Design, synthesis, and antitumor screening of certain novel tetrahydroquinoline sulfonamides

Article abstract of DOI:10.3109/14756366.2014.899595

Sulfonamide containing molecules are of sound biomedical interest. This work comprises the synthesis and in vitro antitumor testing of new library of 20 such molecules. These compounds were screened for cytotoxic activity against three tumor cell lines MC

Full text of DOI:10.3109/14756366.2014.899595

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ISSN: 1475-6366 (print), 1475-6374 (electronic)
J Enzyme Inhib Med Chem, Early Online: 1–6
2014 Informa UK Ltd. DOI: 10.3109/14756366.2014.899595
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RESEARCH ARTICLE
Design, synthesis, and antitumor screening of certain novel
tetrahydroquinoline sulfonamides
Ahmed M. Alafeefy
Department of Pharmaceutical Chemistry, College of Pharmacy, Salman Bin Abdulaziz University, Alkharj, Saudi Arabia
Abstract
Keywords
Sulfonamide containing molecules are of sound biomedical interest. This work comprises the
synthesis and in vitro antitumor testing of new library of 20 such molecules. These compounds
were screened for cytotoxic activity against three tumor cell lines MCF-7, HeLa, and HepG2
using MTT assay. The yield was low but all the target compounds exhibited antiproliferative
activity better than the standard drug Doxorubicin (CAS-23214-92-8). Seven compounds were
more potent and four compounds were as active as the standard drug. There were no great
difference between compounds obtained from dimedone and those obtained from
cyclohexandione. Also no significant difference found in activity between compounds bearing
o-amino ethyl ester side chain and compounds bearing o-amino amide derivatives. However,
compounds bearing o-amino-cyano group, although retained considerable activity they were
far less active than the preceding two. It was clear that monohydroxy aldehyde derivatives were
less active compared with the di and trihydroxy ones.
Antitumor, sulfonamide, synthesis,
tetrahydroquinoline
History
Received 7 February 2014
Accepted 24 February 2014
Published online 25 March 2014
Introduction
Our interest was to develop a series of some small molecules
as potential multi-targeted agents that can block biologically
relevant molecular targets. In this application, we prepared certain
quinoline containing sulfonamide pharmacophores and/or their
isosteres. The quinoline core has been shown to be a suitable
carrier that allows for an effective DNA intercalation. In that
context, several quinoline derivatives have been shown to exhibit
high affinity for receptor tyrosine kinases (RTKs), as well as other
oncogenic targets, and to possess remarkable antitumor activity
Tumor growth and metastasis depend on multiple factors,
including several physiological processes. For example, elevated
expression of different growth factors is associated with tumor
angiogenesis, metastases, survival, and resistance to apoptosis1–3
.
Therefore, these growth factors have represented potential
molecular targets for inhibition of tumor growth and progression.
Mono-targeted therapies have in many cases shown clinical utility
with many drawbacks. This is because tumors harbor manyirre-
gular growth, survival, invasion, and metastasis pathways, which
may develop during the course of treatment4. In addition, data
accumulate that substantial levels of cross talk exist within and
between signaling networks in most tumors, necessitating the
combined inhibition of multiple targets in order to establish
efficient tumor growth inhibition5. Consequently, cell signaling
network models indicate that partial inhibition of a number of
targets is more effective than the complete inhibition of a single
target6. Therefore, various tactics were followed to inhibit
multiple steps by the development of multi-targeted drugs or
the combination of single targeted agents. The use of a
combination of different compounds can introduce adverse effects
related to pharmacokinetics, toxicity, and patient compliance.
Alternatively, the use of multi-targeted agents can avoid most of
the problems due to combination therapy7.
both in vitro and in vivo1–7
.
Many new sulfonamide derivatives, such as HMN-214,
E7010 (ABT-751), and E7070 (Indisulam), have shown substan-
tial antitumor activity via different mechanisms as multidrug
resistance down-regulation, tubulin polymerization, inhibition
of receptor tyrosine kinases (RTKs) among others8–21
.
