Design, synthesis, and antiproliferative activity of new 1H-pyrrolo[3,2-c]pyridine derivatives against melanoma cell lines. Part 2

Article abstract of DOI:10.1016/j.bmcl.2012.05.004

A new series of diarylureas and diarylamides possessing 1H-pyrrolo[3,2-c]pyridine scaffold was designed and synthesized. Their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-9 human melanoma cell line panel were tested. All the target compounds, except three amino derivatives 8g, h and 9h, demonstrated superior potencies against A375P to Sorafenib. In addition, compounds 8a and 9b-f demonstrated higher potencies than Vemurafenib against A375P. Compounds 8c and 9b were 7.50 and 454.90 times, respectively, more selective towards A375P melanoma cells over NIH3T3 fibroblasts. Furthermore, compounds 8d, e and 9a-d, f demonstrated very high potencies against the nine tested melanoma cell lines at the NCI. The bisamide derivatives 9a-c, f showed 2-digit nanomolar IC₅₀ values over different cell lines of the NCI-9 melanoma cell lines.

Full text of DOI:10.1016/j.bmcl.2012.05.004

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4362–4367
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and antiproliferative activity of new
1H-pyrrolo[3,2-c]pyridine derivatives against melanoma cell lines. Part 2
Myung-Ho Jung a, Mohammed I. El-Gamal a,b,d, Mohammed S. Abdel-Maksoud a,b, Taebo Sim c,
Kyung Ho Yoo c, Chang-Hyun Oh a,b,
⇑
a Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea
b Department of Biomolecular Science, University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea
c Chemical Kinomics Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea
d Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of diarylureas and diarylamides possessing 1H-pyrrolo[3,2-c]pyridine scaffold was designed
and synthesized. Their in vitro antiproliferative activities against A375P human melanoma cell line and
NCI-9 human melanoma cell line panel were tested. All the target compounds, except three amino deriv-
atives 8g, h and 9h, demonstrated superior potencies against A375P to Sorafenib. In addition, compounds
8a and 9b–f demonstrated higher potencies than Vemurafenib against A375P. Compounds 8c and 9b
were 7.50 and 454.90 times, respectively, more selective towards A375P melanoma cells over NIH3T3
fibroblasts. Furthermore, compounds 8d, e and 9a–d, f demonstrated very high potencies against the nine
tested melanoma cell lines at the NCI. The bisamide derivatives 9a–c, f showed 2-digit nanomolar IC50
values over different cell lines of the NCI-9 melanoma cell lines.
Received 16 March 2012
Revised 20 April 2012
Accepted 1 May 2012
Available online 9 May 2012
Keywords:
Pyrrolo[3,2-c]pyridine
A375P
Antiproliferative activity
Melanoma
Ó 2012 Elsevier Ltd. All rights reserved.
Diarylurea
Diarylamide
Melanoma is the most aggressive form of skin cancer. It is a
malignant tumor that arises from melanocytic cells. The major risk
factors for development of melanoma include exposure to solar
ultraviolet irradiation, fair skin, dysplastic nevus syndrome, and a
family history of melanoma. Melanomas can metastasize either
by the lymphatic or by the hematogenous route.1 Metastatic mel-
anoma is a particularly aggressive form of cancer that is resistant
to standard anticancer therapies. Early stage melanoma (stage
I/II) primary tumors can be cured surgically with more than 95%
success rate.2 On the other hand, late-stage (stage IV) metastatic
melanoma is one of the most deadly forms of cancer, with the
median survival of patients with distant metastases being
7–9 months.3 Due to the rapid incidence of melanoma in the Uni-
ted States and other developed countries, there is an urgent need
to develop more effective drugs.4–6
trials.19 Encouraged by the interesting antiproliferative activity of
diarylurea and diarylamide derivatives, we synthesized a new series
of diarylureas and diarylamides containing pyrrolo[3,2-c]pyridine
scaffold. The target compounds were designed as new conforma-
tionally restricted analogs of Sorafenib by isosteric replacement of
the 4-phenoxypyridine moiety of the reference drug with a pyrrol-
o[3,2-c]pyridine nucleus (Fig. 1). Their in vitro antiproliferative
activities against 10 human melanoma cell lines and NIH3T3 fibro-
blasts are reported. We have reported the synthesis and in vitro
antiproliferative activities of another series of diarylureas and dia-
rylamides containing pyrrolo[3,2-c]pyridine scaffold.17 The target
compounds in the present investigation are considered as positional
isomers for the previously reported compounds in order to compare
their antiproliferative potencies against human melanoma cell
lines.
