5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H) -diones as potential anticancer agents with anti-inflammatory properties

Article abstract of DOI:10.1016/j.bmcl.2012.12.053

A series of novel 5-((1-aroyl-1H-indol-3-yl)methylene)-2- thioxodihydropyrimidine-4,6(1H,5H)-diones (3a-z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI₅₀ = 850 nM), against leukemia SR cancer cells (GI₅₀ = 1.45 μM), and OVCAR-3 (GI₅₀ = 1.26 μM) ovarian cancer cell lines. The structurally related compound 3s had a GI₅₀ value of 1.77 μM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI₅₀ values of 1.30 and 1.91 μM against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI₅₀ values of 1.09 μM against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy.

Full text of DOI:10.1016/j.bmcl.2012.12.053

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1442–1446
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,
6(1H,5H)-diones as potential anticancer agents with
anti-inflammatory properties
⇑
Narsimha Reddy Penthala, Purushothama Rao Ponugoti, Vinod Kasam, Peter A. Crooks
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones
(3a–z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Com-
pound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells
Received 6 November 2012
Revised 15 December 2012
Accepted 17 December 2012
Available online 22 December 2012
(GI50 = 850 nM), against leukemia SR cancer cells (GI50 = 1.45
cancer cell lines. The structurally related compound 3s had a GI50 value of 1.77
cells. The N-naphthoyl analogue 3t had GI50 values of 1.30 and 1.91 M against HOP-92 non-small cell
lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI50 values
of 1.09 M against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active
l
M), and OVCAR-3 (GI50 = 1.26
lM) ovarian
l
M against MDA-MB-435
l
Keywords:
N-Benzoyl indole-3-carboxaldehydes
N-Naphthoylindole-3-carboxaldehydes
Thiobarbituric acid
In vitro cytotoxicity
Anti-inflammatory agents
l
molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands
with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w consti-
tute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer
therapy.
Ó 2013 Elsevier Ltd. All rights reserved.
Recently, we have reported on the cytotoxicity of (Z)-2-
amino-5-(1-benzyl-1H-indol-3-yl)methylene-1-methyl-1H-imida-
zol-4(5H)-ones against human tumor cell lines (A, Fig. 1),1 and we
have also described the radiosensitizing activity of some related
N-benzylindole analogs (B, Fig. 1) in parallel with their cytotoxic
properties.2–4 Singh et al. have recently synthesized and studied
a series of structurally related N-benzylindolyl- and N-benzoyl ind-
olylbarbituric (C, Fig. 1) acids as new hybrid molecules with signif-
icant anticancer activity5, and De Belin et al. have also described a
series of thiobarbituric acid analogs (D, Fig. 1), which inhibit
hypoxia-inducible factor 1 (HIF-1).6
Interestingly, 2-thiobarbituric acids have been reported as anti-
convulsant,7 immunotropic,8 anti-inflammatory,8 and anti-neo-
plastic agents,9 as well as anti-hypnotic,10 and anticancer
agents.11 More importantly, two analogs of scaffold B (Fig. 1) have
recently been reported to possess both anticancer and anti-inflam-
matory properties.5 Molecules with these dual properties consti-
analogs of scaffold C (Fig. 1). These compounds were initially eval-
uated in single dose anticancer screens and the most promising
agents (3k, 3s, 3t and 3w) selected for five dose testing against a
panel of 60 human cancer cell lines. In addition, two of the above
four compounds were evaluated for their ability to bind to cycloox-
ygenase 2 (COX-2), the most frequently evaluated anticancer/anti-
inflammatory target, in molecular docking studies.
In the preparation of compounds 3a–z, a small sub-library of
the required N-aroylindole-3-carboxaldehyde precursors (1a–z)
was synthesized by available literature procedures.14 2-Thiobar-
bituric acid (2) is a strong organic acid, having a pKa of 2.1 in
water. The 2-thiobarbituric acid ‘active’ methylene group can
participate in Knoevenagel condensation reactions with appropri-
ate aldehydes or ketones that do not contain an a-hydrogen. This
reaction can be performed without a base or acid catalyst. The
procedure involves refluxing the appropriate indole-3-carboxal-
dehyde with 2-thiobarbituric acid in methanol (Scheme 1) to
afford the desired 5-((1-aroyl-1H-indol-3-yl)meth-ylene)-2-thiox-
odihydropyrimidine-4,6-(1H,5H)-dione (Table 1). Yields obtained
were in the range 89–95% and purities were generally >99%. All
the synthesized compounds were fully characterized by 1H and
13C NMR spectroscopy.15
tute
a new approach for treating cancer, since it is well
established that inflammation plays a major role in the initiation,
progression, and prognosis of cancer.12,13
In this current study we report on a series of novel N-aroyl
aplysinopsin analogs, 5-((1-aroyl-1H-indol-3-yl) methylene)-2-
thioxodihydropyrimidine-4,6(1H,5H)-diones (3a–z), that are thio
The preliminary evaluation of compounds (3a–z) was carried
out at a single dose of 10 lM, against a panel of 60 human tumor
cell lines, according to the procedure described by Rubinstein
⇑
Corresponding author. Tel.: +1 501 686 6495; fax: +1 501 526 5945.
