9566132233 (T.S.).
E-mail address: t_sree_latha@yahoo.com (T. Sreelatha).
http://dx.doi.org/10.1016/j.bmcl.2014.04.080
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
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2
T. Sreelatha et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
O
O
OH
2
3
NH
O
O
OH
OH
O
O
HN
H3C
H2N
N
NH
Figure 4. Structure of naphthoquinone.
O
HN
O
O
by the Michael addition of thioglycollic acid at C-3 position of the
quinone ring. The naturally occurring quinones, plumbagin 1a, jug-
lone 1b and lawsone 1c have a phenolic hydroxyl group chelated to
the quinone carbonyl group. Prior to the thio-Michael addition, this
phenolic –OH group was protected by methylation. While the qui-
nones 1a and 1b were methylated using iodomethane with Ag2O as
base,20 lawsone 1c required more vigorous conditions for methyl-
ation (Scheme 1).
The O-methyl lawsone 3c was synthesized by refluxing lawsone
in acidic methanol for 3 h.21 The thio-Michael addition of O-methyl
plumbagin 3a, O-methyl juglone 3b and O-methyl lawsone 3c was
achieved in good yield using water as the solvent and triethyl-
amine22 as the base. On completion of the reaction, the solution
was acidified and extracted with ethyl acetate. The thio-Michael
addition of methyl juglone gave a mixture of two isomers, where
the substitution at the 3-position of the quinone ring gave the
major isomer. This isomer was separated by column chromatogra-
phy and structure confirmed by HMBC correlations in NMR
spectrum. Menadione 1d underwent Michael addition with thio-
glycollic acid with DBU as the base.23 The procedure reported pre-
viously in the literature was adopted.24 It is interesting to note that
no reaction was observed in case of quinones 1a, 1b and 1c with
thioglycollic acid 4 in presence of DBU/ether. The lack of solubility
of 5a, 5b and 5c in ether hinders the reaction. The amides of qui-
none carboxylic acids were synthesized by coupling with the
NH
H2N
Mitomycin C
NH2
Mitoxantrone
OH
HO
O
O
OH
O
O
H3C
O
O
OH
OH
O
O
OH
CH3
O
O
H
OMe O
OH
H
O
HO
O
CH3
HN
CF3
O
Daunorubicin
Valrubicin
Figure 1. Structures of quinone-based anticancer drugs.
O
O
OH
O
OH
O
O
Psychorubrin
Lapachol
O
N
O
O
CH3
H3C
N
CH3
O
O
methylated
(Scheme 2).
L-amino acids using DCC/HOBT/DIPEA procedure
Cribrostatin 6
Thymoquinone
Figure 2. Bioactive cytotoxic quinones.
All the amino acids chosen for the study were neutral amino
acids such as glycine 7a, alanine 7b, phenylalanine 7c, isoleucine
7d, leucine 7e, valine 7f and 4-amino butyric acid 8 (GABA)
(Scheme 3).
O
O
All the amides were characterized by 1H NMR, 13C NMR, IR,
mass and elemental analysis. The IR spectrum of the 11c amide
shows three bands at 1743, 1628 and 1533 cmꢀ1, respectively,
corresponding to ester carbonyl, quinone carbonyl and amide
CH3
OH
O
OH
O
Plumbagin (1a)
Juglone (1b)
O
O
CH3
OH
O
O
R1
R3
Methylation
O
O
+
2
Lawsone (1c)
Menadione (1d)
O
R2
O
R4
Figure 3. Naturally occurring quinones.
1a-c
3a-c
3a: R3 = -CH3, R4 = -OCH3
3b: R3 = -H, R4 = -OCH3
3c: R3 = -OCH3, R4 = -H
1a, 1b; 2=CH3I, Ag2O, DCM
1c; 2=
MeOH, Conc. HCl
1a: R1 = -CH3, R2 = -OH
1b: R1 = -H, R2 = -OH
1c: R1 = -OH, R2 = -H
effect of thiolated side chain on the quinone moiety in an effort to
enhance the pharmacological activity of the parent bioactive qui-
nones against HeLa and SAS cancer cell lines.
Scheme 1. General schematic representation for methylation.
The naturally occurring naphthoquinones plumbagin, juglone
and lawsone show anti-bacterial activity against many aerobic
and anaerobic organisms.13 Previously many derivatives of 1,4-
naphthoquinones have been synthesized with substitution at posi-
tion 2 or 3 of the quinone ring. Analogues with halogen and amine
substitutions have been reported.14–16A combination of the thiol
and amide substitution in the 1,4 naphthoquinone has yet not been
explored (see Fig. 4).
