Broad-spectrum antiproliferative activity of a series of 6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl)imidazo[2,1-b]thiazole derivatives

Article abstract of DOI:10.1007/s00044-016-1529-7

This article described the synthesis and in vitro antiproliferative activities a series of 6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl)imidazo[2,1-b]thiazole derivatives. The nine target compounds were tested for in vitro antitumor effect against a

Full text of DOI:10.1007/s00044-016-1529-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1529-7
ORIGINAL RESEARCH
Broad-spectrum antiproliferative activity of a series of
6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl)imidazo
[2,1-b]thiazole derivatives
Mohammed S. Abdel-Maksoud1,2,3 Mohammed I. El-Gamal4,5,6 Mahmoud M. Gamal El-Din1,2,3
•
•
•
Seong-Shin Kwak7 Hyun-Il Kim7 Chang-Hyun Oh1,2
•
•
Received: 8 November 2015 / Accepted: 5 February 2016
Ó Springer Science+Business Media New York 2016
Abstract This article described the synthesis and in vitro
antiproliferative activities a series of 6-(4-fluorophenyl)-5-
were more potent than Sorafenib against UO-31 renal
cancer cell line and MCF7 breast cancer cell line. Com-
pound 1d was also more potent than Sorafenib against
COLO 205 colon cancer cell line, and compound 1e
showed higher potency than Sorafenib against OVCAR-3
ovarian cancer cell line and DU-145 prostate cancel cell
line also. For instance, the IC50 value of compound 1e
against DU-145 prostate cancer cell line was 1.04 lM,
which is threefold more potent than Sorafenib.
(2-substituted
pyrimidin-4-yl)imidazo[2,1-b]thiazole
derivatives. The nine target compounds were tested for
in vitro antitumor effect against a panel of 55 cell lines of
nine different cancer types at the NCI, and their activities
were compared with that of Sorafenib as a reference
standard drug. Compounds 1d and 1e possessing terminal
arylamide moiety exerted superior potencies than Sor-
afenib against different cancer cell lines. Both compounds
Keywords Antiproliferative Á Biological activity Á
Broad-spectrum Á Imidazo[2,1-b]thiazole
Mohammed S. Abdel-Maksoud and Mohammed I. El-Gamal co-first
authors.
Introduction
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-016-1529-7) contains supplementary
material, which is available to authorized users.
Cancer is one of the major leading causes of death
worldwide. According to the American Cancer Society
report, more than 585,720 cancer patients estimated to die,
and more than 1.6 million new cancer cases were
diagnosed in 2014 only in USA (http://www.cancer.
org/research/cancerfactsstatistics/cancerfactsfigures2014/).
More than 70 % of all cancer deaths have occurred in low-
and middle-income countries. According to the World
Health Organization (WHO) report, death cases because of
cancer all over the globe are estimated to exceed 13 million
in 2030 (http://www.who.int/mediacentre/factsheets/fs297/
en/). In spite of the extensive efforts and investment in
research, more efforts are required from the medicinal
chemists for development of more efficient and safer
anticancer agents.
& Chang-Hyun Oh
choh@kist.re.kr
1
Center for Biomaterials, Korea Institute of Science and
Technology, PO Box 131, Cheongryang, Seoul 130-650,
Republic of Korea
2
Department of Biomolecular Science, Korea University of
Science and Technology, 113 Gwahangno, Yuseong-gu,
Daejeon 305-333, Republic of Korea
3
Pharmaceutical and Drug Industries Research Division,
National Research Centre, Dokki-Giza 12622, Egypt
4
Department of Medicinal Chemistry, College of Pharmacy,
University of Sharjah, 27272 Sharjah, UAE
5
Sharjah Institute for Medical Research, University of Sharjah,
27272 Sharjah, UAE
6
Imidazo[2,1-b]thiazole nucleus is a very interesting
scaffold in terms of chemistry and biological activity.
Several reports have recently highlighted imidazo[2,1-
b]thiazole derivatives as potential antiproliferative agents
Department of Medicinal Chemistry, Faculty of Pharmacy,
University of Mansoura, Mansoura 35516, Egypt
7
CTCBIO Inc., 450-34, Noha-ri, Paltan-myeon, Hwaseong-si,
Gyeonggi-Do 445-913, Republic of Korea
123

Med Chem Res
0.1 % formic acid) and infused directly in combined mode
with a flow rate of 0.3 mL/min. Unless otherwise noted, all
solvents and reagents were commercially available and
used without further purification.
Fig. 1 Structure of Sorafenib
6-(4-Fluorophenyl)imidazo[2,1-b]thiazole (3) (Ashwell
et al., 2005)
against several human cancer cell lines (Abdel-Maksoud
et al., 2015; Andreani et al., 2000; Andreani et al., 2005;
El-Subbagh et al., 2001; Gu¨rsoy and Gu¨zeldemirci, 2007;
Park and Oh, 2010; Park et al., 2011; Srimanth et al.,
2002). We have previously reported the activity of a series
of imidazo[2,1-b]thiazole derivatives possessing terminal
arylamide or aryl urea moiety against A375P human mel-
anoma cell line (Park and Oh, 2010). Herein, we report
their activity against a panel of 55 cancer cell line panel of
nine different cancer types. The biological results of the
target compounds were compared with those of Sorafenib
(Fig. 1) as a reference standard drug.
A solution of 2-aminothiazole (2, 2.37 g, 23 mmol) and
a-bromo-4-fluoroacetophenone (5.0 g, 23 mmol) in etha-
nol (60 mL) was heated under reflux for 16 h. The mixture
was concentrated to 30 mL under reduced pressure. Ice
water (40 mL) was added to the remaining solution; then,
30 % ammonium hydroxide solution was added. The
formed orange colored solid was filtered, washed with
water, and dried overnight under vacuum at 50°C. 4.3 g of
the title compound was obtained (yield 86 %). Mp
1
132–133°C; H-NMR (CDCl3, 300 MHz) d 7.84–7.79 (m,
2H), 7.70 (s, 1H), 7.44 (d, 1H, J = 3.0 Hz), 7.12 (t, 2H,
J = 9.0 Hz), 6.84 (d, 1H, J = 3.0 Hz); 13C NMR (CDCl3,
75 MHz) d 150.2, 147.0, 130.3, 126.9, 126.8, 118.4, 115.7,
115.4, 112.5, 107.6; LC-MS: m/z calculated for C11H7
?