Recently, the mechanism of sulfonamide antitumor activity
has been reported to involve inhibition of carbonic anhydrase
(CA) isoforms IX and XII19–21. Therefore, in this work,
we will prepare some acrylamide containing sulfonamide
derivatives and will study their activity against some selected
cell lines.
We proposed that the quinoline backbone will act as a carrier
for the sulfonamide moiety, and being selectively trapped within
cancerous cells, it will target other oncogenic targets, as RTKs
(Scheme 1).
Experimental protocols
Chemistry
Address for correspondence: Ahmed M. Alafeefy, Department of
Pharmaceutical Chemistry, College of Pharmacy, Salman Bin
Abdulaziz University, P.O. Box 173, Alkharj 11942, Saudi Arabia. Tel:
+966 50 706 9896. E-mail: a.alafeefy@sau.edu.sa
All reactions were performed in an efficient fume hood. Solvents
and reagents were purchased from commercial sources and
were used without further purification. Melting points

2
A. M. Alafeefy
J Enzyme Inhib Med Chem, Early Online: 1–6
R2
Scheme 1. Synthesis of the target tetra-
hydroquinoline derivatives 16–23.
R3
O
R1
O
O
NH2
R
R
NH
aldehyde /
ethanol
+
ethanol/TEA
NC
N
O
NH2
SO2NH2
4-15
1
3
SO2NH2
2
SO2NH2
R1
R2
R3
O
O
O
O
NH2
O
R
R
ethanol
aldehyde /
ethanol/TEA
+
NH
NC
O
N
NH2
SO2NH2
1a
2
16-23
3a
SO2NH2
R
R
R
R
3
1
2
SO2NH2
4
5
6
7
8
CO Et
CONH
CN
H
H
H
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
H
2
R
R
R
R
1
2
3
2
2
2
2
16
17
18
19
20
21
22
H
H
OH
OH
OH
OH
OEt
NH
OEt
NH
OEt
NH
OEt
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
CO Et
OH
OH
OH
OH
OH
OH
OCH
OCH
OCH
2
2
CONH
CN
H
9
10
H
2
OH
OH
H
CO Et
OH
OH
OH
H
H
H
2
11 CONH
12 CN
13 CO Et
14 CONH
15 CN
2
OCH
OCH
3
3
23 NH
H
2
2
3
3
3
Experimental Protocols
(ꢀC, uncorrected) were determined in open capillaries on a 4-(3-Oxo-5,5-dimethylcyclohex-1-enylamino)benzenesul-
Gallenkamp melting point apparatus (Sanyo Gallenkamp, fonamide (3)
Southborough, UK) and were uncorrected. Precoated silica gel
Yield: 82%, M.P.: 164–66 ꢀC. IR, u (cmꢁ1): 3411, 3326
plates (silica gel 0.25 mm, 60 G F254; Merck, Darmstadt,
(SO2NH2), 3063 (Ar-CH), 2947 (Aliph. CH), 1758 (C¼O).
Germany) were used for thin layer chromatography, dichloro-
1H NMR (DMSOd6): ꢀ 1.12 (s, 6H, 2CH3), 1.42 (s, 2H, CH2),
methane/methanol (9.5:0.5) mixture was used as a developing
2.39 (s, 2H, CH2), 2.51 (s, 2H, CH2), 6.14 (s, 2H, SO2NH2), 7.20
solvent system and the spots were visualized by ultraviolet light
(d, J ¼ 7.5 Hz, 2H, H-3 and H-5, C6H4SO2), 7.58 (d, J ¼ 7.5 Hz,
and/or iodine. Infra red spectra were recorded in KBr discs
2H, H-2 and H-6, C6H4SO2). 13C NMR: ꢀ 27.8 (2CH3), 32.2
using IR-470 Shimadzu spectrometer (Shimadzu, Tokyo, Japan).
