Indenoindolone derivatives as topoisomerase II-inhibiting anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2012.12.063

Based on known heterocyclic topoisomerase II inhibitors and anticancer agents, various indenoindolone derivatives were predicted as potential topoisomerase II-inhibiting anticancer agents. They are hydrazones, (thio)semicarbazones, and oximes of indenoind

Full text of DOI:10.1016/j.bmcl.2012.12.063

Bioorganic & Medicinal Chemistry Letters 23 (2013) 934–938
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Indenoindolone derivatives as topoisomerase II–inhibiting
anticancer agents
Maneesh Kashyap a, Somnath Kandekar a, Ashish T. Baviskar b, Dipon Das c, Ranjan Preet c,
Purusottam Mohapatra c, Shakti Ranjan Satapathy c, Sumit Siddharth c, Sankar K. Guchhait a,
,
⇑
Chanakya N. Kundu c, , Uttam C. Banerjee
b
⇑
a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India
b Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India
c School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Odisha 751024, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Based on known heterocyclic topoisomerase II inhibitors and anticancer agents, various indenoindolone
derivatives were predicted as potential topoisomerase II–inhibiting anticancer agents. They are hydra-
zones, (thio)semicarbazones, and oximes of indenoindolones, and indenoindolols. These derivatives with
Received 14 September 2012
Revised 5 December 2012
Accepted 20 December 2012
Available online 3 January 2013
suitable substitutions exhibited potent specific inhibition of human DNA TopoIIa while not showing inhi-
bition of topoisomerase I and DNA intercalation, despite the fact that parent indenoindolones are known
poor/moderate inhibitors of topoisomerase II. The potent topoisomerase II inhibitor indenoindolone
derivatives exhibited good anticancer activities compared to etoposide and 5-fluorouracil, and relatively
low toxicity to normal cells. These derivatizations of indenoindolones were found to result in enhance-
ment of anticancer activities.
Keywords:
Indenoindolone
(Thio)semicarbazone
Oxime
Topoisomerase II
Anticancer agent
Ó 2012 Elsevier Ltd. All rights reserved.
Topoisomerase II plays key role in transcription, replication, and
chromosome segregation. This enzyme maintains topological
changes of DNA by creating double-stranded DNA breaks and pas-
sage of a second double-stranded DNA through the transiently bro-
ken duplex.1 Its b isozyme expresses almost constant and at
relatively low level throughout the cell cycle. However, the expres-
as functional side chains or monocyclic rings when attached to the
key scaffold are known to enhance potency in inhibition of topoiso-
merase II. They act as minor groove binders to DNA and prevent it to
be available in suitable geometry for binding with topoisomerase II.
These moieties can also directly bind to topoisomerase II. The pres-
ence of such moieties have led to the development of novel thera-
peutic agents in the form of derivatives of original scaffolds.8
These derivatizations improve pharmacodyanamic as well as phar-
macokinetic properties.8c-e Mitoxantrone, which acts as a topoiso-
merase II poison, on derivatization with incorporation of extended
alkylamine shows its enhanced DNA-binding affinity.8f The thio-
sion of
a
isozyme increases throughout S phase and peaks with 2-
isozyme
to 3-fold at G2/M phase of mitosis. The concentration of
a
is even higher in rapidly proliferating tissues than in quiescent cell
populations.2 Some of antitumoral drugs that target topoisomerase
II are doxorubicin and daunorubicin (anthracycline class), etopo-
side and teniposide (epipodophyllotoxin class), mitoxantrone,
amonafide, and amsacrine.3 Topoisomerase II has been recognized
as an important target in anticancer drug discovery4 and the devel-
opment of its novel inhibitors is recently emerging.5 Recently, we
developed N-fused imidazole as topoisomerase II-targeting novel
anticancer agents.6
semicarbazone derivatives of
a-hererocyclic carboxaldehyde inhibit
catalytic activity of topoisomerase II
a. 2-Benzoxazolylhydrazones
have been found to be potent anticancer agents.8g,h Compared to
b-lapachone, its 7-hydroxy derivative have been found to possess
higher antiproliferating activity in human solid tumor cell lines.8i
As a part of our research on anticancer drug discovery, we have
recently explored that indenoindolones possess anticancer activi-
ties.9 Based on the relevance of side chains/moieties towards
enhancement of the topoisomerase II-inhibitory and anticancer
activities; we considered various indenoindolone derivatives as
potential topoisomerase II–inhibiting anticancer agents (Fig. 1).