O
O
O
O
O
R1
HS
R1
R1
R
H
OH
O
OMe
i
ii
+
H
N
+
H2N
OH
O
S
OMe
S
O
H
R
O
R2
O
O
R2
R2
1d, 3a-c
4
5a-d
7
8a-f, 9a-f, 10a-f, 11a-f
8a-f R1= -CH3 R2= -OCH3 a: R= -H
1d i= DBU, ether, rt
3a-c i= TEA, H2O, 0-10O
C
9a-f R1= -H
R2= -OCH3 b: R= -CH3
3a R1= -CH3. R2= -OCH3
3b R1= -H R2= -OCH3
3c R1= -OCH3 R2= -H
10a-f R1= -OCH3 R2= -H
11a-f R1= -CH3 R2= -H
c: R= -CH2Ph
The quinones plumbagin17 juglone18 and lawsone19 were iso-
lated from their natural sources. Our strategy in designing the
cytotoxic naphthoquinone amides is to introduce thioether func-
tionality as the side chain in the quinone ring. This was achieved
d: R= -CH2.CH(CH3)2
e: R= -CH(CH3).CH2.CH3
f: R= -CH(CH3)2
Scheme 2. Synthesis of quinone amides.
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T. Sreelatha et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
O
plates were incubated at 37 °C for 24 h. Susceptibility was assessed
on the basis of diameter of the zone of inhibition (ZOI) against the
test pathogens and the results are presented (Table 2).
O
O
R1
R1
O
ii
OMe
H
N
H N
+
2
OH
S
OMe
O
S
O
O
The amide derivatives showed moderate to good antimicrobial
activity against MRSA and FRCA than the parent quinones with
ZOI up to 26 mm. The in vitro minimum inhibitory concentration
(MIC) of all the compounds against MRSA and FRCA was deter-
mined by the method of National Committee for Clinical Labora-
tory Standards (NCCLS).26 The MIC values are summarized in
Table 3. The MIC results of the tested compounds showed that
most of the compounds were active against MRSA and FRCA at a
lower concentration than their parent quinones and almost all of
them were inactive against Gram-negative bacterium, P. aerugin-
osa. Interestingly the compound 9a, the glycine amide of juglone
exhibited good antibacterial and anti-yeast activities at MIC 3.9
R2
O
R2
ii) DCC/HOBt, DIPEA, DMF, 0-25O
C
8g, 9g, 10g, 11g
Scheme 3. Synthesis of GABA amide.
carbonyl stretching frequency. The 1H NMR spectrum of 11c shows
peaks in the range of d 7.08–8.06 ppm integrating for nine aromatic
protons. A quartet at d 4.80 ppm with the coupling constant
of 6.0 Hz integrating for a single proton indicates the presence of
–NHCH-proton. A singlet at d 3.84 integrating for two protons
confirms the presence of –SCH2 group. The carboxy methyl group
shows a singlet at d 3.63 ppm. The 13C NMR spectrum in CDCl3
and 7.8 lg/mL and it was much lower than the MIC of its parent
compound juglone (Table 3). Further, the compound 10e, the leu-
cine amide of lawsone showed good antibacterial and anti-yeast
shows two quinone carbonyl carbons at
d 181.2 ppm and
182.0 ppm. The presence of amide and ester groups was confirmed
by peaks at d 167.8 ppm and 171.7 ppm, respectively. The –SCH2
carbon showed a chemical shift at d 37.7 ppm. A prominent peak
was observed at m/z at 424.07 for [M+H]+ ion confirms the forma-
tion of the product.
Cytotoxicity studies: The cytotoxicity of the derivatives was
determined using MTT assay. From the 28 compounds synthesized,
nine were eliminated from the analysis as they crystallized in cell
culture medium. The remaining 19 derivatives were tested for
their cytotoxicity to HeLa and SAS cells and the results show that
their cytotoxic effects differed between the derivatives as well as
the cell lines used (Table 1). SAS cells were more sensitive than
HeLa to the cytotoxic effects of all the parent quinones (plumbagin,
juglone, menadione and lawsone) and their derivatives suggesting
that the cytotoxicity may differ between cancer cells of different
tissue origin (Table 1).
Antimicrobial activity studies: The naphthoquinones: plumbagin,
juglone, lawsone, menadione and their analogues were initially
screened for their antimicrobial activity against the Gram-positive
bacterium, Methicillin resistant Staphylococcus aureus (MRSA),
Gram-negative bacterium, Pseudomonas aeruginosa MTCC 201
and a yeast strain, Fluconazole resistant Candida albicans (FRCA).