Experimental
FN2S: 218, Found: 219 (M?1)
.
6-(4-Fluorophenyl)-5-(2-(methylthio)pyrimidin-4-yl)imi-
dazo[2,1-b]thiazole (4) A mixture of compound 3 (6.0 g,
27.6 mmol), 4-chloro-2-(methylthio)pyrimidine (10.4 g,
41.3 mmol), cesium carbonate (13.4 g, 41.3 mmol), pal-
ladium acetate (1.22 g, 5.5 mmol), and triphenylphosphine
(2.896 g, 11.04 mmol) in anhydrous DMF (60 mL) was
stirred at 80 °C for 12 h. The mixture was cooled to room
temperature and separated between ethyl acetate (150 mL)
and water (200 mL). The organic layer was separated, and
the aqueous layer was extracted with ethyl acetate
(3 9 100 mL). The combined organic layer extracts were
washed with brine, dried over anhydrous Na2SO4, and fil-
tered. The organic solvent was evaporated under reduced
pressure, and the residue was purified by flash column
chromatography. The purified title product was obtained as
white solid (3.5 g, 37 %). Mp 151–152 °C; 1H NMR
(CDCl3, 300 MHz) d 8.64 (d, 1H, J = 6.0 Hz), 8.30 (d,
1H, J = 6.0 Hz), 7.67–7.62 (m, 2H), 7.22–7.16 (m, 2H),
7.02 (d, 1H, J = 6.0 Hz), 6.88 (d, 1H, J = 3.0 Hz), 2.67 (s,
3H); 13C NMR (CDCl, 75 MHz) d 172.5, 156.2, 150.0,
146.5, 131.0, 130.9, 126.7, 126.6, 118.5, 115.9, 115.6,
Synthesis of the target compounds
General
All melting points were obtained on a Walden Precision
Apparatus Electrothermal 9300 apparatus and are uncor-
rected. Nuclear magnetic resonance (NMR) spectroscopy
was performed using either a Bruker ARX-300, 300 MHz
spectrometer or a Bruker ARX-400, 400 MHz spectrome-
ter (Bruker Bioscience, Billerica, MA, USA) with TMS as
an internal standard. IR spectra (KBr disks) were recorded
with a Bruker FT-IR instrument (Bruker Bioscience, Bil-
lerica, MA, USA). Purity of the target compounds was
proven to be more than 95 % by HPLC. The chromato-
graphic system consisting of an ACQUITY UPLC (Waters,
USA) coupled with SYNAPT G2 (Waters, UK) mass
spectrometer equipped with an ESI source. The HRMS was
done on positive mode with Capillary: 3.1 kV, desolvation
gas: 800 L/h and Extraction cone 4.0. Chromatography was
performed on ACQUITY UPLC BEH C18 (1.6 lm,
2.1 9 100 mm) at 25 °C using acetonitrile and water
(containing 0.1 % formic acid as mobile phase in gradient
elution mode at a flow rate of 0.4 mL/min, and injection
volume: 5 lL. The data acquisition was under the control
of Mass Hunter workstation software. LC-MS analyses
were carried out in positive ion mode by electrospray
ionization (ESI) on (Waters) ACQUITY UPLC triple
Quadrupole (Xevo TQD) instrument equipped with
MassLynx software. The samples were dissolved in
115.5, 115.2, 112.9, 112.4, 111.7, 107.7, 14.1; LC-MS: m/z
?
calculated for C16H11FN4S2 : 342. Found: 343 (M?1)
.
6-(4-Fluorophenyl)-5-(2-(methylsulfonyl)pyrimidin-4-
yl)imidazo[2,1-b]thiazole (5) To a solution of compound
4 (2.05 g, 6 mmol) in methanol (250 mL), a solution of
oxone (12.3 g, 18 mmol) in water (50 mL) was added. The
mixture was stirred at room temperature for 16 h. The
organic solvent was evaporated under reduced pressure, the
remaining aqueous solution was extracted with CH2Cl2
v
methanol diluted in spray solution (methanol/water 1:1 /v
123

Med Chem Res
(50 mL), and the organic layer was separated. The aqueous
layer was extracted with CH2Cl2 (3 9 25 mL), and the
combined organic layer extracts were washed with brine,
dried over anhydrous MgSO4, and filtered. The organic
solvent was evaporated under reduced pressure, and the
residue was purified by flash column chromatography.
2.1 g of the title compound was obtained, yield 98 %. Mp
128.2, 128.1, 68.6, 66.9, 40.4, 37.3; LC-MS: m/z calculated
?
for C11H15NO5S: 273, Found: 274 (M?1)
.
Benzyl 2-azidoethylcarbamate (9) A mixture of sodium
azide (4.75 g, 73.2 mmol) and compound 8 (5.0 g,
18.3 mmol) in DMSO (50 mL) was stirred at 70 °C for 2 h.
The mixture was allowed to cool to room temperature,
quenched with water (200 mL), and then extracted with
ethyl acetate (3 9 200 mL). The combined organic layer
extracts were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
The title product was obtained as a colorless oil (3.8 g,
94 %). 1H NMR (CDCl3, 300 MHz) d 7.34 (s, 5H), 5.11 (s,
2H), 3.41 (d, 2H, J = 6.0 Hz), 3.35 (t, 2H, J = 4.5 Hz);
13C NMR (CDCl3, 75 MHz) d 156.6, 138.1, 136.5, 128.3,
1
197–198°C; H NMR (CDCl3, 300 MHz) d 8.90 (d, 1H,
J = 3.0 Hz), 8.55 (d, 1H, J = 6.0 Hz), 7.68–7.63 (m, 2H),
7.36 (d, 1H, J = 6.0 Hz), 7.30–7.21 (m, 2H), 7.11 (d, 1H,
J = 6.0 Hz), 3.41 (s, 3H); 13C NMR (CDCl3, 75 MHz) d
171.1, 165.7, 157.3, 157.0, 154.2, 151.7, 131.0, 130.9,
129.9, 123.1, 119.4, 117.4, 116.4, 116.1, 114.2, 39.2; LC-
MS: m/z calculated for C16H11FN4O2S2: 374. Found: 375
?
(M?1)
.
