Indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones: Synthesis, characterization and evaluation of anticancer and antimicrobial activities

Article abstract of DOI:10.1016/j.bmcl.2014.07.030

A series of novel 10-((1H-indol-3-yl)methylene)-7-aryl-7,10-dihydro-5H- benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-ones (8a-t) have been synthesized in good yields by the reaction of benzo[h]quinazoline-2(1H)-thiones (4a-f) with 2-chloro-N-phenylacetamide (5) followed by Knoevenagel condensation with various indole-3-carbaldehydes (7a-d) under conventional method. All the synthesized compounds were characterized by spectral studies and screened for their in vitro anticancer and antimicrobial activities. Compound 8c has exhibited excellent activity against MCF-7 (breast cancer cell line) than the standard drug Doxorubicin. Compound 8d against both the cancer cell lines, 8q against MCF-7 and 8c, 8h against HepG2 have also shown good activity. Remaining compounds have shown moderate activity against both the cell lines. Antimicrobial activity revealed that, the compound 8q and 8t against Staphylococcus aureus and 8i, 8k, 8l, 8q & 8t against Klebsiella pneumoniae have shown equipotent activity on comparing with the standard drug Streptomycin. Remaining compounds have shown significant antibacterial and comparable antifungal activities against all the tested microorganisms.

Full text of DOI:10.1016/j.bmcl.2014.07.030

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4239–4242
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones: Synthesis,
characterization and evaluation of anticancer and antimicrobial
activities
Rajitha Gali a, Janardhan Banothu a, Mahendar Porika b, Ravibabu Velpula a, Sairengpuii Hnamte c,
Rajitha Bavantula a, , Sadanandam Abbagani b, Siddhardha Busi c
⇑
a Department of Chemistry, National Institute of Technology, Warangal 506004, Telangana, India
b Department of Bio-Technology, Kakatiya University, Warangal 506009, Telangana, India
c Centre for Microbiology, School of Life Sciences, Pondicherry University, Puducherry 605014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 10-((1H-indol-3-yl)methylene)-7-aryl-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]quinaz-
olin-9(6H)-ones (8a–t) have been synthesized in good yields by the reaction of benzo[h]quinazoline-
2(1H)-thiones (4a–f) with 2-chloro-N-phenylacetamide (5) followed by Knoevenagel condensation with
various indole-3-carbaldehydes (7a–d) under conventional method. All the synthesized compounds were
characterized by spectral studies and screened for their in vitro anticancer and antimicrobial activities.
Compound 8c has exhibited excellent activity against MCF-7 (breast cancer cell line) than the standard
drug Doxorubicin. Compound 8d against both the cancer cell lines, 8q against MCF-7 and 8c, 8h against
HepG2 have also shown good activity. Remaining compounds have shown moderate activity against both
the cell lines. Antimicrobial activity revealed that, the compound 8q and 8t against Staphylococcus aureus
and 8i, 8k, 8l, 8q & 8t against Klebsiella pneumoniae have shown equipotent activity on comparing with
the standard drug Streptomycin. Remaining compounds have shown significant antibacterial and compa-
rable antifungal activities against all the tested microorganisms.
Received 16 April 2014
Revised 23 June 2014
Accepted 11 July 2014
Available online 17 July 2014
Keywords:
Anticancer activity
Antimicrobial activity
Indole-3-carbaldehyde
Thiazolo[2,3-b]quinazolinone
Ó 2014 Elsevier Ltd. All rights reserved.
Cancer is one of the deathliest diseases in the medical field
worldwide, characterized by uncontrolled, rapid, and pathological
proliferation of abnormal cells. It represents the second leading
cause of human mortality after cardiovascular diseases.1 According
to information from the World Health Organization (WHO), it is
estimated that there will be 12 million deaths from cancer in
2030. World statistics on cancers have revealed that hepatocarci-
noma is the sixth most common malignancy which is highly resis-
tant to chemotherapeutic treatment resulting in increased
mortality rates.2 Breast cancer is the most commonly diagnosed
malignant tumor in women and accounting for approximately
23% of all female cancers and the second most lethal cancer in
women worldwide today.3 Therefore, the search for potent, safe,
and selective anticancer compounds is a crucial aspect of modern
cancer research. On the other hand bacterial infections have
increased at an alarming rate causing deadly diseases. The treat-
ment of infectious diseases remains as an important issue because
of increasing number of multi-drug resistant microbial pathogens.4
Considering this, the development of newer chemotherapeutics
which selectively acts on the target without side effects has
become a primary objective of medicinal chemists.