In 2011, Vemurafenib (PLX4032, ZelborafÒ) was approved by the
U.S. food and drug administration (FDA) for treatment of late-stage
melanoma.7 In addition, a number of reports have recently high-
lighted diarylureas and diarylamides as potential antiproliferative
agents against melanoma cell lines.8–18 Sorafenib (NexavarÒ) is a
diarylurea derivative that has been extensively used in clinical
Synthesis of the target compounds 8a–f and 9a–f was success-
fully achieved as illustrated in Scheme 1. 7-Hydroxy-1H-pyrrol-
o[2,3-b]pyridinium 3-chlorobenzoate (2) was prepared by
reacting 7-azaindole (1) with 3-chloroperbenzoic acid.20,21
Compound 2 was then heated with phosphorus oxychloride to pro-
duce 4-chloro-7-azaindole (3).21 Compound
4 was prepared
according to the literature procedure.17,22,23 Fusion of 3 with
m-nitroaniline neat led to nucleophilic displacement of the
4-chloro group by the aromatic amino group, followed by rear-
rangement of the resulting secondary amine to give the amine
⇑
Corresponding author. Tel.: +82 2 958 5160; fax: +82 2 958 5189.
E-mail address: choh@kist.re.kr (C.-H. Oh).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.004

M.-H. Jung et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4362–4367
4363
F
Cl
O
O
CF3
O
S
H3C
O
Cl
O
N
H
O
N
H
F
N
CH3
N
H
N
H
N
N
H
Vemurafenib
Sorafenib
R1 NH
A
NH
N
H
N
N
N
R2
N
O
O
N
B
H
R1 = H, PhCO
R2 = Ar, ArNH
A = H, PhCO
B = Ar, ArNH
The target compounds 8a-h and 9a-h
Figure 1. Structures of Vemurafenib, Sorafenib, reported pyrrolo[3,2-c]pyridine derivatives,17 and the target compounds 8a–h and 9a–h.
Cl
N
O
NO2
N
O-
b
H2N
HCl
a
c
N
H
N
N
N
N
N
H
H
OH
Cl
4
1
3
2
NO2
NH2
H
N
H
e
N
d
N
N
O
N
O
N
6
5
g
f
H
N
H
Ar
H
Ar
N
N
H
H
N
N
O
N
N
O
O
N
O
N
9a-f
8a-e
CF3
H
NH2
H
N
N
h
H
N
O
N
N
CF3
O
N
N
N
N
8f
7
Scheme 1. Reagents and conditions: (a) 3-chloroperoxybenzoic acid, DME:heptane (1:2), rt, 2.5 h, 89.2%; (b) POCl3, 55 °C then rt then 85-90 °C, 18 h, 80%; (c) m-nitroaniline,
180 °C, 2-5 h, 9.5%; (d) benzoyl chloride, diisopropylamine, CH3CN, rt, 8 h, 15%; (e) Pd/C, H2, THF, rt, 2 h, 32%; (f) aryl isocyanate, THF, rt, 8 h, 6.7ꢀ53%; (g) benzoic acid
derivative, HOBt, EDCI, TEA, DMF, 80 °C, 12 h, 9ꢀ26%; (h) (i) 4-nitrophenyl chloroformate, TEA, 1,4-dioxane, 60 °C, 2 h, (ii) 6 in 1,4-dioxane, 90 °C, overnight, 45%.
hydrochloride salt 4. Reaction of the amino group of 1-(3-nitro-
phenyl)-1H-pyrrolo[3,2-c]pyridin-4-amine hydrochloride (4) with
benzoyl chloride in the presence of diisopropylamine as a base pro-
duced the benzamido derivative, N-(1-(3-nitrophenyl)-1H-pyrrol-
o[3,2-c]pyridin-4-yl)benzamide (5). Reduction of the nitro group
of 5 using Pd-C/H2 gave the corresponding amino compound,
N-(1-(3-aminophenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)benzamide (6).
Reaction of 6 with the appropriate aryl isocyanates produced the
corresponding diarylurea derivatives 8a–e. The bisamide derivatives
9a–f were obtained by condensation of the amino intermediate 6
with the corresponding benzoic acid derivatives in the presence of
HOBt/EDCI/triethylamine.