127.9, 66.3, 40.5, 40.3; LC-MS: m/z calculated for
?
Benzyl 2-hydroxyethylcarbamate (7) (Tully et al., 2006)
To a stirred solution of 2-Aminoethanol (6, 4.94 mL,
81.86 mmol) in CH2Cl2 (50 mL) at 0 °C, triethylamine
(22.2 mL, 159.6 mmol) was added dropwise. Benzyloxy-
carbonyl chloride (15.2 mL, 106.42 mmol) was added
dropwise over 30 min. After completion of the addition,
the mixture was stirred at 0 °C for 1 h. The mixture was
quenched with water (50 mL) and extracted with CH2Cl2
(3 9 50 mL). The combined organic layer extracts were
washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography. The desired
product was obtained as white solid (9.5 g, 59 %). Mp
73–75°C; 1H NMR (CDCl3, 300 MHz) d 7.34 (s, 5H), 5.73
(bs, 1H), 5.10 (s, 2H), 3.74 (s, 2H), 3.29 (bs, 2H); 13C NMR
(CDCl3, 75 MHz) d 157.2, 136.4, 128.5, 128.1, 128.1,
C10H12N4O2: 220, Found: 221 (M?1)
.
Benzyl 2-aminoethylcarbamate (10) Triphenylphosphine
(6.7 g, 25.56 mmol) and water (15 mL) were added to a
solution of compound 9 (3.8 g, 17.4 mmol) in MeOH
(40 mL). The mixture was heated under reflux for 2 h. The
mixture was concentrated under reduced pressure and
purified by column chromatography. The target product
was obtained as light brown oil (3 g, 90 %). 1H NMR
(CDCl3, 300 MHz) d 7.33 (s, 5H), 5.73 (bs, 1H), 5.08 (s,
2H), 3.19 (bs, 2H), 2.76 (bs, 2H); 13C NMR (CDCl3,
75 MHz) d 156.8, 136.6, 128.5, 128.0, 66.6, 43.6, 41.5;
LC-MS: m/z calculated for C10H14N2O2: 194, Found :195
?
(M?1)
.
Benzyl 2-(3-phenylureido)ethylcarbamate (11a) A solu-
tion of compound 10 (0.15 g, 0.772 mmol) and phenyl
isocyanate (0.17 g, 0.926 mmol) in THF (5 mL) was stir-
red at room temperature for 2 h. The solvent was evapo-
rated under reduced pressure, and the residue was purified
by flash column chromatography. The desired product was
66.8, 61.7, 43.4; LC-MS: m/z calculated for C10H13NO3:
?
195, Found: 196 (M?1)
.
2-(Benzyloxycarbonylamino)ethyl methanesulfonate (8)
(Townsend and Basak, 1991)
1
obtained as white solid (0.2 g, 51 %). Mp 124–125°C; H
To a stirred solution of compound 7 (29.7 g, 152 mmol)
in CH2Cl2 (300 mL) at 0 °C, triethylamine (31.58 mL,
227 mmol) was added dropwise. Methanesulfonyl chloride
(14.1 mL, 182 mmol) was then added dropwise to the
reaction mixture over 30 min. After completion of the
addition, the mixture was stirred at 0 °C for 1 h. The
mixture was quenched with water (300 mL) and extracted
with CH2Cl2 (3 9 300 mL). The combined organic layer
extracts were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography.
The desired product was obtained (22 g, 53 %). Mp 70 °C;
1H NMR (CDCl3, 300 MHz) d 7.37 (s, 5H), 5.52 (bs, 1H),
5.11 (s, 2H), 4.28 (t, 2H, J = 6.0 Hz), 3.52 (s, 2H), 2.98 (s,
3H); 13C NMR (CDCl3, 75 MHz) d 156.4, 136.3, 128.5,
NMR (CD3OD, 300 MHz) d 7.70 (t, 1H, J = 3.0 Hz),
7.34–7.20 (m, 7H), 5.06 (d, 2H, J = 6.0 Hz), 3.37–3.26
(m, 4H).
Synthesis of compounds 11b, c was carried out by the
same procedure as described for preparation of 11a.
1
11b. Yield: 60 %; mp 138–139°C; H NMR (CDCl3,
300 MHz) d 7.32 (s, 5H), 7.18–7.14 (m, 1H), 6.99 (s,
1H), 6.78 (d, 1H, J = 9.0 Hz), 6.62 (dd, 1H, J = 2.4 and
2.4 Hz), 6.56 (bs, 1H), 5.27 (d, 1H, J = 14.1 Hz), 5.08
(s, 2H), 3.78 (s, 3H), 3.40–3.32 (m, 4H).
11c. Yield: 87 %; mp 108°C; 1H NMR (CDCl3,
300 MHz) d 7.62 (s, 2H), 7.45 (d, 1H, J = 9.0 Hz),
7.26 (s, 5H), 5.72 (s, 1H), 5.49 (s, 1H), 5.12 (s, 1H), 5.06
(s, 2H), 3.38–3.29 (m, 4H).
123

Med Chem Res
1-(2-Aminoethyl)-3-phenylurea (12a) Pd/C (0.05 g) was
added to a solution of compound 11a (0.2 g, 0.52 mmol) in
MeOH (10 mL). The mixture was stirred under hydrogen
atmosphere at room temperature for 1 h. Pd/C was
removed by Celite filter, and the filtrate was evaporated
under reduced pressure. 0.08 g of the title product was
obtained and used in the next step without further purifi-
cation (yield 85.8 %).
In addition, synthesis of compounds 14a-f was carried
out by the same procedure as described for preparation of
12a.
1-(2-(4-(6-(4-Fluorophenyl)imidazo[2,1-b]thiazol-5-
yl)pyrimidin-2-ylamino)ethyl)-3-phenylurea (1a) (Park
and Oh, 2010)
A mixture of compound 5 (0.34 g, 0.92 mmol), com-
pound 12a (0.444 g, 2.48 mmol), and DIPEA (0.57 mL,
3.3 mmol) in DMSO (10 mL) was stirred at 80 °C for 8 h.