Recently, thiazoloquinazolines have emerged as an important
target molecules due to their therapeutic and pharmacological
properties such as antibiofilm,5 anticancer,6 anticonvulsant,7 anti-
HSV-1,8 antitubercular,9 anti-inflammatory,10 antimicrobial,11
analgesic, antioxidant,12 antinociceptive,13 and antiparkinsonian14
activities. They also serve as inhibitors of Bcl-2 family proteins15
and CDC25B phosphatase enzymes.16 Indole ring system is one of
the most ubiquitous heterocycles in nature, with wide range of bio-
logical activities17 and also found as an active ingredient in various
drugs, pharmaceuticals, natural products and agrochemicals.18
Prompted by the above facts and in continuation of our work on
thiazoloquinazolines19 herein, we report the synthesis of novel
indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones and eval-
uated for their in vitro anticancer and antimicrobial activities.
Benzo[h]quinazoline-2(1H)-thiones (4a–f) which were obtained
by a modified Biginelli reaction involving 1-tetralone (1a, b),
arylaldehydes (2a–d) and thiourea (3) in the presence of poly
(4-vinylpyridinium)hydrogen sulfate,20 on cyclization with
⇑
Corresponding author. Tel.: +91 0870 2459445; fax: +91 0870 2459547.
E-mail address: rajitabhargavi@yahoo.com (R. Bavantula).
http://dx.doi.org/10.1016/j.bmcl.2014.07.030
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

4240
R. Gali et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4239–4242
Table 1
2-chloro-N-phenylacetamide (5) furnished benzo[h]thiazolo[2,3-
b]quinazolinones (6a–f).19 Compounds 6a–f on Knoevenagel con-
densation with various indole-3-carbaldehydes21 (7a–d) in ethanol
with catalytic amount of piperidine under reflux condition affor-
ded the title compounds (8a–t) in good yields (Table 1). The syn-
thetic pathway has shown in Scheme 1.
Structures of all the synthesized compounds were established
on the basis of their analytical and spectral studies. The appearance
of a broad band at 3400 cmÀ1 (indole NH stretching), a sharp band
at 1690 cmÀ1 (thiazole C@O stretching) and a medium band at
1634 cmÀ1 (pyrimidine C@N stretching) from IR spectrum, disap-
pearance of a multiplet at 4.01–4.12 ppm (thiazole –CH2– protons
of intermediate 6) and presence of a singlet at 8.00 ppm (indolylm-
ethylene @CHA proton) from the 1H NMR spectrum, and appear-
ance of a signal at 138.99 ppm (indolylmethylene @CHA carbon)
from 13C NMR confirmed the formation of product (8g). Molecular
ion peak from the mass spectrum as well as elemental analysis fur-
ther confirmed the formation of the product (8g).
In vitro anticancer activity was carried out against human
breast cancer cell line (MCF-7) and hepatocellular liver carcinoma
cell line (HepG2). Doxorubicin was used as a reference drug. Cell
viability in the presence of the test samples were measured by
the MTT-microcultured tetrazolium assay.22 The relationship
between surviving fraction and drug concentration was plotted
to obtain the survival curve of MCF-7 and HepG2 (Fig. 1). The
response parameter calculated was the IC50 value, which
Synthesis of indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones (8a–t)a
Analog
R
R1
R2
R3
R4
Time (h)
Yieldb (%)
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
OCH3
OCH3
OCH3
OCH3
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
OCH3
OCH3
OCH3
OCH3
Cl
Cl
Cl
OCH3
Cl
Cl
Cl
Cl
OCH3
H
H
H
H
OCH3
OCH3
H
F
F
H
H
H
H
H
H
H
H
H
CH3
H
H
CH3
H
H
H
H
CH3
H
H
H
CH3
H
H
H
H
CH3
H
H
H
Br
Br
H
H
OCH3
Br
H
H
CH3
Br
H
H
OCH3
H
Br
OCH3
H
H
3.5
3.5
3.0
2.0
3.5
4.0
3.0
2.5
3.0
3.0
3.5
2.0
2.5
3.0
2.5
3.0
2.0
3.0
2.5
3.0
80
78
82
84
77
75
79
84
79
76
79
85
76
80
83
79
87
81
82
80
H
NO2
NO2
NO2
NO2
H
H
NO2
H
H
H
H
8s
8t
F
F
a
Reaction conditions: Benzo[h]thiazolo[2,3-b]quinazolinones (6a–f, 1 mmol),
1H-indole-3-carbaldehyde (7a–d, 1 mmol), ethanol (10 mL) and piperidine (cat.),
reflux.