The N-ethylpiperazinyl diarylurea derivative 8f was synthesized
by a modified method through heating the aniline derivative 7

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M.-H. Jung et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4362–4367
H
N
H
N
Ar
NO2
NH2
H
N
N
N
N
O
H2N
H2N
b
a
N
O
N
N
8g,h
5
10
c
H
N
Ar
N
O
H2N
N
9g,h
Scheme 2. Reagents and conditions: (a) SnCl2.H2O, EtOH, reflux, 2 h, 51%; (b) aryl isocyanate, THF, rt, 8 h, 18% (for 8g), 15% (for 8h); (c) benzoic acid derivative, HOBt, EDCI,
TEA, DMF, 80 °C, 12 h, 11% (for 9g), 10% (for 9h).
with 4-nitrophenyl chloroformate in the presence of triethylamine
as a base to form the corresponding carbamate intermediate, and
subsequent heating with compound 6.
In addition, the target amino compounds 8g, h and 9g, h were
prepared by the sequence of reactions illustrated in Scheme 2.
Refluxing the nitro compound 5 with stannous chloride in ethanol
led to simultaneous reduction of the nitro group and hydrolysis
of the benzamido moiety to produce the diamino compound,
1-(3-aminophenyl)-1H-pyrrolo[3,2-c]pyridin-4-amine (10). Inter-
action of the aniline amino group of 10 with 1,2-dichloro-4-isocy-
anatobenzene
or
1-(trifluoromethyl)-3-isocyanatobenzene
produced the target diarylurea derivatives 8g, h, respectively,
Table 1
Antiproliferative activities of the urea derivatives 8a–h against A375P melanoma cell line and NIH3T3 fibroblasts
R1
R2
IC50 (l
M)
Selectivity indexb
a
Structure
Compound No.
A375P
0.10
NIH3T3
R1 NH
N
H
N
8a
8b
8c
PhCO
PhCO
PhCO
0.413
—
4.13
—
H
N
N
R2
Cl
Cl
Cl
O
Cl
3.50
0.30
0.70
2.25
7.50
CF3
Cl
8d
8e
PhCO
PhCO
—
—
—
—
CF3
CF3
2.70
0.40
CF3
Et
N
N
8f
PhCO
—
—
CF3
Cl
8g
8h
H
H
>20
>20
—
—
—
—
Cl
CF3
Sorafenib
Vemurafenib
5.60
0.254
24.75
—
4.42
—
a
Values are expressed as mean IC50 of the triplicate experiment.
Values are calculated by dividing the IC50 value of the compound against NIH3T3 fibroblasts over that against A375P.
b

M.-H. Jung et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4362–4367
4365
and the amino group at position 4 on the pyrrolo[3,2-c]pyridine
nucleus remained unaffected. Preparation of compounds 9g, h
was carried out in a similar way as described for preparation of
compounds 9a–f, and the amino group at position 4 on the pyrrol-
o[3,2-c]pyridine scaffold remained unaffected also.
IC50 in sub-micromolar scale. Compound 9e was previously
screened against a panel of kinases, and it showed selective FMS
kinase inhibitory activity.23 In addition, compounds 8b, e were
more potent than Sorafenib against A375P but with IC50 in micro-
molar scale. As compared with Vemurafenib, compounds 8a and
9b–f demonstrated higher potencies against A375P than this latter
reference drug.
The antiproliferative activity of the newly synthesized com-
pounds against A375P human melanoma cell line was examined.
The results (IC50
,
l
M) are summarized in Tables 1 and 2. Sorafenib
The effect of substituents on the phenyl ring of the tail was
investigated. The introduction of para-chloro, meta-(trifluoro-
methyl), or 40-(ethylpiperazinyl)methyl moieties on the 30-(trifluo-
romethyl)phenyl ring of the tail (compounds 8d–f, respectively)
slightly reduced the potency compared with compound 8c. Simi-
larly, compounds 9c, d, f with para-chloro, meta-(4-methyl-1
H-imidazol-1-yl), and meta-morpholino substituents, respectively,
on the 30-(trifluoromethyl)phenyl ring of the tail were less potent
than compound 9b. This may be attributed to the steric and/or
electronic effects of these moieties, which may lead to reduced
affinity to the target protein.
was utilized as the reference standard drug because of its struc-
tural similarity with the target compounds, and it has been exten-
sively used in clinical trials for treatment of melanoma.4,19,24
Sorafenib also showed high in vitro antiproliferative activity
against a variety of melanoma cell lines.19 Vemurafenib was also
utilized as a second reference standard in this experiment because
of its high potency against melanoma cell lines,25 and it has been
recently approved by the FDA for treatment of advanced
melanoma.7
All of the newly synthesized compounds, except three amino
compounds 8g, h and 9h, showed superior potencies against
A375P to Sorafenib. Among all of these derivatives, compounds
8a, c, d, f and 9a–g showed high potencies against A375P with
The reduced antiproliferative activity produced by para-chloro
substituent on the phenyl ring of the tail can be confirmed by com-
paring the IC50 values of compounds 8a, b. Compound 8b with
Table 2
Antiproliferative activities of the amide derivatives 9a–h against A375P melanoma cell line and NIH3T3 fibroblasts
R1
R2
IC50 (lm)
Selectivity indexb
a
Structure
Compound No.