The mixture was cooled to room temperature, quenched
with water (20 mL), and then extracted with ethyl acetate
(3 9 20 mL). The combined organic layer extracts were
washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography. The title product
was obtained as white solid (0.24 g, 56 %). Mp 140 °C; 1H
NMR (CDCl3, 400 MHz) d 8.50 (d, 1H, J = 4.4 Hz), 7.93
(d, 1H, J = 5.4 Hz), 7.56 (q, 2H, J = 4.6 Hz), 7.33 (d, 1H,
J = 7.3 Hz), 7.21 (s, 4H), 7.12 (t, 2H, J = 8.4 Hz),
7.08–6.96 (m, 2H), 6.87 (d, 1H, J = 4.2 Hz), 6.41 (d, 1H,
J = 5.4 Hz), 5.80 (bs, 1H), 3.58 (t, 2H, J = 5.2 Hz), 3.45
(d, 2H, J = 4.7 Hz); 13C NMR (CDCl3, 75 MHz) d 162.2,
157.1, 156.6, 138.6, 131.1, 131.0, 130.8, 129.1, 128.2,
123.6, 122.1, 120.8, 115.8, 115.6, 112.6, 42.1, 39.9; LC-
Synthesis of compounds 12b, c was carried out by the
same procedure as described for preparation of 12a
Benzyl 2-benzamidoethylcarbamate (13a) A mixture of
compound 10 (0.15 g, 0.772 mmol), HOBt (0.23 g,
1.70 mmol), EDCI (0.37 g, 1.93 mmol), benzoic acid
(0.19 g, 1.54 mmol), and TEA (0.32 mL, 2.32 mmol) in
dry DMF (20 mL) was stirred at 80 °C for 8 h. The mixture
was quenched with water (40 mL), then extracted with
ethyl acetate (3 9 40 mL). The combined organic layer
extracts were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography.
The desired product was obtained as white solid (0.13 g,
1
56.4 %). Mp 126–128 °C; H NMR (CDCl3, 400 MHz) d
7.77 (d, 2H, J = 7.6 Hz), 7.51 (t, 1H, J = 4.0 Hz), 7.31 (s,
5H), 6.96 (bs, 1H), 5.30 (bs, 1H), 5.10 (s, 2H), 3.59 (q, 2H,
J = 5.3 Hz), 3.47 (q, 2H, J = 5.6 Hz).
MS: m/z calculated for C24H20FN7OS: 473, Found: 474
?
(M?1)
.
Synthesis of compounds 13b–f was carried out by the
same procedure as described for preparation of 13a.
Synthesis of the target compounds 1b, c and 1d–i, was
carried out by the same procedure as described for prepa-
ration of 1a.
1
13b. Yield: 87 %; mp 139–140°C; H-NMR (CD3OD,
300 MHz) d 7.71 (dd, 2H, J = 1.6 and 1.7 Hz),
7.35–7.25 (m, 7H), 5.08 (s, 2H), 3.49 (t, 2H,
J = 5.9 Hz), 3.36 (t, 2H, J = 6.1 Hz).
1-(2-((4-(6-(4-Fluorophenyl)imidazo[2,1-b]thiazol-5-
yl)pyrimidin-2-yl)amino)ethyl)-3-(3-methoxyphenyl)urea
(1b) Yield: 68 %; mp 194–196 °C; 1H NMR (DMSO-d6,
300 MHz) d 8.56 (s, 1H), 8.10 (d, 1H, J = 5.7 Hz), 7.63
(q, 1H, J = 4.6 Hz), 7.44 (bs, 1H), 7.30 (t, 1H,
J = 8.8 Hz), 7.15–7.07 (m, 2H), 6.86 (d, 1H, J = 8.1 Hz),
6.46 (dd, 1H, J = 2.0 and 2.1 Hz), 6.31 (d, 1H,
1
13c. Yield: 85 %; mp 155–157°C; H NMR (CDCl3,
300 MHz) d 7.52 (s, 1H), 7.32 (s, 6H), 6.94 (bs, 1H),
6.86 (d, 1H, J = 6.2 Hz), 5.25 (bs, 1H), 5.10 (s, 2H),
3.93 (s, 6H), 3.53 (t, 2H, J = 3.9 Hz), 3.48 (t, 2H,
J = 3.8 Hz).
13d. Yield: 68 %; mp 153–155°C; 1H NMR (DMSO-d6,
300 MHz) d 8.77 (bs, 1H), 8.18 (s, 1H), 8.13 (d, 1H,
J = 7.8 Hz), 7.90 (d, 1H, J = 7.7 Hz), 7.72 (t, 1H,
J = 7.5 Hz), 7.40–7.32 (m, 7H), 5.01 (s, 2H), 3.49–3.16
(m, 4H).
13e. 1H NMR (CDCl3, 300 MHz) d 7.54 (s, 1H), 7.47 (s,
1H), 7.30 (s, 5H), 7.18 (s, 1H), 5.29 (bs, 1H), 5.09 (s,
2H), 3.85 (t, 4H, J = 4.8 Hz), 3.58 (q, 2H, J = 5.1 Hz),
3.47 (q, 2H, J = 5.3 Hz), 3.25 (t, 4H, J = 4.8 Hz).
13f. Yield: 73 %; mp 135–137°C; 1H NMR (CDCl3,
300 MHz) d 8.05 (s, 2H), 8.00 (bs, 1H), 7.84 (s, 1H),
7.68 (s, 1H), 7.25 (s, 5H), 7.08 (s, 1H), 5.57 (bs, 1H),
5.08 (s, 2H), 3.61 (q, 2H, J= 4.9 Hz), 3.48 (q, 2H, J=
5.3 Hz), 2.26 (s, 3H).
J = 5.3 Hz), 3.69 (s, 3H), 3.51–3.24 (m, 4H); LC-MS: m/z
?
calculated for C25H22FN7O2S: 503, Found: 504 (M?1)
.