b
Isolated yields.
R1
R
R2
S
+
+
H2N NH2
O
CHO
3
1(a,b)
2(a-d)
(i)
R1
R1
R1
R2
R2
R2
O
O
(iii)
NH
(ii)
N
N
R4
S
S
N
H
S
N
N
R3
R
R
N
H
R
8(a-t)
4(a-f)
6(a-f)
Scheme 1. Synthesis of indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones (8a–t). Reaction conditions: (i) P(4-VPH)HSO4 (0.015 g), solvent-free, 120 °C, 10–20 min
(yield: 88–94%); (ii) 2-chloro-N-phenylacetamide (5), acetic acid, reflux, 4–6 h (yield: 64–73%); (iii) 1H-indole-3-carbaldehyde (7a–d), ethanol, piperidine (cat.) reflux, 2–4 h
(yield: 75–87%).
Figure 1. Survival curves of MCF-7 and HepG2 for indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones (8a–t).

R. Gali et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4239–4242
4241
Table 2
HepG2 have exhibited promising activity with IC50 values ranging
from 16.26 to 94.53 M. Remaining compounds have shown mod-
erate activity against both the cell lines.
Inhibition values (IC50) of indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones
(8a–t) on human tumor cell lines MCF-7 and HepG2
l
Entry
Product
MCF-7 (IC50
)
HepG2 (IC50)
All the synthesized compounds were screened for their in vitro
antibacterial activity against Staphylococcus aureus, Streptococcus
pyogenes (Gram-positive), Pseudomonas aeruginosa and Klebsiella
pneumoniae (Gram-negative) bacterial strains, and in vitro anti-
fungal activity against Candida albicans, Candida glabrata, Aspergil-
lus niger and Aspergillus parasiticus fungal strains using agar well
diffusion method.23 Streptomycin for bacteria and Clotrimazole
for fungi are taken as standard drugs.
Antibacterial activity results (Table 3) revealed that, the com-
pounds possessing 4-fluoro phenyl on pyrimidine ring and 5-
bromo indol-3-ylmethylene/indol-3-ylmethylene on thiazole ring,
that is, 8q and 8t have shown excellent activity against gram-posi-
tive bacterial strain S. aureus and gram-negative bacterial strain P.
aeruginosa on comparing with the standard drug Streptomycin.
These compounds (8q & 8t) have also shown good activity against
K. pneumoniae. Similarly, compounds 8e & 8f against P. aeruginosa,
8i–l against both gram positive bacterial strains and 8k,8l against
K. pneumoniae have shown good activity. Remaining compounds
have shown moderate activity against all the tested bacterial
strains. From the antifungal activity results (Table 3) we noticed
that, the compound possessing 3-nitro phenyl on pyrimidine ring
and 2-methyl-5-bromo indol-3-ylmethylene on thiazole ring (8j)
is highly active against A. niger on comparing with the standard
drug Clotrimazole. Remaining compounds are moderately active
against all the tested fungal strains with ZOI ranging from 8 to
20 mm.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
23.53
61.90
2.59
34.91
38.76
11.55
8.60
7.72
166.45
42.83
20.74
18.85
54.36
>200
>200
>200
>200
112.46
30.62
>200
8.96
69.84
16.26
27.65
13.73
61.11
94.53
51.62
>200
70.26
>200
57.52
199
8q
8r
8s
8t
22.1
192.78
82.41
67.34
3.00
86.75
73.77
25.82
1.10
Doxorubicin
corresponds to the concentration required for 50% inhibition of cell
viability (Table 2).