Well diffusion assay was carried out to determine the antibacterial
activity.25 For the well diffusion assay, 17 h old bacterial cultures
were inoculated over the agar surface of Muller Hinton agar plates
using sterile cotton swabs. After 10 min, wells were cut using a
activities at MIC of 7.8
compound, lawsone. Menadione as well as its derivatives exhibited
similar antibacterial and anti-yeast activities at MIC of 15.6 g/mL.
The compound 8d, the isoleucine amide of plumbagin exhibited
good antibacterial and anti-yeast activities at MIC 7.8 g/mL than
the other derivatives and its parent compound, plumbagin for
which the MIC was determined as 125 g/mL (Table 3).
lg/mL, which was lower than its parent
l
l
l
Structure–activity relationship study: The amides of lawsone are
the most active among the tested compounds; especially the gly-
cine and alanine amides were the most potent with an IC50 value
Table 2
Antimicrobial activity of the compounds against human pathogens
S.
Sample code
Zone of inhibition (mm)
No.
Gram-positive
bacterium
MRSA
Gram-negative
bacterium
P. aeruginosa
Fungal
strain
FRCA
1
2
3
4
5
6
7
8
9
1b
9a
9b
9c
9d
9e
9f
9g
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
13
N
N
19
N
19
15
15
11
19
15
12
12
17
19
14
21
15
18
26
11
23
23
13
18
16
19
13
12
20
18
15
21
N
17
12
15
12
N
14
16
26
N
19
12
20
26
11
22
26
16
20
19
19
12
12
21
18
13
25
N
cork borer and each well was loaded with 10
l
l of each compound
1c
from 10 mg/mL stock (100
lg/well) along with DMSO control. The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
10a
10b
10c
10d
10e
10f
10g
1d
11a
11b
11c
11d
11e
11f
11g
1a
8a
8b
8c
8d
8e
8f
8g
Table 1
IC50 values of naphthoquinone amide derivatives on the growth of human cancer cell
lines
S. No.
Derivatives
HeLa (IC50) (
l
M)
SAS (IC50) (lM)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
8c
8d
1d
11f
1b
9a
9c
9e
25.5
>100
>100
18.0
20.0
>100
>100
58.0
94.5
>100
>100
77.5
39.0
63.0
82.0
93.5
24.0
3.0
56.5
78.5
14.0
16.0
>100
>100
40.0
63.0
45.0
>100
12.0
14.0
25.5
60.0
56.0
24.5
9f
1c
10a
10b
10d
10e
10f
10g
12
20
13
21
N
Streptomycin 24
Fluconazole
N
N
N: No inhibition.
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T. Sreelatha et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 3
rather than that of C-5 of the phenyl group as in case of juglone
and plumbagin. The methyl substituent at C-2 in menadione also
proved to be quite effective. Hence, we can conclude the anticancer
activity of 1,4 naphthoquinone is highest with an oxygenated func-
tionality in the quinone ring. This is further enhanced with a thio-
ether linkage at C-3 position of the quinone. The antimicrobial
studies against Methicillin resistant S. aureus and Fluconazole
resistant C. albicans (Table 3) indicate the derivatives 8g, 10g and
Minimum inhibitory concentration of the compounds against MRSA and FRCA
S. No. Sample code
Minimum inhibitory concentration (MIC) (
l
g/mL)
Gram-positive bacteria
MRSA
Fungal strain
FRCA
1
2
3
4
5
1b
9a
9b
9c
ND
ND
3.9
7.9
7.8
ND
7.8
7.8
11g were most active with MIC values of 15.6 lg/mL. These are
9d
7.8
7.8
4-amino butyric amides of plumbagin, lawsone and menadione.
Based on the zone of inhibition (Table 2) again 8g, 10g and 11g
were most active. Hence we believe introduction of the GABA
group increases the antimicrobial activity of the quinones.
QSAR study: 3D QSAR relating the anticancer activity of the com-
pounds against the two cell lines were developed using VLife QSAR
Plus 1.0 molecular modelling software based on earlier references
with the modelling methodology.28,29 The data were randomly
divided into training and test sets (compounds which did not show
activity were ignored for modelling purposes). The model was
developed using the former and the performance of the model
was tested with the latter set.
The pharmacophore models were generated by aligning all the
molecules on a common template in conjunction with partial least
square method. The alignment of all the molecules on a common
template is shown in (Fig. 6) (A and B). The model with the highest
q2 and pred_r2 is reported below with the corresponding statistical
parameters. Based on the statistical parameters, it could be con-
cluded that the models developed are satisfactory.