1-(2-((4-(6-(4-Fluorophenyl)imidazo[2,1-b]thiazol-5-
yl)pyrimidin-2-yl)amino)ethyl)-3-(3-(trifluo-
romethyl)phenyl)urea (1c) Yield: 57 %; mp 146 °C; IR
(KBr) [cm-1]: 3333, 3116, 1663, 1497, 1444, 1333, 1165;
1H NMR (CDCl3, 400 MHz) d 8.52 (d, 1H, J = 4.0 Hz),
7.99 (d, 1H, J = 8.0 Hz), 7.84 (dd, 1H, J = 4.0,
J = 8.0 Hz), 7.70–7.58 (m, 4H), 7.14 (t, 2H, J = 8.0 Hz),
7.08 (t, 1H, J = 8.0 Hz), 6.93(d, 1H, J = 8.0 Hz), 6.48 (d,
1H, J = 8.0 Hz), 6.09 (bs, 1H), 3.67 (bs, 2H), 3.55 (t, 4H,
J = 4.0 Hz); 13C NMR (CDCl3, 75 MHz) d 162.2, 157.1,
156.9, 155.9, 152.1, 149.0, 139.5, 138.1, 131.6, 131.1,
131.0, 129.4, 122.1, 120.7, 115.9, 115.6, 112.6, 107.0,
123

Med Chem Res
41.9,40.0; HRMS calculated for C25H19F4N7OS: 541.1308,
?
N-(2-((4-(6-(4-Fluorophenyl)imidazo[2,1-b]thiazol-5-
yl)pyrimidin-2-yl)amino)ethyl)-3-(4-methyl-1H-imidazol-1-
yl)-5-(trifluoromethyl)benzamide (1h) Yield: 48 %; mp
Found: 542.1389 (M?H)
.
N-(2-((4-(6-(4-Fluorophenyl)imidazo[2,1-b]thiazol-5-
1
164–166°C; H-NMR (CDCl3, 300 MHz) d 8.52 (d, 1H,
yl)pyrimidin-2-yl)amino)ethyl)benzamide
(1d) Yield:
J = 3.2 Hz), 8.06 (d, 1H, J = 5.5 Hz), 7.62–7.54 (m, 3H),
7.29 (s, 1H), 7.15–7.09 (m, 3H), 6.91 (d, 1H, J = 4.5 Hz),
6.52 (d, 1H, J = 5.5 Hz), 5.69 (t, 1H, J = 4.5 Hz), 3.83 (t,
4H, J = 4.8 Hz), 3.77–3.72 (m, 4H), 3.21 (t, 4H,
J = 4.8 Hz); 13C NMR (CDCl3, 75 MHz) d 165.1, 162.7,
157.3, 156.9, 152.3, 149.5, 140.5, 138.1, 137.3, 134.4,
131.1, 130.6, 122.9, 121.9, 121.5, 120.5, 119.8, 115.8,
60 %; mp 136 °C; IR (KBr) [cm-1]: 3289, 3115, 1724,
1645, 1535, 1495, 1383, 1228; 1H-NMR (CDCl3,
400 MHz) d 8.52 (d, 1H, J = 4.0 Hz), 8.07 (d, 1H,
J = 8.0 Hz), 7.71 (d, 2H, J = 4.0 Hz), 7.59 (dd, 3H,
J = 4.0, J = 8.0 Hz), 7.42 (t, 1H, J = 8.0 Hz), 7.31(t, 2H,
J = 8.0 Hz), 7.13 (dd, 2H, J = 4.0, J = 8.0 Hz), 6.90 (d,
1H, J = 4.0 Hz), 6.49 (d, 1H, J = 8.0 Hz), 6.05 (bs, 1H),
3.76 (bs, 4H); 13C NMR (CDCl3, 100 MHz) d 167.9, 164.2,
162.7, 161.7, 157.1, 156.0, 152.1, 149.1, 134.2, 131.4,
131.1, 131.0, 128.3, 126.8, 121.9, 120.6, 115.8, 115.6,
115.5, 114.1, 112.6, 107.7, 41.0, 13.5; LC-MS: m/z cal-
?
culated for C29H22F4N8OS: 606, Found: 607 (M?1)
.
N-(2-((4-(6-(4-Fluorophenyl)imidazo[2,1-b]thiazol-5-
112.7, 107.4, 41.4,40.9; HRMS calculated for C24H19
?
yl)pyrimidin-2-yl)amino)ethyl)-3-morpholino-5-(trifluo-
romethyl)benzamide (1i) Yield: 42 %; mp 155–157°C;
1H-NMR (CDCl3, 300 MHz) d 8.50 (d, 1H, J = 4.5 Hz),
8.07 (s, 1H), 8.02 (d, 1H, J = 5.5 Hz), 7.90 (s, 1H), 7.81 (s,
1H), 7.66 (s, 1H), 7.55 (q, 2H, J = 4.6 Hz), 7.11 (t, 2H,
J = 8.6 Hz), 7.02 (s, 1H), 6.91 (d, 1H, J = 4.5 Hz), 5.86
(bs, 1H), 3.78–3.76 (m, 4H), 2.24 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 166.8, 162.7, 157.3, 157.1, 152.2,
151.6, 149.4, 136.1, 131.3, 131.1, 131.0, 122.0, 120.5,
117.4, 115.8, 115.5, 114.0, 113.2, 112.5, 107.7, 66.5, 48.3,
FN6OS, 458.1325 Found: 459.1491 (M?H)
.
N-(2-((4-(6-(4-Fluorophenyl)imidazo[2,1-b]thiazol-5-
yl)pyrimidin-2-yl)amino)ethyl)-4-methoxybenzamide (1e)
Yield: 66 %; mp 235°C; 1H-NMR (DMSO-d6, 300 MHz) d
8.85 (bs, 1H), 8.54 (s, 1H), 8.11 (d, 1H, J = 5.1 Hz), 7.75
(d, 2H, J = 7.5 Hz), 7.62 (t, 3H, J = 6.6 Hz), 7.46 (d, 1H,
J = 3.7 Hz), 7.33–7.23 (m, 3H), 6.30 (d, 1H, J = 5.3 Hz),
3.49–3.40 (m, 4H), 2.33 (s, 3H); LC-MS: m/z calculated
?
for C25H21FN6O2S: 488, Found: 489 (M?1)
.
41.1; LC-MS: m/z calculated for C29H25F4N7O2S: 611,
?
Found: 612 (M?1)
.