Activity results (Table 2) revealed that, the compound derived
from 6-methoxy-1-tetralone, 4-chloro benzaldehyde and 5-bromo
indole-3-carbaldehyde, that is, 8c has exhibited excellent activity
against MCF-7 (IC50 2.59
drug Doxorubicin (IC50 3.00
cancer cell lines (IC50 7.72 & 8.60
8.96 M) and 8c, 8h against HepG2 (8c: IC50 11.55
13.73 M) have shown good activity. Compounds 8a,b, 8f–i, 8o,
l
M, 1.15 fold potent) than the standard
M). Compound 8d against both the
M), 8q against MCF-7 (IC50
M; 8h:
In conclusion, we have synthesized a series of novel indolylm-
ethylene benzo[h]thiazolo[2,3-b]quinazolinones via Knoevenagel
condensation of benzo[h]thiazolo[2,3-b]quinazolinones with vari-
ous indole-3-carbaldehydes under conventional method in good
yields. All the compounds were screened for their in vitro antican-
cer and antimicrobial activities. Among the series, compound 8c
l
l
l
l
l
8s,t against MCF-7 and 8a,b, 8e–g, 8i–k, 8m, 8o, 8q–t against
Table 3
Antimicrobial activity of indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones (8a–t)
Analog
Antibacterial activity
S. pyogenes P. aeruginosa
Antifungal activity
S. aureus
K. pneumoniae
C. albicans
C. glabrata
A. niger
A parasiticus
ZOI
MIC
ZOI
MIC
ZOI
MIC
ZOI
MIC
ZOI
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8
8
8
8
13
12
14
13
17
16
17
19
8
8
8
8
22
8
13
21
22
—
200
200
200
200
100
100
100
100
50
8
8
8
8
8
8
8
8
18
15
17
16
8
8
8
8
8
200
200
200
200
200
200
200
200
50
8
8
8
8
17
18
14
15
8
13
8
8
8
8
8
8
22
8
13
21
20
—
200
200
200
200
50
8
8
8
8
8
8
8
8
15
14
17
17
8
8
8
8
200
200
200
200
200
200
200
200
50
8
8
8
8
16
8
15
8
18
17
8
8
8
8
8
8
8
8
8
14
8
8
8
10
12
10
10
14
12
18
8
18
18
8
10
8
10
10
12
8
10
8
10
—
20
10
12
19
12
16
10
20
14
12
8
8
8
8
10
10
10
8
8
—
10
8
14
12
18
8
18
20
8
10
12
8
14
12
8
10
12
10
—
50
100
100
200
100
200
200
200
200
200
200
25
200
100
25
12.5
—
50
50
50
50
50
50
100
50
50
200
200
200
200
25
200
100
25
200
200
200
200
200
200
200
200
12.5
—
200
200
200
200
50
100
100
50
8q
8r
8s
8t
18
15
16
17
22
—
8
8
8
21
—
8
—
24
Streptomycin
Clotrimazole
25
—
50
—
22
20
Zone of inhibition values (mm) for analogs (8a–t) and positive control drugs (Streptomycin and Clotrimazole) were measured at 150 and 30
were given in g/mL.
lg/mL, respectively. MIC values
l
Bacterial strains: S. aureus—Staphylococcus aureus, S. pyogenes—Streptococcus pyogenes, P. aeruginosa—Pseudomonas aeruginosa and K. pneumoniae—Klebsiella pneumonia.
Fungal strains: C. albicans—Candida albicans, C. glabrata—Candida glabrata, A. niger—Aspergillus niger, A. parasiticus—Aspergillus parasiticus.
‘—’ Not performed.

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R. Gali et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4239–4242
5. Pan, B.; Huang, R.; Zheng, L.; Chen, C.; Han, S.; Qu, D.; Zhu, M.; Wei, P. Eur. J.
Med. Chem. 2011, 46, 819.
bearing 4-chlorophenyl on pyrimidine ring and 5-bromo indol-3-
ylmethylene on thiazole ring has shown 1.15 fold potent activity
against breast cancer cell line-MCF-7 than the standard drug Doxo-
rubicin, remaining compounds have shown moderate activity
against both MCF-7 and HepG2 cell lines. Compounds 8q and 8t
bearing 4-fluoro phenyl on pyrimidine ring and 5-bromo indol-3-
ylmethylene/indol-3-ylmethylene on thiazole ring have shown
equipotent antibacterial activity against S. aureus whereas com-
pound 8j bearing 3-nitrophenyl on pyrimidine ring and 2-
methyl-5-bromo indol-3-ylmethylene on thiazole ring has shown
good antifungal activity against A. niger. These results are suggest-
ing that the synthesized compounds can be better candidates for
future investigations.