(C(CH3)2), 42.0, 50.0, (2CH2), 98.6 (vinyl ¼ CH), 112.4, 127.4,
129.9, 151.8, 158.8 (Ar-C), 196.2 (C¼O). MS m/z (Rel. Int.): 294
(M+, 67). Anal. (C14H18N2O3S), Calcd/Found C: 57.12 (56.88);
H: 6.16 (5.92); N: 9.52 (9.75); S: 10.89 (11.08).
1H NMR spectra (DMSO-d6) were acquired at ambient tempera-
tures on Bruker AC-300 Ultra Shield NMR spectrometer
(Bruker, Flawil, Switzerland, d ppm) at 300 MHz for 1H and
75 MHz for 13C, using TMS as internal standardand peak
multiplicities are designed as follows: s-singlet; d-doublet; t-
triplet and m-multiplet. Electron impact Mass Spectra were
recorded on a Shimadzu GC-MS-QP 5000 instrument (Shimadzu,
4-[2-Amino-3-substituted-4-aryl-5-oxo-5,6,7,8-tetrahydro-
quinolin-1(4H)-yl]benzene sulfonamide (4–23)
Tokyo, Japan). Elemental analyses were performed on Carlo Erba A mixture of compound 3 (2.66 g, 0.01 mol) the appropriate
1108 Elemental Analyzer (Heraeus, Hanau, Germany) at the aldehyde (0.01 mol) and the active methylene component
Microanalytical Unit, Faculty of Science, Cairo University, Cairo, (0.01 mol) in absolute ethanol (30 mL) containing three drops of
Egypt, and the results were within 0.4% of the theoretical triethylamine, was refluxed for 5 h. The solid obtained after
values.
concentration and cooling, was filtered, and crystallized from
1-butanol to give 4–23, respectively.
General procedures for the preparation of compounds
4-(3-oxo-5,5-dimethylcyclohex-1-enylamino)benzenesul-
fonamide (3) and 4-(3-oxo-cyclohex-1-enylamino)benzene
sulfonamide (3a)
4-[2-Amino-3-(ethoxycarbonyl)-4-(4-hydroxyphenyl)-
5-oxo-5,6,7,8-tetrahydro-7,7-dimethyl quinolin-1(4H)-
yl]benzenesulfonamide (4)
A
cyclohexane-1,3-dione 1a (0.01 mol) and sulfanilamide
(1.72 g, 0.01 mol) in ethanol (30 mL) was refluxed for 3 h. 1736 (2C¼O). H NMR (DMSOd6): ꢀ 1.01 (s, 6H, 2CH3), 1.23
The reaction mixture was cooled and then poured onto cold (t, J ¼ 2.8 Hz,3H, CH3), 1.90 (s, 2H, CH2),2.31 (s, 2H, CH2), 4.27
water and the obtained solid was crystallized from ethanol to give (q, 2H, CH2), 4.55 (s, 1H, CH), 5.39 (s, 1H, OH), 6.13 (s, 2H,
3 and/or 3a22.
mixture of 5,5-dimethylcyclohexane-1,3-dione
1
and/or Yield: 20%, M.P.: 157–59 ꢀC. IR, u (cmꢁ1): 3452, 3381, 3264
(OH, NH2, SO2NH2), 3061 (Ar-CH), 2965 (Aliph. CH), 1754,
2
1
SO2NH2),6.77–7.60 (m, 8H, Ar-H), 8.31 (s, 2H, NH2). 13C NMR:

DOI: 10.3109/14756366.2014.899595
Synthesis and in vitro antitumor testing of 20
3
ꢀ15.1,23.5, 35.2, 38.5, 45.7,55.0, 62.6 (CH and CH2,CH3), 86.2, 4-[2-Amino-3-(ethoxycarbonyl)-4-(3,4-dihydroxyphenyl)-
114.5, 126.3, 128.0, 128.4, 133.7,136.5, 142.0, 144.9, 147.2 5-oxo-5,6,7,8-tetrahydro-7,7-dimethylquinolin-1(4H)-
(Ar-C), 166.7,181.5 (2C¼O). MS m/z (Rel. Int.): 511 (M+, 34). yl]benzenesulfonamide (9)
Anal. (C26H29N3O6S), Calcd/Found C: 61.04 (61.27); H: 5.71
Yield: 23%, M.P.: 294–96 ꢀC. IR, u (cmꢁ1): 3450, 3383, 3265 (OH,
NH2, SO2NH2), 3063 (Ar-CH), 2961 (Aliph. CH), 2228 (CꢂN),
(5.54); N: 8.21 (8.47); S: 6.27 (6.09).