A375P
0.30
NIH3T3
—
R1 NH
N
Cl
H
N
9a
9b
9c
PhCO
PhCO
PhCO
—
N
R2
Cl
O
0.0153
0.0868
6.96
0.02
454.90
0.23
CF3
Cl
CF3
CH3
N
N
9d
PhCO
0.20
0.68
3.4
CF3
N
O
9e
9f
PhCO
PhCO
H
0.016
0.024
0.60
0.025
0.013
—
1.56
0.54
—
CF3
O
N
CF3
9g
9h
CF3
O
N
H
15.20
—
—
CF3
Sorafenib
Vemurafenib
5.60
0.254
24.75
—
4.42
—
a
Values are expressed as mean IC50 of the triplicate experiment.
Values are calculated by dividing the IC50 value of the compound against NIH3T3 fibroblasts over that against A375P.
b

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M.-H. Jung et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4362–4367
30,40-dichlorophenyl moiety demonstrated 35 times less potent
antiproliferative potency than compound 8a with 20,30-dichloro-
phenyl moiety against A375P cell line.
Table 3
IC50 values (
l
M) of compounds 8d, e and 9a–d, f over NCI-9 melanoma cell lines
Compound No.
Upon comparing the potencies of derivatives with amide or
urea moieties at 1H-pyrrolo[3,2-c]pyridine side chain as a linker,
it was found that the derivatives with amide moieties 9a–c, and
9g were in a general way more potent than the corresponding urea
derivatives 8b–d, and 8h. Moreover, compounds 9a–g with amide
linker demonstrated higher potencies than Sorafenib, possessing
urea moiety, against A375P melanoma cell line.
8d
8e
9a
9b
9c
9d
9f
Melanoma
cell line
LOX IMVI 0.670 2.12 0.269 0.090 0.124 0.475 0.091
MALME- 0.856 3.09 0.281 0.042 0.133 0.464 1.55
3M
M14
MDA-
MB-435
0.305 1.11 0.137 0.023 0.135 0.542 0.114
0.257 1.23 0.035 0.017 0.018 0.247 0.025
SK-MEL- 0.358 1.32 1.12 0.055 0.195 0.342 0.167
Compounds 8b, c and 9b, f with benzamido moiety at position 4
on the pyrrolo[3,2-c]pyridine scaffold showed higher potencies
than the corresponding amino compounds 8g, h and 9g, h. This
may be probably due the steric and/or electronic effects of benzoyl
moiety, which may permit appropriate drug–receptor interaction,
and hence high potency.
2
SK-MEL- 0.583 2.14 0.228 0.047 0.225 0.678 0.083
28
SK-MEL- 0.351 0.946 0.085 0.036 0.071 0.292 0.052
5
UACC-
257
1.55 2.45 1.14 0.10 0.645 0.796 0.092
As compared with the previously reported positional isomers,17
we found that compound 8a, c, d and 9b, d, f were more potent
than the corresponding para-disubstituted phenyl derivatives
against A375P.
UACC-62 0.439 2.00 0.046 0.029 0.060 0.327 0.039
melanoma cell line with IC50 less than 0.1
pounds, 8a, c, d, f and 9a, d, g, were more potent than Sorafenib
against A375P with IC50 ranging from 0.1 to 0.7 M. In addition,
compounds 8b, were more potent than Sorafenib against
A375P but with IC50 in the micromolar scale. Moreover, com-
pounds 8a and 9b–f showed superior potencies against A375P to
Vemurafenib. They were 2.54, 16.60, 2.93, 1.27, 15.88, and 10.58
times, respectively, more potent than Vemurafenib.
Compounds 8c and 9b showed superior selectivity towards
melanoma cells than NIH3T3 fibroblasts, compared with Sorafenib.
Compound 9b, with IC50 = 15.3 nM over A375P, showed very high
selectivity (454.90 times) towards A375P human melanoma cell
line over NIH3T3 fibroblasts.