In this Letter, we present relevant indenoindolone derivatives
(hydrazones, (thio)semicarbazones, and oximes of indenoindol-
ones, and indenoindolols) as potent topoisomerase II–inhibiting
Towards development of novel anticancer agents, the structural
modification/hybridization of known natural/synthetic target-spe-
cific anticancer agents is a valuable approach.7 Certain moieties such
⇑
Corresponding authors. Tel.: +91 (0)172 2214683; fax: +91 (0)172 2214692
(S.K.G.); tel.: +91 (0)674 272 5466; fax: +91 (0)674 272 5732 (C.N.K.).
E-mail addresses: skguchhait@niper.ac.in (S.K. Guchhait), cnkundu@gmail.com
(C.N. Kundu).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.12.063

M. Kashyap et al. / Bioorg. Med. Chem. Lett. 23 (2013) 934–938
935
O
HO
O
N
N
N
N
H
O
S
N
N
R
O
N
3
N
N
H
N
OCH3
OCH3
N
2
H
Compounds with side chain/moiety
4 S35794
8
as topo II inhibitors (1-4)
HO
S
N
OH
5
O
N
N
H
NH2
O
1
O
X
O
R2
R2
R3
R3
N
N
R1
R1
Indenoindolone derivatives predicted
as potential topoisomerase II-inhibiting
anticancer agents
9
Anticancer indenoindolone
Figure 1. Known Topo II inhibitors and anticancer agents; indenoindolone derivatives (hydrazone, (thio)semicarbazone, and oxime derivatives, and indenoindolols) as
potential topoisomerase II–inhibiting anticancer agents.
O
O
R2
Cl
+
R2
1. Aroylation
R3
N
R1
R3
2. Intramolecular
arylation or
dehydrogenative coupling
X
N
R1
X = Br, H
R4
6
3
4
5
H
(S)O
N
N
R4
R3
HO
NH
NH
OH
N
N
R2
R2
R2
R2
R3
R3
R3
N
R1
N
N
R1
N
R1
R1
Ser
ies
III
Ser
Series II
ies
I
Series I, Compound 1-16
Series IV, Compound 37-45
Series II, Compound 17-26
Series III, Compound 27-36
R2
R4
R1
R3
a
R3
#
R2
a
a
R1
a
R2
R3
R4
R1 R2
R3
R1
#
#
#
-
-
-
-
-
-
1
Me
Bn
Me
Me
Me
Me
H
Me
Me
Me
Bn
Bn
Me
Me
Me
H
17b
18
19
20
21
22
23
24
25b
26
-
-
-
27
28
29
30
31
32
33
34
-
-
-
-
-
-
37
H
-
H
H
H
-
-
2
-
-
38 Bn
39 Me
40 Me
41 Me
-
Bn
Me
Me
Me
Me
H
-
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
8-OMe
-
Bn
Me
H
3
2-OMe
-
-
2-OMe
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
4-Br
-
4
3-OMe
2,3,4-(OMe)3
-
5
-
8-OMe
8-OMe
-
2-Et
-
6
8-OMe
-
Me
H
2,3,4-(OMe)3
-
-
2,3,4-(OMe)3
3-F
-
-
-
-
Me
H
42
43
44
45
-
7
-
-
3-F
3-F
-
4-Me
4-OMe
2,3-(Me)2
4-Me
4-OMe
-
8
3-OMe
2-OMe
H
8-OMe
2,3-(OMe)2
2,3-(OMe)2
H
H
-
9
2,3-(OMe)2
-
8-OMe -
-
-
H
35 Me
36 Me
Me
-
10
11
12
13
14
15