N-(2-((4-(6-(4-Fluorophenyl)imidazo[2,1-b]thiazol-5-
yl)pyrimidin-2-yl)amino)ethyl)-3,4-dimethoxybenzamide
(1f) Yield: 65 %; mp 208°C; 1H-NMR (CDCl3,
400 MHz) d 8.50 (d, 1H, J = 4.4 Hz), 8.08 (d, 1H,
J = 5.3 Hz), 7.59 (q, 2H, J = 4.5 Hz), 7.40 (s, 1H),
7.37–7.29 (m, 1H), 7.12 (t, 2H, J = 8.4 Hz), 6.91 (d, 1H,
J = 4.5 Hz), 6.60 (bs, 1H), 6.49 (d, 1H, J = 5.3 Hz), 5.78
Antiproliferative screening of the target compounds
against NCI-55 cancer cell line panel
Screening against the cancer cell lines was carried out at
the National Cancer Institute (NCI), Bethesda, Maryland,
USA (www.dtp.nci.nih.gov) applying the standard protocol
of the NCI. The human cell lines are grown in RPMI 1640
(bs, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.77–3.64 (m, 4H); 13
C
NMR (CDCl3, 100 MHz) d 167.5, 162.7, 151.6, 149.1,
148.9, 131.1, 131.0, 121.8, 119.0, 115.8, 115.6, 112.7,
medium containing 5 % fetal bovine serum and 2 mM -
L
glutamine. For a typical screening experiment, cells are
inoculated into 96-well microtiter plates in 100 lL at
plating densities ranging from 5000 to 40,000 cells/well
depending on the doubling time of individual cell lines.
After cell inoculation, the microtiter plates are incubated at
37 °C, 5 % CO2, 95 % air and 100 % relative humidity for
24 h prior to addition of experimental drugs. After 24 h,
two plates of each cell line are fixed in situ with TCA, to
represent a measurement of the cell population for each
cell line at the time of drug addition (Tz). Experimental
drugs are solubilized in dimethyl sulfoxide at 400-fold, the
desired final maximum test concentration and stored frozen
prior to use. At the time of drug addition, an aliquot of
frozen concentrate is thawed and diluted to twice the
desired final maximum test concentration with complete
medium containing 50 lg/mL gentamicin. Additional four,
tenfold or 1/2 log serial dilutions are made to provide a
110.6, 109.9, 107.6, 56.0, 55.9, 41.9, 41.4; LC-MS: m/z
?
calculated for C26H23FN6O3S: 518, Found: 519 (M?1)
.
N-(2-((4-(6-(4-Fluorophenyl)imidazo[2,1-b]thiazol-5-
yl)pyrimidin-2-yl)amino)ethyl)-3-(trifluoromethyl)benza-
mide (1g) Yield: 59 %; mp 156–157°C; IR (KBr) [cm-1]:
3298, 3133, 1645, 1535, 1452, 1415, 1278; 1H-NMR
(CDCl3, 400 MHz) d 8.50 (d, 1H, J = 4.0 Hz), 8.07 (d, 1H,
J = 8.0 Hz), 7.93 (s, 1H), 7.86 (bs, 1H), 7.69 (d, 1H,
J = 8.0 Hz), 7.58 (dd, 2H, J = 4.0, J = 8.0 Hz), 7.44 (bs,
1H), 7.12 (t, 2H, J = 8.0 Hz), 6.89 (d, 1H, J = 4.0 Hz),
6.51(d, 1H, J = 8.0 Hz), 6.03 (bs, 1H), 3.77–7.74 (m, 4H);
13C NMR (CDCl3, 100 MHz) d 166.4, 164.2, 162.7, 161.8,
157.1, 152.2, 149.3, 135.1, 131.1, 131.0, 130.7, 130.7,
130.3, 129.0, 127.9, 123.8, 122.3, 121.9, 120.5, 115.8,
115.6, 112.6, 107.6, 41.1; HRMS calculated for C25H18
?
F4N6OS, 526.1199, Found: 527.1285 (M?H)
.
123

Med Chem Res
total of five drug concentrations plus control. Aliquots of
100 lL of these different drug dilutions are added to the
appropriate microtiter wells already containing 100 lL of
medium, resulting in the required final drug concentrations.
Following drug addition, the plates are incubated for an
additional 48 h at 37 °C, 5 % CO2, 95 % air, and 100 %
relative humidity. For adherent cells, the assay is termi-
nated by the addition of cold TCA. Cells are fixed in situ by
the gentle addition of 50 lL of cold 50 % (w/v) TCA (final
concentration, 10 % TCA) and incubated for 60 min at 4
°C. The supernatant is discarded, and the plates are washed
five times with tap water and air dried. Sulforhodamine B
(SRB) solution (100 lL) at 0.4 % (w/v) in 1 % acetic acid
is added to each well, and plates are kept for 10 min at
room temperature. After staining, unbound dye is removed
by washing five times with 1 % acetic acid and the plates
are air dried. Bound stain is subsequently solubilized with
10 mM trizma base, and the absorbance is read on an
automated plate reader at a wavelength of 515 nm. For
suspension cells, the methodology is the same except that
the assay is terminated by fixing settled cells at the bottom
of the wells by gently adding 50 lL of 80 % TCA (final
concentration, 16 % TCA). Using the seven absorbance
measurements [time zero, (Tz), control growth, (C), and
test growth in the presence of drug at the five concentration
levels (Ti)], the percentage growth is calculated at each of
the drug concentrations levels. Percentage growth inhibi-
tion is calculated as:
methylthiopyrimidinyl compound 4. Oxidation of the sul-
fide moiety of compound 4 using oxone produced the
corresponding sulfonyl compound 5.
The amino side chains used for synthesis of the target
compounds 1a-i were synthesized through the pathway
illustrated in Scheme 2. Interaction of 2-aminoethanol (6)
with benzyl chloroformate in the presence of triethylamine
(TEA) produced the N-Boc protected compound 7 (Tully
et al., 2006). Reaction of compound 7 with methanesul-
fonyl chloride in the presence of TEA afforded the corre-
sponding mesyl compound 8 (Townsend and Basak, 1991).
Replacement of the mesyl moiety of compound 8 with
azido group was done by reaction with sodium azide.
Reduction of the azido group of 9 using PPh3/H2O afforded
the corresponding amino compound 10, which was subse-
quently treated with the appropriate isocyanates to produce
the corresponding urea derivatives 11a–c. Moreover, the
amide derivatives 13a–f were obtained by condensation of
the amino compound 10 with the appropriate carboxylic
acid derivatives using 1-hydroxybenzotriazole (HOBt),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),
and TEA. Deprotection of compounds 11a–c and 13a–
f using palladium over carbon in hydrogen atmosphere
afforded the corresponding amino compounds 12a–c and
14a–f, respectively.