E-mail address: pacrooks@uams.edu (P.A. Crooks).
et al.16 The human tumor cell line panel included leukemia,
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.12.053

N. R. Penthala et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1442–1446
1443
Figure 1. N-Benzyl and N-benzoylindole analogs (A–D).
non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate,
Table 1
and breast cancer cell lines. From the single dose-response studies,
analogs3k, 3s, 3t and 3w showed P60% growth inhibition in more
than eight of the 60 cancer cell lines.
List of N-aroyl indolethioxodihydropyrimidine-4,6(1H,5H)-dione analogs (3a–z)
S. No.
R
Ar
a
b
c
H
Cl
Br
C6H5
C6H5
C6H5
Compounds 3k, 3s, 3t and 3w were subsequently evaluated in
five dose-response studies for their in vitro cytotoxic effects on
growth parameters against each of the 60 human tumor cell lines.
Dose–response curves were created by plotting cytotoxic effect
against the log10 of the drug concentration for each cell line. Cyto-
toxic effects of each compound were determined as GI50 and LC50
values, which represent the molar drug concentration required to
cause 50% growth inhibition, and the concentration that kills 50%
of the cells, respectively. The growth inhibition results are pre-
sented in Tables 2 and 3.
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
OCH3
H
Cl
Br
H
Cl
Br
OCH3
H
Cl
C6H5
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-OCH3-C6H4
4-OCH3-C6H4
4-OCH3-C6H4
4-OCH3-C6H4
4-CN-C6H4
4-CN-C6H4
4-COOCH3-C6H4
4-COOCH3-C6H4
2-Br-C6H4
2-Br-C6H4
2-Br-C6H4
The N-4-methoxybenzoyl analog 3k exhibited good growth
inhibition in all four leukemia cell lines in the panel, with GI50 val-
H
Cl
H
Cl
ues in the range of 1.45–3.91
growth inhibitory activity against SR leukemia (GI50 = 1.45
l
M. This compound exhibited potent
M;
(GI50 = 850 nM;
l
Br
LC50 = 39.4
LC50 = 3.86
l
l
M),
melanoma
MDA-MB-435
M; LC50 = >50
s
t
OCH3
H
Cl
Br
OCH3
H
2-Br-C6H4
M) and LOX IMVI (GI50 = 1.86
l
l
l
M)
M;
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
cancer cell lines, and against ovarian OVCAR-3 (GI50 = 1.26
LC50 = >50 M), colon cancer HCT-116 (GI50 = 1.95
>50 M), HCT-15 (GI50 = 1.80 M; LC50 = >50 M), KM12
(GI50 = 1.99 M; LC50 = >50 M) cell lines (Table 2).
u
v
w
x
y
z
l
lM; LC50 =
l
l
l
l
l
Cl
OCH3
The related N-2-bromobenzoyl compound 3s also exhibited
growth inhibitory properties against all four leukemia cell lines
in the panel (GI50 values in the range of 2.55–4.00
3s also showed good growth inhibitory activity against melanoma
MDA-MB-435 cell lines (GI50 = 1.77 M; LC50 = 8.43 M) (Table 2).
lM). Compound
cancer (GI50 = 1.09
cancer cells (GI50 and LC50 values of 2.38 and 20.9
l
M; LC50 = >100
l
M) and OVCAR-3 ovarian
l
l
lM, respec-
The N-1-naphthoyl analog 3t exhibited growth inhibitory prop-
tively) (Table 3).
erties against all four leukemia cancer cell lines in the panel (GI50
Interestingly, the isomeric N-2-naphthoyl analogs of 3t and 3w
(3x and 3z, respectively) were not identified as potent cytotoxic
agents against any of the human cancer cell lines in the 60 cell
panel.
values in the range of 2.74–3.71
good growth inhibitory activity against HOP-92 non-small cell lung
cancer (GI50 = 1.30 M; LC50 = 44.8 M), and MDA-MB-435 mela-
noma (GI50 = 1.91 M; LC50 = 9.23 M) cell lines (Table 3).