16
-
-
-
H
-
2,3,4-(OMe)3
Me
-
2-OMe
b thiosemicarbazones
2,3-(OMe)2 4-OMe
2,3,4-(OMe)3 4-OMe
2,3,4-(OMe)3 4-Me
a compound number
Scheme 1. Step 1: Fridel–Crafts aroylation;10a Step 2: intramolecular arylation10b or dehydrogenative coupling;10c Step 3: indeno[1,2-b]indol-10(5H)-one (0.5 mmol) and
arylhydrazine (0.5 mmol), ethanol, a drop of glacial acetic acid, reflux;8g,11 Step 4: indeno[1,2-b]indol-10(5H)-one (0.5 mmol) and (thio)semicarbazides (0.5 mmol), ethanol, a
drop of glacial acetic acid, reflux;8h,11 Step 5: indeno[1,2-b]indol-10(5H)-one (0.5 mmol), hydroxylamine hydrochloride (1.7 mmol), ethanol/water (7:3), reflux;12; Step 6:
indeno[1,2-b]indol-10(5H)-one (0.5 mmol), methanol, sodium borohydride (1.5 mmol), rt.
anticancer agents. Whilst indenoindolones are poor/moderate
inhibitors of topoisomerase II,9 these derivatives with suitable sub-
The potent topoisomerase II inhibitor indenoindolone derivatives
exhibited good anticancer activities in kidney cancer cells
(HEK-293), compared to etoposide (a clinically used anticancer drug
that targets topoisomerase II) and 5-fluorouracil (5-FU, a widely
stitutions exhibited potent specific inhibition of hTopoII
a without
any effect of topoisomerase I–inhibition and DNA intercalation.

936
M. Kashyap et al. / Bioorg. Med. Chem. Lett. 23 (2013) 934–938
Figure 2. (A) Effect of investigational compounds on catalytic activity of hTopoII
100 M etoposide or investigational compounds. Reaction mixture was incubated at 37 °C for 30 min and electrophoresis was carried out in 1% agarose gel in TAE buffer; (B)
quantification of decatenated product formed in kDNA decatenation assay.
a in kDNA decatenation assay. kDNA was treated with hTopoIIa in the presence of either
l
Figure 3. MTT assay: cells after treatment with investigational compounds or etoposide of various concentrations for 48 h. The sign —ꢀ—, —j—, –Á–N–Á– and —d— represent
for Vero/etoposide, HEK-293/etoposide, Vero /investigational compound and HEK-293/investigational compound, respectively. Data is the mean SD of three different
experiments.
used anticancer drug), and relatively low toxicity to normal cells.
Compared to indenoindolones, their (thio)semicarbazone and
oxime derivatives, and indenoindolols were found to possess 3- to
4-fold enhanced anticancer activities.