6. (a) Holla, B. S.; Rao, B. S.; Sarojini, B. K.; Akberali, P. M. Eur. J. Med. Chem. 2004,
39, 777; (b) Flefel, E. E.; Salama, M. A.; El-Shahat, M.; El-Hashash, M. A.; El-
Farargy, A. F. Phosphorus, Sulfur Silicon Relat. Elem. 2007, 182, 1739.
7. Nehad, A. A.; Abd El-Galil, E. A.; Alhusain, A. I. Monatsh. Chem. 2007, 138, 559.
8. Mohamed, S. F.; Flefel, E. M.; Ael-G, A.; Abd El-Shafy, D. N. Eur. J. Med. Chem.
2010, 45, 1494.
9. Selvam, T. P.; Palanirajan, V. J. Malay. J. Pharm. Sci. 2010, 8, 45.
10. (a) Tozkoparan, B.; Ertan, M.; Kelicen, P.; Demirdamar, R., II Farmaco 1999, 54,
588; (b) Ramesh, L. S.; Charusheela, A. B.; Jyoti, B. W. Med. Chem. Res. 2013, 22,
1884.
11. Ashok, M.; Holla, B. S.; Kumari, N. S. Eur. J. Med. Chem. 2007, 42, 380.
12. Maddila, S.; Damu, G. L. V.; Oseghe, E. O.; Abafe, O. A.; Venakata Rao, C.;
Lavanya, P. J. Korean Chem. Soc. 2012, 56, 334.
13. Ozair, A.; Suroor, A. K.; Nadeem, S.; Waquar, A. Med. Chem. Res. 2010, 19, 1245.
14. Abd El-Galil, E. A.; Maigali, S. S.; Abdulla, M. M. Monatsh. Chem. 2008, 139, 1409.
15. Feng, Y.; Ding, X.; Chen, T.; Chen, L.; Liu, F.; Jia, X.; Luo, X.; Shen, X.; Chen, K.;
Jiang, H.; Wang, H.; Liu, H.; Liu, D. J. Med. Chem. 2010, 53, 3465.
16. Kolb, S.; Mondesert, O.; Goddard, M. L.; Jullien, D.; Villoutreix, B. O.;
Ducommun, B.; Garbay, C.; Braud, E. Chem. Med. Chem. 2009, 4, 633.
17. (a) Andreani, A.; Burnelli, S.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.;
Rambaldi, M.; Varoli, L.; Calonghi, N.; Cappadone, C.; Voltattorni, M.; Zini, M.;
Stefanelli, C.; Masotti, L.; Shoemaker, R. H. J. Med. Chem. 2008, 51, 7508; (b)
Penthala, N. R.; Yerramreddy, T. R.; Crooks, P. A. Bioorg. Med. Chem. Lett. 2011,
21, 1411; (c) Vikas, S.; Pradeep, K.; Devender, P. J. Heterocycl. Chem. 2010, 47,
491.
Acknowledgment
The authors R.G. and R.V. are thankful to the University Grant
Commission (UGC) New Delhi, for financial assistance.
Supplementary data
18. (a) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.; Verma, A. K.;
Choi, E. H. Molecules 2013, 18, 6620; (b) Won, C.; Shen, X. L.; Mashiguchib, K.;
Zheng, Z.; Dai, X. H.; Cheng, Y. F.; Kasahara, H.; Kamiya, Y.; Chory, J.; Zhao, Y. D.
Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 18518; (c) Abdel-Motaleb, R. M.;
Makhloof, A.-M. A.; Ibrahim, H. M.; Elnagdi, M. H. J. Heterocycl. Chem. 2007,
44, 109; (d) Moth, C. W.; Prusakiewicz, J. J.; Marnett, L. J.; Lybrand, T. P. J. Med.