1
1748 (C¼O). H NMR (DMSOd6): ꢀ 1.03 (s, 6H, 2CH3), 1.87
4-[2-Amino-3-(aminocarbonyl)-4-(4-hydroxyphenyl)-
5-oxo-5,6,7,8-tetrahydro-7,7-dimethylquinolin-1(4H)-
yl]benzenesulfonamide (5)
(s, 2H, CH2), 2.61 (s, 2H, CH2), 4.46 (s, 1H, CH), 5.60 (s, 2H,
2OH), 6.16 (s, 2H, SO2NH2), 6.76–7.62 (m, 7H, Ar-H), 8.47 (s, 2H,
NH2). 13C NMR: ꢀ 26.8, 33.8, 38.5, 40.9, 51.4 (CH, CH2, CH3),
Yield: 20%, M.P.: 273–75 ꢀC. IR, u (cmꢁ1): 3409, 3372, 3258 58.7 (C-CN), 112.3, 116.3, 116.8, 117.4, 124.0, 128.1, 129.4,
(OH, NH2, SO2NH2), 3055 (Ar-CH), 2965 (Aliph. CH), 1751, 135.9, 144.9, 145.2, 147.1, 153.8, 162.3 (Ar-C), 196.0 (C¼O). MS
1738 (2C¼O). H NMR (DMSOd6): ꢀ 1.04 (s, 6H, 2CH3), 1.89 m/z (Rel. Int.): 480 (M+, 47). Anal. (C24H24N4O5S), Calcd/Found:
1
(s, 2H, CH2), 2.33 (s, 2H, CH2), 4.54 (s, 1H, CH), 5.42 (s, 1H, C, 59.99 (60.27); H, 5.03 (4.77); N, 11.66 (11.92); S, 6.67 (6.95).
OH), 6.11 (s, 2H, SO2NH2), 6.78–7.60 (m, 10H, Ar-H, NH2), 8.32
(s, 2H, NH2). 13C NMR: ꢀ 26.5, 33.2, 38.5, 44.3, 52.1 (CH, CH2,
CH3), 81.8, 110.5, 115.2, 117.0, 130.0, 130.4, 130.9, 137.3, 153.1,
4-[2-Amino-3-(aminocarbonyl)-4-(3,4-dihydroxyphenyl)-
5-oxo-5,6,7,8-tetrahydro-7,7-dimethylquinolin-1(4H)-
yl]benzenesulfonamide (10)
155.7, 159.3 (Ar-C), 176.4, 194.1 (2C¼O). MS m/z (Rel. Int.):
482 (M+, 61). Anal. (C24H26N4O5S), Calcd/Found: C, 59.74
(59.49); H, 5.43 (5.15); N, 11.61 (11.39); S, 6.64 (6.85).
Yield: 28%, M.P.: 273–75 ꢀC. IR, u (cmꢁ1): 3447, 3378, 3267
(OH, NH2, SO2NH2), 3067 (Ar-CH), 2958 (Aliph. CH), 1769,
1
1747 (2C¼O). H NMR (DMSOd6): ꢀ1.13 (s, 6H, 2CH3), 1.25
4-[2-Amino-3-cyano-4-(4-hydroxyphenyl)-5-oxo-5,6,7,8-
tetrahydro-7,7-dimethyl quinolin-1(4H)-yl]benzenesulfo-
namide (6)
(t, J ¼ 2.7 Hz, 3H, CH3), 1.88 (s, 2H, CH2), 2.68 (s, 2H, CH2),
4.28 (q, J ¼ 4.2 Hz, 2H, CH2), 4.55 (s, 1H, CH), 5.53 (s, 3H,
3OH), 5.96 (s, 2H, Ar-H), 6.18 (s, 2H, SO2NH2), 6.91–7.53 (m,
4H, Ar-H), 8.39 (s, 2H, NH2). 13C NMR: ꢀ 14.6, 26.4, 32.6, 39.9,
40.5, 52.1, 62.4 (CH and CH2, CH3), 81.5, 109.4, 112.3, 116.8,
127.6, 130.0, 134.2, 137.5, 144.3, 149.0, 152.8, 159.3 (Ar-C),
164.9, 196.5 (2C¼O). MS m/z (Rel. Int.): 543 (M+, 38). Anal.