lM). Compound 3t also showed
l
l
l
l
It is well known that inflammation is closely linked to cancer,
and there are strong correlations between the presence of inflam-
mation and the development of pre-cancerous lesions, suggesting
that the presence of inflammation can induce or facilitate carcino-
genesis.12,13 COX-2 is the most frequently evaluated oxygenase for
assessing anti-inflammatory/anticancer potential, although other
targets such as NF-kB, cytokines, chemokines, fibroblast growth
factor (FGF), and VEGF have also been utilized.17–20
The N-1-naphthoyl analog 3w, which differs from 3t in possess-
ing an indolic 5-methoxy group exhibited good growth inhibition
in all four leukemia cancer cell lines in the panel (GI50 values in
the range of 3.31–3.95
lM), and in the three melanoma cell lines
(GI50 values in the range of 1.91–3.80
l
M), and also showed potent
growth inhibitory activity against HOP-92 non-small cell lung
Based on recent modeling studies5 on the structurally related 5-
((1-aroyl-1H-indol-3-yl)methylene)-2-oxodihydropyrimidine-
4,6(1H,5H)-diones, we performed molecular docking studies with
the two active molecules 3k and 3w at the active site of COX-2
with PDB ID: 6COX. The Fred 2.2.5 program from Openeye scien-
tific software was used as the docking tool in this work.21 The
built-in Chemscore score was selected as the optimization filter
and consensus score for the final selection of docking poses.22
The active site was composed of all the atoms within the 8 Å of
Scheme 1. Synthesis of N-aroyl indolethiobarbituric acids.

1444
N. R. Penthala et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1442–1446
In the earlier studies by Singh et al.,5 it was shown that carbonyl
and amine groups on the barbiturate moiety in analogs related to
scaffold B (Fig. 1) are involved in hydrogen bonding interactions
with residues SER353, GLN192 and HIS90. In contrast to the Singh
et al. observations, in the current work we discuss a novel possible
binding mode for the thiobarbituric acid analogs 3k and 3w. The
major dissimilarity arises at the positioning of the thiobarbituric
acid moiety. In the binding mode proposed by Singh et al., the bar-
biturate moiety occupies the pocket formed by residues SER353,
GLN192 and HIS90 (see Ref. 5). Unlike the binding mode proposed
by Singh et al., in the current study we found that the thiobarbitu-
rate moiety occupies the pocket formed by residues TYR385,
VAL523, TRP387 and SER530. The binding mode proposed in this
study seems to be more reliable, mainly due to the more favorable
interactions that the thiobarbiturate moiety makes with the sur-
rounding residues (TYR385, VAL523, TRP387 and SER530). The
docking of compound 3k and 3w into the active site are displayed
in Figures 2 and 3, respectively.
Table 2
Growth inhibition concentration (GI50/lM) and cytotoxicity (LC50/lM) data of
5-methoxy N-benzoyl indole analogs 3k and 3s on various human tumor cell lines
Panel/cell line
3k
3s
GI50
(l
M)
LC50
(
lM)
GI50
(lM)
LC50 (lM)
Leukemia
CCRF-CEM
HL-60(TB)
K-562
2.23
3.91
2.55
1.45
>50.0
>50.0
>50.0
39.4
4.00
3.24
3.80
2.55
>100
>100
>100
>100
SR
Non-small cell lung cancer
HOP-62
3.12
>50.0
3.59
64.3
>100
89.9
51.9
Colon cancer
HCT-116
HCT-15
1.95
1.80
1.99
>50.0
>50.0
>50.0
3.76
3.83
3.87
KM-12
CNS cancer
SF-268
SF-539
U251
2.65
2.56
1.93
>50.0
>50.0
>50.0
3.86
3.00
3.09
52.2
57.8
42.1
From Figure 2 it is evident that the ligand is strongly stabilized
by both polar and non-polar interactions. The indolic moiety in the
molecule plays the anchor role, holding the ligand in position by
strong hydrophobic interactions with multiple residues at the ac-
tive site: that is SER353, VAL523. The 2-thiobarbituric acid group
is stabilized by hydrogen bonding interactions with the side chain
of TYR385, hydrogen bonding with the backbone of VAL523,
Melanoma
LOX IMVI
M14
MDA-MB-435
SK-MEL-5
UACC-62
1.86
2.03
0.85
2.31
2.33
>50.0
>50.0
3.86
>50.0
>50.0
2.92
3.52
1.77
3.47
3.38
47.9
>100
8.43
>50.0
39.6
Ovarian cancer
OVCAR-3
NCI/ADR-RES
hydrophobic interactions with TRP387, and CH–p interactions
1.26
2.91
>50.0
>50.0
2.77
3.23
33.1
>100
with SER530 residues. The indolic methoxy group is strongly stabi-
lized by hydrogen bonding to GLN192 and the phenyl ring of the
indole moiety by van der Waals interactions with HIS90, Val523.