Recently, we developed efficient synthesis of indenoindolones
via Friedel–Crafts benzoylation10a of indoles and followed by
intramolecular direct arylation10b or cross dehydrogenative
coupling10c (Scheme 1, steps 1 and 2). These protocols afford
the convenient preparation of diverse substituted/functionalized
indenoindolones from easily accessible starting materials in re-
duced number of reaction steps. Various relevant substituted
indenoindolones were prepared by these methods. The
indenoindolone derivatives arylhydrazones, (thio)semicarba-
zones, and oximes of indenoindolones, and indenoindolols were
prepared by the reactions of indenoindolones with hydrazines,
(thio)semicarbazides, hydroxylamines, and NaBH4, respectively,

M. Kashyap et al. / Bioorg. Med. Chem. Lett. 23 (2013) 934–938
937
Table 1
(Fig. 2 B). Other compounds which exhibited poor or moderate
inhibition of topo II compared to etoposide have not been included
in the Figure 2. Quantification of decatenation products formed
was done by densitometric data obtained using QuantityOne (Bio-
Rad) (Fig. 2B). These results indicate that the indenoindolone
derivatives with incorporation of relevant side chain/moiety are
LC50 values of the investigational compounds in VERO and HEK-293 cells at 48 h
Compounds
LC50, 48 h
VERO ( M)
l
HEK-293 (lM)
17
27
29
39
42
Etoposide
50
60
60
30
40
29
2
2
2
2
2
2
7
6
2
2
2
2
2
2
potent inhibitors of topoisomerase IIa in comparison to etoposide.
5
4
This activity of indenoindolone derivatives is particularly interest-
ing considering the fact that indenoindolones are poor/moderate
inhibitors of topoisomerase II.9
8
17
The potent topoisomerase II inhibitor indenoindolone deriva-
tives (as in Fig. 2) were considered for the investigation of their
anticancer activities using MTT assay6,9,14 in human embryonic
kidney cancer cells (HEK-293, cat. # CRL-1573) and normal mon-
key kidney cells (Vero, cat. # CCL-81), purchased from ATCC, VA,
USA (Fig. 3). Cells were plated in a 96-well tissue culture plate
and then treated with the investigational compounds for 48 h.
Then, MTT was added for formation of formazan crystal which
was dissolved by a detergent solution and the colour intensity
was measured at 570 nm using a microplate reader (Berthold, Ger-
many). Compounds 17, 27, 29, 39 and 42 showed relatively higher
anticancer activities compared to other derivatives. They caused
50% cell death (LC50) of HEK-293 cells at 7, 6, 5, 4, and 8
tively while the LC50 values in Vero cells were 50, 60, 60, 30 and
40 M, respectively (Fig. 3 and Table 1). The LC50 values for etopo-
side were 17 M in HEK-293 cells and 29 M in Vero cells. Cell
lM, respec-
l
l
l
death of HEK-293 cells significantly increased in comparison to
Vero cells with increase in the concentration of these compounds.
After 48 h of treatment, the anti-cell proliferative effect of these
investigational derivatives did not further change significantly.
The anti-proliferative activities of investigational compounds 17,
27, 29, 39 and 42 were further compared with a clinically used com-
mon anticancer drug 5-FU in HEK-293 cells using MTT assay (Fig. 4).
Figure 4. MTT assay: Comparison of anti-cell survival activities of compounds (17,
27, 29, 39, 42) with 5-FU in HEK-293 cells. Data is the mean SD of three different
experiments. The symbols —d—, –ÁÁ
–ÁÁ, —ꢀ—, – – –
– – –, —j—and –
Á–N–Á– represent 5-FU, compounds 17, 27, 29, 39, 42, respectively.
following corresponding conventional methods (Scheme 1, steps
3–6).8g,h,11,12
The topoisomerase II–inhibitory activities of investigational
indenoindolone derivatives (compounds 1–45, Series I–IV) were
The LC50 value of 5-FU was found to be 25 lM. Therefore, all these
results indicate that the indenoindolone derivatives 17, 27, 29, 39
and 42 are more potent anticancer agents compared to 5-FU and
etoposide in HEK-293 cells. The investigational compounds (17,
investigated against human topoisomerase II
a (hTopoIIa) by
27, 29, 39, 42) have shown LC50 in the range of 4–8
293 cells, whereas parent indenoindolones have exhibited LC50 in
the range of 14–24
M.9 This indicates that the derivatizations of
lM for HEK-
in vitro ATP-dependent decatenation assay (agarose gel electro-
phoresis)6 using a commercially available topoisomerase drug
screening kit purchased from TopoGEN, Inc. (Columbus, OH). Kine-
toplast DNA (kDNA) as substrate was used. Etoposide, an antican-
cer drug that targets topoisomerase II, was used as positive
standard. Catenated kDNA appears at the top and cannot enter into
the gel because of its overall size, while other decatenated products
nicked (Nck), relaxed (Rel), and supercoiled (SC) DNA move into
the gel.13 For many investigational compounds of each class of
indenoindolone derivatives, very less or no decatenated products
were formed in the assay, compared to that in case of etoposide
(Fig. 2A). Compared to parent indenoindolones,9 the following
investigational compounds showed more potent inhibition of
topoisomerase II, series I (1, 2, 3, 7, 8, 9, 12, 13, 14, 15), series II
(17, 18, 19), series III (27, 28, 29), and series IV (39, 40, 42)
l
indenoindolones as (thio)semicarbazones and oximes, and indeno-
indolols enhance anticancer activities by 3- to 4-fold.