Heating compound 4 with the previously prepared
reagents 12a–c or 14a–f in the presence of diisopropy-
lethylamine (DIPEA) produced the target compounds 1a–
c and 1d–i, respectively (Scheme 3) (Park and Oh, 2010).
Table 1 illustrates the exact structure of every target
compound.
•
•
[(Ti - Tz)/(C - Tz)] 9 100 for concentrations for
which Ti C Tz
[(Ti - Tz)/Tz] 9 100 for concentrations for which
Ti \ Tz.
Antiproliferative activities of the target compounds
Growth inhibition of 50 % (IC50) is calculated from
[(Ti - Tz)/(C - Tz)]9100 = 50, which is the drug con-
centration resulting in a 50 % reduction in the net protein
increase (as measured by SRB staining) in control cells
during the drug incubation.
Single-dose testing
The target compounds were accepted for in vitro anticancer
assay against a panel of fifty-five cancer cell line panel of
nine cancer types at the National Cancer Institute (NCI),
Bethesda, Maryland, USA (www.dtp.nci.nih.gov). The
compounds were tested at a single-dose concentration of
10 lM, and the percentages of growth inhibition over the
55 tested cell lines were determined. The mean inhibition
percentages for each of the tested compounds over the full
panel of cell lines are illustrated in Fig. 2.
Results and discussion
Chemistry
The intermediate mesyl compound 5 was successfully
synthesized according to the pathway illustrated in
Scheme 1. Upon refluxing 2-aminothiazole (2) with a-
bromo-4-fluoroacetophenone, cyclization to 6-(4-fluo-
rophenyl)imidazo[2,1-b]thiazole (3) occurred (Ashwell
et al., 2005). Heating compound 3 with 4-iodo-2-
(methylthio)pyrimidine in the presence of palladium acet-
ate, cesium carbonate, and triphenylphosphine led to a
The results showed that compound 1d with amide linker
was more active than the corresponding urea analogue 1a.
On the contrary, the urea derivative 1c exerted higher
activity than the corresponding amide compound 1 g. Upon
comparing the mean %inhibition results of the amide
compounds 1d and 1f with the corresponding analogues
possessing sulfonamide moiety (Abdel-Maksoud et al.,
2015), it was found that compounds 1d and 1f were more
coupling
reaction
and
formation
of
the
123

Med Chem Res
Scheme 1 Reagents and conditions: (i) a-bromo-4-fluoroacetophenone, EtOH, reflux, 16 h; (ii) 4-iodo-2-(methylthio)pyrimidine, Pd(OAc)2,
Cs2CO3, PPh3, DMF, 80 °C, 12 h; (iii) oxone, MeOH, H2O, rt, 16 h. (Park and Oh, 2010)
Scheme 2 Reagents and
conditions: (i) benzyl
chloroformate, TEA, CH2Cl2,
0°C; (ii) methanesulfonyl
chloride, TEA, CH2Cl2, 0°C;
(iii) NaN3, DMSO, 70°C, 2 h;
iv) PPh3, MeOH, H2O, reflux,
2 h; (v) appropriate aryl
isocyanate, THF, rt, 2 h; (vi)
appropriate benzoic acid
derivative, HOBt, EDCI, TEA,
DMF, 80°C, 8 h; (vii) H2/Pd-C,
MeOH, rt, 1 h. (Park and Oh,
2010)
Scheme 3 Reagents and
conditions: (i) 12a–c, DIPEA,
DMSO, 80°C, 8 h; (ii) 14a–f,
DIPEA, DMSO, 80°C, 8 h.
(Park and Oh, 2010)
active. So the amide group may be the best spacer for the
antiproliferative activity of this series of compounds. This
may be rationalized that the amide group exerts the opti-
mum affinity with the receptor site and, hence, optimum
activity.
terminal ring such as in compounds 1f, 1h, and 1i is
detrimental for activity.
The importance of the fluorophenyl ring at position 6 of
the imidazothiazole ring on the activity was also studied.
The results of compound 1d were compared with those of
the corresponding compounds possessing 3-methox-
yphenyl or 3-hydroxyphenyl moieties (Park et al., 2011).
It was found that the fluoro analogue 1d was more active
than m-methoxy or m-hydroxyl derivatives. So the
hydrophobicity difference and/or group orientation might
affect the affinity with the receptor site and, hence,
antiproliferative activity.
Upon studying the effect of the terminal ring sub-
stituents on the activity, it was found that m-(trifluo-
romethyl) group was the best among the urea derivatives.
Among the amide derivatives, compounds 1d and 1e pos-
sessing phenyl and p-methoxyphenyl rings, respectively,
showed the highest activities compared with the other
derivatives. It seems that the increased bulkiness on the
123

Med Chem Res
Table 1 Structures of the target compounds 1a–i
Compound No.
R
1a
1b
1c
1d
1e
1f
1g
1h
1i
The %inhibitions of the most active compounds 1c–e at
10 lM concentration against each cell line of the panel are
illustrated in Fig. 3. The results showed broad-spectrum
antiproliferative activity of the three compounds over the
nine tested cancer types. The urea compound 1c expressed
89.49 and 88.93 % inhibitions over CCRF-CEM leukemia
and TK-10 renal cancer cell lines, respectively. Compound
1d possessing terminal benzamido moiety produced 79.98,
81.88, and 84.45 % inhibition values against NCI-H460
non-small cell lung cancer, HT29 colon cancer, and MCF7
breast cancer cell lines, respectively. And compound 1e
containing p-methoxybenzamido moiety exerted the high-
est activity against HT29 colon cancer cell line with
85.38 % inhibition.