Compound 3w differs from 3k by replacement of the N-4-
methoxybenzoyl group in 3k with an N-1-naphthoyl group. Never-
theless both compounds are bound in a similar orientation at the
active site of COX-2. The N-1-naphthoyl moiety occupies the
hydrophobic pocket formed by TYR355, LEU359, LEU531,
VAL116, and LEU117; moreover, the non-polar N-1-naphthoyl
moiety is an ideal group for occupying this hydrophobic pocket.
The binding of 3w at the active site of COX-2 is shown in Figure 3.
Prostate cancer
DU-145
2.41
>50.0
3.01
53.6
the co-crystallized ligand. After validation, molecular docking was
performed on the two active compounds (3k and 3w). The molec-
ular docking experiment was validated using the standard re-dock-
ing procedure. Re-docking of the existing ligand, Sc-558, into its
binding site resulted in <1.5 Å RMSD between the co-crystallized
ligand and the docked ligand.
Table 3
Growth inhibition concentration (GI50/lM) and cytotoxicity (LC50/lM) data of N-1-
naphthoyl analogs 3t and 3w on various human tumor cell lines
Panel/cell line
3t
3w
GI50
(l
M)
LC50
(lM)
GI50
(lM)
LC50 (lM)
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
SR
3.35
3.36
3.71
3.49
2.74
>100
>100
>100
79.0
92.3
3.31
3.47
3.52
3.95
3.32
>100
>100
>100
>100
>100
Non-small cell lung cancer
HOP-92
1.30
44.8
1.09
>100
Colon cancer
HCT-116
HCT-15
2.90
3.60
>100
>100
3.35
3.10
>100
>100
CNS cancer
SF-539
U251
3.68
3.58
58.6
50.7
2.30
3.23
>100
>100
Melanoma
LOX IMVI
M14
3.59
3.22
1.91
55.6
>100
9.23
3.80
1.91
2.01
>100
>100
12.0
MDA-MB-435
Ovarian cancer
OVCAR-3
NCI/ADR-RES
2.46
2.59
46.2
>100
2.38
3.14
20.9
>100
Figure 2. Illustration showing compound 3k binding at the active site of COX-2.
Compound 3k is displayed in orange color ball and sticks and the active site
residues are displayed in cyan color sticks.
Renal cancer
UO-31
3.93
>100
3.72
>100

N. R. Penthala et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1442–1446
1445
orientation and conformation as compound 3k at the active site of
COX-2 (Fig. 4).
In conclusion, a series of novel substituted 5-((1-aroyl-1H-in-
dol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-
diones (3a–z) have been synthesized and evaluated for their anti-
cancer activity against a panel of 60 human tumor cell lines. In the
N-benzoyl substituted indole series (3a–s), the presence of a 5-
methoxy-N-benzoylindole moiety (3k and 3s) and an N-2-bromo-
benzoyl or N-4-methoxybenzoyl moiety afforded two molecules
with potent growth inhibition against human tumor cell lines. In
the N-naphthoylindole series (3t–y), the two N-1-naphthoylindole
analogs 3t and 3w also exhibited potent anticancer activity when
compared to their isomeric N-2-naphthoyl analogs (3x and 3z,
respectively). Representative cytotoxic analogs from both the N-
benzoyl substituted and the N-naphthoyl substituted series of thio-
barbiturate analogs (3k and 3w, respectively) have also been
shown to bind to the active site of COX-2 with strong hydrophobic
and hydrogen bonding interactions in molecular docking studies,
indicating high affinity for this oxygenase. The use of anti-inflam-
matory agents in combination with conventional anticancer thera-
pies is already gaining ground as a new approach for treating
certain cancers. Thus, these novel anticancer/anti-inflammatory
molecules may represent potentially new therapeutics for cancer
treatment.
Figure 3. Illustration showing compound 3w binding at the active site of COX-2.
Compound 3w is displayed in yellow color ball and sticks and the active site
residues are displayed in cyan color sticks.
Acknowledgments
We are grateful to NCI/NIH (Grant Number CA 140409) and to
the Arkansas Research Alliance (ARA) for financial support, and
to the NCI Developmental Therapeutic Program (DTP) for screening
data.