Compounds 17, 27, 29, 39 and 42 showed relatively higher anti-
cancer activities. They were also found to possess significant inhib-
itory activities of hTopoIIa in decatenation assay, compared to
other investigational compounds and etoposide. Therefore, these
derivatives were chosen for further studies of their possible speci-
ficity in inhibition of the enzyme. In order to check whether com-
pounds are DNA intercalators or non-intercalators, DNA
intercalation assay15 was performed using negatively supercoiled
small circular plasmid DNA (isolated from Escherichia coli) as sub-
strate. It was found that in the presence of intercalative agent (ethi-
Figure 5. (A) DNA intercalation assay: in this assay, 250 ng of plasmid was incubated with ethidium bromide (EtBr), etoposide or investigational compounds. Reaction
mixture was incubated at 37 °C for 20 min and electrophoresis was carried out in 1% agarose gel in TAE buffer; (B) effect of investigational compounds on hTopoI activity in
relaxation assay. Negatively supercoiled DNA was treated with TopoI in the presence of either 100 lM camptothecin or investigational compounds. Reaction mixture was
incubated at 37 °C for 30 min and electrophoresis was carried out in 1% agarose gel in TAE buffer.

938
M. Kashyap et al. / Bioorg. Med. Chem. Lett. 23 (2013) 934–938
Redwood, C.; Wells, N. J.; Hickson, I. D. Biochim. Biophys. Acta 1998, 1400, 121;
(c) Bromberg, K. D.; Burgin, A. B.; Osheroff, N. A. J. Biol. Chem. 2003, 278, 7406.
3. (a) Zunino, F.; Capranico, G. Anti-Cancer Drug Disc. 1990, 5, 307; (b) Nitiss, J. L.;
Liu, Y. X.; Harbury, P.; Jannatipour, M.; Wasserman, R.; Wang, J. C. Cancer Res.
1992, 52, 4467.
4. (a) Nitiss, J. L. Nat. Rev. Cancer 2009, 9, 338; (b) Wang, H. K.; Morris-Natschke, S.
L.; Lee, K. H. Med. Res. Rev. 1997, 17, 367.
5. Bailly, C. Chem. Rev. 2012, 112, 3611.
dium bromide), there was retardation in the migration of the DNA,
whereas, in the case of etoposide (DNA non-intercalator) and com-
pounds tested, there was no such retardation. These indicate that
these derivatives acted as DNA non-intercalators (Fig. 5A).
To determine whether the tested compounds are selective topo-
isomerase II inhibitors, topoisomerase I mediated relaxation as-
say16 was performed. As compared to camptothecin used as
positive standard, it was observed that the investigational com-
pounds did not show any topoisomerase I inhibitory activity
(Fig. 5B). These results imply that the investigational derivatives
6. (a) Baviskar, A. T.; Madaan, C.; Preet, R.; Mohapatra, P.; Jain, V.; Agarwal, A.;
Guchhait, S. K.; Kundu, C. N.; Banerjee, U. C.; Bharatam, P. V. J. Med. Chem. 2011,
54, 5013; (b) Guchhait, S. K.; Kundu, C. N.; Banerjee, U. C.; Baviskar, A.; Madaan,
C.; Agarwal, A.; Preet, R.; Mohapatra, P. Indian Patent 91/DEL/2011, 2011.