6
7
8
9
9e
9f
1c
15.6
15.6
125
15.6
62.5
62.5
7.8
15.6
15.6
250
15.6
62.5
ND
10a
10b
10c
10d
10e
10f
10g
1d
11a
11b
11c
11d
11e
11f
11g
1a
8a
8b
8c
8d
8e
8f
8g
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
62.5
7.8
7.8
15.6
15.6
15.6
15.6
15.6
15.6
15.6
15.6
15.6
15.6
125
125
125
125
7.8
15.6
15.6
15.6
15.6
15.6
15.6
15.6
15.6
15.6
15.6
125
125
125
125
7.8
Model for HeLa
ND
15.6
15.6
ND
7.8
15.6
ND
ND
Activity ¼ ꢀ1:5126 þ 0:0416 ½ESꢁ
ð1Þ
r2 = 0.77, q2 = 0.63, F test = 20.6, pred_r2 = 0.6, n training set = 8, n
Streptomycin 3.9
Fluconazole ND
test = 3.
ND: not determined, as they did not show antimicrobial activity in the well diffu-
sion assay.
Model for SAS
Activity ¼ ꢀ0:13 ꢀ 1:74 ½ESꢁ
ð2Þ
r2 = 0.76, q2 = 0.61, F test = 25.6, pred_r2 = 0.6, n training set = 10, n
test = 4.
of 12 and 14
adione 11f also showed good anticancer activity with an IC50 value
of 16 M (Table 1). It is interesting to note that contrary to our
lM, respectively (Table 1). The valine amide of men-
Both the models reveal that the activity is a function of the
electrostatic nature of the groups near sulphur. For HeLa, as the
electrostatic or electron donating groups near sulphur increases
(like methyl group), activity also increases (since the coefficient
in Eq. 1 is positive). Compound 11f has maximum contribution of
the electrostatic descriptor and it also exhibits very high activity.
Whereas, in the case of SAS cell line, the reverse is true (since
the coefficient in Eq. 2 is negative). So electron donating or with-
drawing groups near the sulphur affect the anticancer activities
of these compounds against these two cell lines. The parity plots
(Figures in Supporting information) which relate the experimental
and predicted activities show the good predictive capability of the
models since all the data points are near the central line.
l
expectations the amides of plumbagin are not bioactive. Since
plumbagin is a potent anticancer compound with an IC50 value of
3 lM against human oral cancer cell lines, it is indeed disappoint-
ing to note that none of its analogues matched its potency. In the
juglone series we have synthesized a more bioactive analogue,
the phenyl alanine amide 9c. Among all the derivatives, those of
lawsone were the most active. This could be attributed to the
chemical structure of lawsone. Lawsone, a hydroxyquinone, can
exist as 1, 2 diketone as well as 1, 4 quinone (Fig. 5).
By structurally modifying the phenolic hydroxyl group, there
should have been a reduction in its activity as reported in previous
studies,27 but we observed an enhancement in the activity. The
MTT assay graphs for selected compounds is shown (Fig. 18) in
Supplementary information. The C-3 substituent, an amino acid
moiety as well as the thioether group could be the reason for ren-
dering the derivatives active. This analogy however fails with the
other quinones. Hence, the factor, which is unique to lawsone, is
the presence of methoxy substituent at C-2 of the quinone ring
O
O
OH
O
O
OH
1, 2-quinone
1, 4-quinone
Figure 5. Keto–enol tautomerism in lawsone.
Figure 6. Alignment of molecules for 3D QSAR for (A) HeLa and (B) SAS cell lines.
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T. Sreelatha et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
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5
The quinones we have chosen for our study are bioactive and
have been investigated for cytotoxicity against many cancer cell
lines. Our aim has been to synthesize derivatives with the thioe-
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plumbagin and menadione were cytotoxic against HeLa and SAS
cell lines, while juglone and lawsone were inactive. Juglone is inac-
tive to MRSA and FRCA strains. We have synthesized derivatives of
juglone with better antimicrobial activity. By simple functional
group transformations we were successful in designing new cyto-
toxic and antimicrobial quinones.
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Acknowledgements
This study was supported by a program support grant to D.K.
(BT/01/COE/07/04) from the Department of Biotechnology and
the Department of Science and Technology to T.S. (Woman Scien-
tist Scheme-A, SR/WOS-A/CS-10/2010), Government of India.
Supplementary data
Supplementary data (general procedures (chemistry and biol-
ogy), structures of the derivatives synthesized, spectral data
(Figs. 8–16) of 8a–g, 9a–g, 10a–g, 11a–g, 1H, 13C NMR, mass and
IR spectra, Tables 2 and 3, parity plot of 3D QSAR) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.bmcl.2014.04.080.
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Please cite this article in press as: Sreelatha, T.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.04.080