References and notes
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3. Vijayakumar, N. S.; Reddy, Y. T.; Sekhar, K. R.; Soumya, S.; Freeman, M. L.;
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5. Singh, P.; Kauer, M. Verma Bioorg. Med. Chem. Lett. 2009, 19, 3054.
6. De Belin, J. Y.; Romer Martin, M. R.; Fin, P. W.; Sayers, L. G.; Law, N. M.;
Billington, D. C.; Ryley, S.; Bhattacharya, S. WO 01/93841 A2, 2001.
7. Goodman, L. S.; Gilman, A. The Pharmacological Basis of Therapeutics; McGraw-
Hill: New Delhi, 1991. p 358.
8. (a) Badawey, E.; El-Ashmawey, I. M. Eur. J. Med. Chem. 1998, 33, 349; (b)
Radwan, M. A. A.; Ragab, E. A.; Sabry, N. M.; El-Shenawy, S. M. Bioorg. Med.
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9. Singh, S.; Behl, C. K. J. Indian Chem. Sect. B 1980, 19B, 625.
10. (a) Andrews, G. Medical Pharmacology; The CV Mosby Company: Saint Louis,
1976. p 243; (b) Foye, W. O. Principles of Medicinal Chemistry; Lea & Febiger:
London, 1989. p 159.
11. Guerin, D. J.; Mazeas, D.; Musale, M. S.; Naguib, N. F. M.; Al Safarjalani, O. N.; El
Kouni, M. H.; Panzica, R. P. Bioorg. Med. Chem. Lett. 1999, 9, 1477.
12. Rayburn, E. R.; Ezell, S. J.; Zhang, R. Mol. Cell. Pharmacol. 2009, 1, 29.
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Vinicio, G.; Stefano, N. Chem. Eur. J. 2003, 9, 3132.
15. Analytical data for two of the most active compounds (3k): MF: C22H17N3O5S, mp:
>300 °C, 1H NMR (DMSO-d6): d 3.74 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 7.54–7.56
(dd, 2H, Ar–H), 7.98–8.05 (m, 2H, Ar–H), 8.17–8.19 (dd, 2H, Ar–H), 8.36 (s, 1H,
C4–H), 8.57 (s, 1H, @CH), 9.49 (s, 1H, C2-H), 12.31 (br s, 1H, NH), 12.48 (br s, 1H,
NH) ppm; 13C NMR (DMSO-d6): d 55.52, 55.56, 102.40, 110.63, 111.0, 113.72,
123.73, 125.88, 127.43, 128.62, 129.16, 129.45, 141.88, 155.10, 157.88, 161.28,
161.31, 162.53, 169.18, 178.42 ppm. (3w): MF: C25H17N3O4S, mp: >300 °C, 1H
NMR (DMSO-d6): d 3.91 (s, 3H, OCH3), 7.10–7.13 (d, 1H, ArH), 7.21 (s, 1H, @CH),
7.61–7.78 (m, 3H, Ar–H), 7.82–7.86 (d, 1H, Ar–H), 7.96–8.01 (d, 1H, Ar–H),
8.12–16 (d, 1H, Ar–H), 8.26–8.43 (dd, 2H, Ar–H), 8.49 (s, 1H, C4–H), 9.23 (s, 1H,
C2-H), 12.33 (br s, 1H, NH), 12.49 (br s, 1H, NH) ppm; 13C NMR DMSO-d6): d
55.48, 100.66, 114.49, 114.63, 115.33, 117.15, 124.22, 124.92, 126.93, 127.17,
127.93, 128.60, 129.40, 129.43, 130.48, 131.59, 131.73, 132.86, 138.92, 141.88,
157.27, 160.18, 161.46, 168.12, 177.62 ppm.
Figure 4. Illustration of the superimposition of binding modes of compounds 3k
and 3w. A close alignment of the carbon chain of both compounds is demonstrated.
Highlighted in the circle is the difference between the two compounds. Compound
3k is displayed in orange and compound 3w is displayed in yellow.
The superimposition of both compounds at the COX-2 active is
further shown in Figure 4. Thus, the binding of these compounds
with strong hydrophobic and hydrogen bonding interactions at
the active site of COX-2 indicates high affinity for COX-2 ligands.
Interestingly, the new binding modes proposed herein by our
docking study further reveals that compound 3w binds in a similar
16. Rubinstein, L. V.; Shoemaker, R. H.; Paull, K. D.; Simo, R. M.; Tosini, S.; Skehan,
P.; Scudiero, P. A.; Monks, A.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82, 1113.
17. Nisam, S.; Pei, S.; Hagan, F.; Jordan, C. T.; Crooks, P. A. Biorg. Med. Chem. Lett.
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