7. (a) Dong, Y.; Shi, Q.; Liu, Y. N.; Wang, X.; Bastow, K. F.; Lee, K. H. J. Med. Chem.
2009, 52, 3586; (b) Meunier, B. Acc. Chem. Res. 2008, 41, 69; (c) Müller-
Schiffmann, A.; März-Berberich, J.; Andreyeva, A.; Rönicke, R.; Bartnik, D.;
Brener, O.; Kutzsche, J.; Horn, A. H. C.; Hellmert, M.; Polkowska, J.; Gottmann,
K.; Reymann, K. G.; Funke, S. A.; Nagel-Steger, L.; Moriscot, C.; Schoehn, G.;
Sticht, H.; Willbold, D.; Schrader, T.; Korth, C. Angew. Chem., Int. Ed. 2010, 49,
8743; (d) Lenhart, J. A.; Ling, X.; Gandhi, R.; Guo, T. L.; Gerk, P. M.; Brunzell, D.
H.; Zhang, S. J. Med. Chem. 2010, 53, 6198; (e) Solary, E.; Leteurtre, F.; Paull, K.
D.; Scudiero, D.; Hamel, E.; Pommier, Y. Biochem. Pharmacol. 1993, 45, 2449.
8. (a) Bal, C.; Baldeyrou, B.; Moz, F.; Lansiaux, A.; Colson, P.; Kraus-Berthier, L.;
Léonce, S.; Pierré, A.; Boussard, M.-F.; Rousseau, A.; Wierzbicki, M.; Bailly, C.
Biochem. Pharmacol. 1911, 2004, 68; (b) Wierzbicki, M.; Boussard, M. F.;
Rousseau, A.; Boutin, J. A.; Delagrange, P. U.S. Patent 6844445 B2, 2005.; (c)
Ferlin, M. G.; Gatto, B.; Chiarelotto, G.; Palumbo, M. Bioorg. Med. Chem. 1843,
2001, 9; (d) Zagotto, G.; Oliva, A.; Guano, F.; Menta, E.; Capranico, G.; Palumbo,
M. Bioorg. Med. Chem. Lett. 1998, 8, 121; (e) Auclair, C.; Pierre, A.; Voisin, E.;
Pepin, O.; Cros, S.; Colas, C.; Saucier, J. M.; Verschuere, B.; Gros, P.; Paoletti, C.
Cancer Res. 1987, 47, 6254; (f) Mansour, O. C.; Evison, B. J.; Sleebs, B. E.; Watson,
K. G.; Nudelman, A.; Rephaeli, A.; Buck, D. P.; Collins, J. G.; Bilardi, R. A.; Phillips,
D. R.; Cutts, S. M. J. Med. Chem. 2010, 53, 6851; (g) Easmon, J.; Pürstinger, G.;
Thies, K.-S.; Heinisch, G.; Hofmann, J. J. Med. Chem. 2006, 49, 6343; (h) Huang,
H.; Chen, Q.; Ku, X.; Meng, L.; Lin, L.; Wang, X.; Zhu, C.; Wang, Y.; Chen, Z.; Li,
M.; Jiang, H.; Chen, K.; Ding, J.; Liu, H. J. Med. Chem. 2010, 53, 3048; (i) Ríos-Luci,
C.; Bonifazi, E. L.; León, L. G.; Montero, J. C.; Burton, G.; Pandiella, A.; Misico, R.
I.; Padrón, J. M. Eur. J. Med. Chem. 2012, 53, 26.
of indenoindolones are selective inhibitors of hTopoII
a while not
showing any inhibition of topoisomerase I and DNA intercalation.