Chem. 2005, 48, 3613; (e) Chen, F. E.; Huang, J. Chem. Rev. 2005, 105, 4671; (f)
Ishikawa, H.; Colby, D. A.; Boger, D. L. J. Am. Chem. Soc. 2008, 130, 420.
19. Janardhan, B.; Srinivas, B.; Rajitha, B.; Crooks, P. A. Tetrahedron Lett. 2014, 55,
224.
20. Janardhan, B.; Rajitha, B.; Crooks, P. A. J. Saudi Chem. Soc. 2012. http://
dx.doi.org/10.1016/j.jscs.2012.10.007.
21. (a) Smith, G. F. J. Chem. Soc. 1954, 3842; (b) Gurkan, A. S.; Karabay, A.;
Buyukbingol, Z.; Adejare, A.; Buyukbingol, E. Arch. Pharm. Chem. Life Sci. 2005,
338, 67.
22. (a) Denizot, F.; Lang, R. J. Immunol. Methods 1986, 89, 271; (b) Myadaraboina, S.;
Alla, M.; Saddanapu, V.; Bommena, V. R.; Addlagatta, A. Eur. J. Med. Chem. 2010,
45, 5208; (c) Upadhyaya, R. S.; Vandavasi, J. K.; Rao, V. N.; Vivek, S.; Dixit, S. S.;
Chattopadhyaya, J. Bioorg. Med. Chem. 2009, 17, 2830.
23. (a) Mert, S.; Kasimogullari, R.; Ica, T.; Colak, F.; Altun, A.; Ok, S. Eur. J. Med.
Chem. 2014, 78, 86; (b) Kaviya, S.; Santhanalakshmi, J.; Viswanathan, B.;
Muthumary, J.; Srinivasan, K. Spectrochim. Acta Part A Mol. Biomol. Spectrosc.
2011, 79, 594; (c) Aruna, J. K.; Arunachalam, J. World J. Microbiol. Biotechnol.
2011, 27, 1209.
Supplementary data (experimental procedures and character-
ization data of compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.bmcl.2014.07.030.
References and notes
1. (a) Bach, P. B.; Jett, J. R.; Pastorino, U.; Tockman, M. S.; Swensen, S. J.; Begg, C. B.
JAMA 2007, 297, 953; (b) Gibbs, J. B. Science 2000, 287, 1969; (c) Canadian
Cancer Statistics. Canadian Cancer Society, Toronto, Canada, 2011.; (d) Arve, L.;
Voigt, T.; Waldmann, H. QSAR Comb. Sci. 2006, 25, 449.
2. (a) Ahmedin, J.; Freddie, B.; Melissa, M. C.; Jacques, F.; Elizabeth, W.; David, F.
CA Cancer J. Clin. 2011, 61, 69; (b) Parkin, D. M.; Bray, F.; Ferlay, J.; Pisani, P. CA
Cancer J. Clin. 2005, 55, 74; (c) Mulcahy, M. F. Curr. Treat. Options Oncol. 2005, 6,
423; (d) Whittaker, S.; Marais, R.; Zhu, A. X. Oncogene 2010, 29, 4989.
3. (a) Sorlie, T. Eur. J. Cancer 2004, 40, 2667; (b) Labrie, F.; Labrie, C.; Belanger, A.;
Simard, J.; Gauthier, S.; Luu-The, V.; Merand, Y.; Giguere, V.; Candas, B.; Luo, S.;
Martel, C.; Singh, S. M.; Fournier, M.; Coquet, A.; Richard, V.; Charbonneau, R.;
Charpenet, G.; Tremblay, A.; Tremblay, G.; Cusan, L.; Veilleux, R. J. Steroid
Biochem. Mol. Biol. 1999, 69, 51; (c) Siegel, R.; Ward, E.; Brawley, O.; Jemal, A. CA
Cancer J. Clin. 2011, 61, 212.
4. (a) Muroi, H.; Nihei, K.; Tsujimoto, K.; Kubo, I. Bioorg. Med. Chem. 2004, 12, 583;
(b) Pfeltz, R. F.; Wilkinson, B. J. Curr. Drug Targets Infect. Disord. 2004, 4, 273; (c)
Tenover, F. C.; McDonald, L. C. Curr. Opin. Infect. Dis. 2005, 18, 300.