Mean % Inhibition
60
50
40
30
20
10
0
-10
1a
1b
1c
1d
1e
1f
1g
1h
1i
Fig. 2 Mean %inhibition values expressed by the target compounds
1a–i at 10 lM concentration against a panel of 55 cancer cell line
panel of nine different cancer types
123

Med Chem Res
% Inhibition at 10 uM concentration
100
80
60
40
20
0
-20
Leukemia
Non-Small Cell Lung Cancer
Colon Cancer
CNS Cancer
Melanoma
Ovarian Cancer
Renal Cancer
Prostate
Cancer
Breast Cancer
a
% Inhibition at 10 uM concentration
90
80
70
60
50
40
30
20
10
0
Leukemia
Non-Small Cell Lung Cancer
Colon Cancer
CNS Cancer
Melanoma
Ovarian Cancer
Renal Cancer
Prostate
Cancer
Breast Cancer
b
% Inhibition at 10 uM concentration
90
80
70
60
50
40
30
20
10
0
Leukemia
Non-Small Cell Lung Cancer
Colon Cancer
CNS Cancer
Melanoma
Ovarian Cancer
Renal Cancer
Prostate
Cancer
Breast Cancer
c
Fig. 3 The inhibition percentages exerted by compounds 1c–e (Fig. 3a–c, respectively) at 10 lM concentration against every cancer cell line of
the NCI panel
Five-dose testing
containing m-(trifluoromethyl)phenylurea terminal moiety
was equipotent to Sorafenib against SK-MEL-5 melanoma
cell line. Compound 1d possessing terminal benzamido
moiety was more potent than Sorafenib against COLO 205
colon cancer, UO-31 renal cancer, and MCF7 breast cancer
cell lines. Moreover, compound 1e with terminal p-
methoxybenzamido moiety showed superior potency to
Sorafenib against OVCAR-3 ovarian cancer, UO-31 renal
cancer, DU-145 prostate cancer, and MCF7 breast cancer
cell lines. The IC50 values of compound 1e against those
four cell lines were the lowest among all the results of
compounds 1c–e against the nine cell lines. For example,
compound 1e was 3 times more potent than Sorafenib
against DU-145 prostate cancer cell line.
Compounds 1c–e which showed promising results in sin-
gle-dose testing were selected for further screening in
5-dose testing mode in order to determine their IC50 values
over the 55-cell line panel. The full results are provided in
the supplementary file. Table 2 illustrates the IC50 values
of those three compounds against the most sensitive cell
line of each subpanel. The results of Sorafenib as a refer-
ence standard compound were obtained from NCI data
warehouse
index
(http://dtp.nci.nih.gov/dtpstandard/
dwindex/index.jsp) and are inserted in Table 2.
Compounds 1c–e showed high potencies, most of the
results were in one-digit micromolar scale. Compound 1c
123

Med Chem Res
Table 2 IC50 values (lM) of compounds 1c–e over the most sensitive cell line of each subpanel
Cell line
Compound No.
1c
1d
3.83
01e
Sorafenib
CCRF-CEMa
NCI-H460b
COLO 205c
SF-295d
3.14
4.50
2.57
4.28
1.58
17.70
2.94
11.60
3.73
4.75
3.55
3.01
2.73
3.01
1.24
1.42
1.04
2.00
2.00
2.51
2.00
1.58
1.58
3.16
2.51
3.16
2.51
f
3.28
1.84
6.97
SK-MEL-5e
OVCAR-3f
UO-31 g
DU-145 h
MCF7i
1.66
16.20
1.75
12.70
1.43
a
b
c
d
e
Leukemia cell line; non-small cell lung cancer cell line; colon cancer cell line; CNS cancer cell line; melanoma cell line; ovarian
i
cancer cell line; renal cancer cell line; prostate cancer cell line; breast cancer cell line
g
h
synthesis, in vitro antiproliferative evaluation, and kinase
inhibitory effects of a new series of imidazo[2,1-b]thiazole
derivatives. Eur J Med Chem 95:453–463
Conclusion
A
series of 6-(4-fluorophenyl)-5-(4-pyrimidinyl)imi-
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dazo[2,1-b]thiazole derivatives was synthesized. They were
tested for in vitro antiproliferative activity over a panel of 55
cancer cell lines of nine different cancer types at the NCI.
The best results were obtained from compounds 1c–e. Those
three compounds exerted broad-spectrum antiproliferative
activity and high potency with IC50 values in one-digit
micromolar scale. Compound 1e with p-methoxybenzamido
terminal moiety gave the highest potency. It was more potent
than Sorafenib against OVCAR-3 ovarian cancer, UO-31
renal cancer, DU-145 prostate cancer, and MCF7 breast
cancer cell lines. Compounds 1c–e can be utilized as
promising lead compounds for future design and synthesis of
efficient anticancer agents.
Gu¨rsoy E, Gu¨zeldemirci NU (2007) Synthesis and primary cytotox-
icity evaluation of new imidazo[2,1-b]thiazole derivatives. Eur J
Med Chem 42:320–326
Park JH, Oh CH (2010) Synthesis of new 6-(4-fluorophenyl)-5-(2-
substituted pyrimidin-4-yl)imidazo[2,1-b]thiazole derivatives
and their antiproliferative activity against melanoma cell line.
Bull Korean Chem Soc 31:2854–2860
The structure–activity relationship studies revealed that
the p-fluorophenyl on position 6 of the imidazo[2,1-b]thi-
azole scaffold and the amide linker are optimal for activity
of this series of compounds. The bulkiness on the terminal
aryl ring was detrimental for activity.
Park JH, El-Gamal MI, Lee YS, Oh CH (2011) New imidazo[2,1-
b]thiazole derivatives: synthesis, in vitro anticancer evaluation,
and in silico studies. Eur J Med Chem 46:5769–5777
Srimanth K, Rao VR, Krishna DR (2002) Synthesis and evaluation of
anticancer activity of some imidazothiazolyl, imidazobenzoth-
iazolyl and dihydroimidazothiazolyl coumarins. Arzneimit-
telforschung 52:388–392
Townsend CA, Basak A (1991) Experiments and speculations on the
role of oxidative cyclization chemistry in natural product
biosynthesis. Tetrahedron 47:2591–2602
Tully DC, Liu H, Chatterjee AK, Alper PB, Epple R, Williams JA,
Roberts MJ, Woodmansee DH, Masick BT, Tumanut C, Li J,
Spraggon G, Hornsby M, Chang J, Tuntland T, Hollenbeck T,
Gordon P, Harris JL, Karanewsky DS (2006) Synthesis and SAR
of arylaminoethyl amides as noncovalent inhibitors of cathepsin
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Acknowledgments This work was supported by Korea Institute of
Science and Technology (KIST), KIST Project (2E24680). We would
like to thank the National Cancer Institute (NCI, Bethesda, Maryland,
USA) for testing the antiproliferative activity of our target compounds
over 55 cancer cell lines of nine different cancer types.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict
of interest.
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123