In conclusion, the derivatives of indenoindolones as hydra-
zones, (thio)semicarbazones and oximes, and indenoindolols
showed potent topoisomerase II inhibition, while parent indenoin-
dolones are poor/moderate inhibitors of the enzyme. These deriv-
atives were non-intercalating to DNA and non-inhibitors of
topoisomerase I, and thus specific for binding to hTopoIIa. Such
derivatization of indenoindolones was found to be important for
inhibition of topoisomerase II and resulted in improvement of anti-
cancer activities. The compounds 17, 27, 29, 39 and 42 were found
to be most potent anticancer agents. They exhibited effective anti-
cancer activities compared to etoposide and 5-FU in kidney cancer
cells and low toxicity to normal cells. This work reveals that the
incorporation of relevant side chain/moiety in the natural/syn-
thetic scaffolds known for anticancer activity can provide en-
hanced topoisomerase II inhibition and cytotoxic activity.
Acknowledgment
9. Kashyap, M.; Das, D.; Preet, R.; Mohapatra, P.; Satapathy, S. R.; Siddharth, S.;
Kundu, C. N.; Guchhait, S. K. Bioorg. Med. Chem. Lett. 2012, 22, 2474.
10. (a) Guchhait, S. K.; Kashyap, M.; Kamble, H. J. Org. Chem. 2011, 76, 4753; (b)
Guchhait, S. K.; Kashyap, M. Synthesis 2012, 619; (c) Guchhait, S. K.; Kashyap,
M.; Kandekar, S. Tetrahedron Lett. 2012, 53, 3919.
We gratefully acknowledge the financial support from CSIR, DBT,
and ICMR, Government of India, New Delhi, for this investigation.
11. Wang, J. B.; Ji, Q. G.; Xu, J.; Wu, X. H.; Xie, Y. Y. Synth. Commun. 2005, 35, 581.
12. Ni, S.; Yuan, Y.; Huang, J.; Mao, X.; Lv, M.; Zhu, J.; Shen, X.; Pei, J.; Lai, L.; Jiang,
H.; Li, J. J. Med. Chem. 2009, 52, 5295.
Supplementary data
13. Jimenez-Alonso, S.; Orellana, H. C.; Braun, A. E.; Ravelo, A. G.; Sacau, E. P.;
Machin, F. J. Med. Chem. 2008, 51, 6761.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.12.
063.
14. (a) Mohapatra, P.; Preet, R.; Choudhuri, M.; Choudhuri, T.; Kundu, C. N. Oncol.
Res. 2011, 19, 311; (b) Preet, R.; Mohapatra, P.; Mohanty, S.; Sahu, S. K.;
Choudhuri, T.; Wyatt, M. D.; Kundu, C. N. Int. J. Cancer 2012, 130, 1660.
15. (a) Besterman, J. M.; Elwell, L. P.; Cragoe, E. J.; Andrews, C. W.; Cory, M. J. Biol.
Chem. 1989, 265, 2324; (b) Burres, N. S.; Sazesh, S.; Gunawardana, G. P.;
Clement, J. J. Cancer Res. 1989, 49, 5267.
References and notes
16. Haung, H.; Chen, Q.; Ku, X.; Meng, L.; Lin, L.; Wang, X.; Zhu, C.; Wang, Y.; Chen,
Z.; Li, M.; Jiang, H.; Chen, K.; Ding, J.; Liu, H. J. Med. Chem. 2010, 53, 3048.
1. Brown, P. O.; Cozzarelli, N. R. Science 1979, 1081, 206.
2. (a) Woessner, R. D.; Mattern, M. R.; Mirabelli, C. K.; Johnson, R. K.; Drake, F. H.
Cell Growth Differ. 1991, 2, 209; (b) Issacs, R. J.; Davies, S. L.; Sandri, M. I.;