Compounds 8d, e and 9a–d, f were further tested over nine hu-
man melanoma cell lines at the NCI. All the tested compounds
demonstrated high potencies over the nine cell line panel. The
highest potencies were demonstrated by compound 9b with benz-
amido moiety at position 4 of the pyrrolo[3,2-c]pyridine nucleus,
amide linker, and meta-(trifluoromethyl)phenyl terminal ring. Its
IC50 values over the NCI-9 melanoma cell line panel were in the
range of 17–100 nM. The superior potency of compound 9b27
against A375P melanoma cell line to both Sorafenib and Vemurafe-
nib, and its high potency against NCI-9 human melanoma cell lines,
together with its interesting selectivity towards melanoma cells
over fibroblasts make it a promising lead for development of new
potent and selective anticancer agents for treatment of melanoma.
lM. Another seven com-
Compounds 8a, c and 9b–f which showed the highest potencies
against A375P melanoma cell line, were then tested against
NIH3T3 fibroblasts in order to investigate their selectivity for mel-
anoma cells over normal cells. Sorafenib was utilized as a reference
drug in this experiment also.
Compounds 8c and 9b showed higher selectivity for A375P cells
than for NIH3T3 fibroblasts. Their selectivity indices (7.50 and
454.90, respectively) were higher than that of Sorafenib (4.42). In
addition, the selectivity index of compound 8a (4.13) was almost
equal to that of Sorafenib. These compounds are promising leads
for design of highly potent and highly selective antiproliferative
agents for treatment of melanoma.
On the other hand, compounds 9c–f demonstrated low selectiv-
ity towards melanoma cells despite of their high potencies. So it
can be concluded that para-chloro, meta-(4-methyl-1H-imidazol-
1-yl), para-morpholino, and meta-morpholino substituents on the
terminal 30-(trifluoromethyl)phenyl ring decreased the selectivi-
ties of compounds 9c–f, respectively, compared with 9b.
After initial single dose screening of the target compounds at
the National Cancer Institute (NCI),26 Bethesda, Maryland, USA, se-
ven compounds, 8d, e and 9a–d, f, with interesting inhibitory
activity in single-dose testing were further tested in a five-dose
testing mode in order to determine their potencies over nine mel-
anoma cell lines. For each of these compounds, the IC50 values were
recorded. The antiproliferative activities of these seven compounds
over the nine tested melanoma cell lines are summarized in
Table 3.
l
e
Acknowledgments
As shown in Table 3, the seven tested compounds have shown
high potencies over the nine tested cell lines. Most of their IC50 val-
ues were in sub-micromolar scale. Of special interest, the bisamide
compounds 9a–c, f demonstrated 2-digit nanomolar IC50 values
over many cell lines. The highest potencies were encountered with
compound 9b with benzamido, amide linker, and meta-(trifluoro-
methyl)phenyl terminal ring. It showed 2-digit nanomolar IC50 val-
ues against 8 cell lines. In addition, compound 9c with amide
spacer was more potent than the corresponding urea derivative
8d against all the nine tested cell lines. This result together with
potencies against A375P suggest that the amide linker is optimum
for antiproliferative activity of this series of compounds against
melanoma cell lines.
In conclusion, a new series of diarylurea and diarylamide deriv-
atives with pyrrolo[3,2-c]pyridine nucleus was designed and syn-
thesized based on our previous literature studies, and as a
continuation of our ongoing anticancer development program.
Among all of these derivatives, bisamide compounds 9b, c, e, f
demonstrated the highest potencies against A375P human
This work was supported by Korea Institute of Science and
Technology (KIST), KIST Project (2E22360). We would like to thank
the National Cancer Institute (NCI), Bethesda, Maryland, USA, for
performing the anticancer testing over nine melanoma cell line
panel.
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27. Selected data. 9b: IR (KBr, cmꢁ1): 3266, 2924, 1671, 1524, 1487, 1311, 1248,
1169, 1123, 1073; 1H NMR (300 MHz, DMSO-d6) d 10.89 (br s, 1H), 10.77 (br s,
1H), 8.31 (d, 2H, J = 9.1 Hz), 8.18–8.09 (m, 2H), 8.02 (d, 1H, J = 7.6 Hz), 7.88–
7.80 (m, 2H), 7.76 (d, 1H, J = 3.3 Hz), 7.68–7.58 (m, 4H), 7.59 (d, 2H, J = 8.6 Hz),
7.44–7.39 (m, 2H), 6.70–6.67 (m, 1H); 13C NMR (75 MHz, DMSO-d6) d 164.3,
154.8, 141.1, 140.1, 136.3, 134.3, 133.7, 133.5, 132.1, 130.8, 129.5, 129.0, 128.6,
128.5, 127.5, 125.7, 124.8, 124.4, 122.9, 122.0, 119.6, 118.3, 117.0, 114.5,
104.6; MS m/z: 503.01 (M+2)+, 502.00 (M+1)+, 501.00 (M)+.
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