(C26H29N3O8S), Calcd/Found: C, 57.45 (57.14); H, 5.38 (5.09);
N, 7.73 (7.52); S, 5.90 (5.66).
Yield: 23%, M.P.: 281–83 ꢀC. IR, u (cmꢁ1): 3452, 3381, 3264
(OH, NH2, SO2NH2), 3061 (Ar-CH), 2969 (Aliph. CH), 2234
(CꢂN), 1749 (C¼O). 1H NMR (DMSOd6): ꢀ 1.06 (s, 6H, 2CH3),
1.86 (s, 2H, CH2), 2.64 (s, 2H, CH2), 4.47 (s, 1H, CH), 5.61
(s, 1H, OH), 6.14 (s, 2H, SO2NH2), 6.79–7.63 (m, 8H, Ar-H), 8.41
(s, 2H, NH2). 13C NMR: ꢀ 26.9, 33.5, 38.2, 40.7, 51.4(CH, CH2,
CH3), 58.1 (C-CN), 111.4, 115.2, 116.5, 117.1, 128.3, 129.5,
130.5, 134.6, 145.1, 153.6, 160.9 (Ar-C), 195.1 (C¼O). MS m/z
(Rel. Int.): 464 (M+, 47). Anal. (C24H24N4O4S), Calcd/Found: C,
62.05 (61.79); H, 5.21 (4.98); N, 12.06 (11.85); S, 6.90 (7.14).
4-[2-Amino-3-cyano-4-(3,4-dihydroxyphenyl)-
5-oxo-5,6,7,8-tetrahydro-7,7-dimethyl quinolin-1(4H)-
yl]benzenesulfonamide (11)
Yield: 25%, M.P.: 4300 ꢀC. IR, u (cmꢁ1): 3405, 3362, 3267
(OH, NH2, SO2NH2), 3067 (Ar-CH), 2968 (Aliph. CH), 1751,
4-[2-Amino-3-(ethoxycarbonyl)-4-(4-hydroxyphenyl)-
5-oxo-5,6,7,8-tetrahydro quinolin-1(4H)-yl]benzenesulfo-
namide (7)
1
1744 (2C¼O). H NMR (DMSOd6): ꢀ 1.10 (s, 6H, 2CH3), 1.86
(s, 2H, CH2), 2.76 (s, 2H, CH2), 4.45 (s, 1H, CH), 5.47 (s, 3H,
3OH), 5.97 (s, 2H, Ar-H), 6.16 (s, 2H, SO2NH2), 6.81–7.59
(m, 6H, Ar-H, NH2), 8.36 (s, 2H, NH2). 13C NMR: ꢀ 26.7, 32.9,
40.2, 40.6, 52.3 (CH, CH2, CH3), 82.6, 109.1, 111.6,116.5, 128.3,
129.9,134.0, 137.3, 144.7, 144.5, 153.5, 159.3 (Ar-C), 169.8,
196.0 (2C¼O). MS m/z (Rel. Int.): 514 (M+, 59). Anal.
(C24H26N4O7S), Calcd/Found: C, 56.02 (55.74); H, 5.09 (5.32);
N, 10.89 (11.05); S, 6.23 (6.47).
Yield: 25%, M.P.: 183–85 ꢀC. IR, u (cmꢁ1): 3455, 3380, 3267
(OH, NH2, SO2NH2), 3069 (Ar-CH), 2968 (Aliph. CH), 1759,
1
1737 (2C¼O). H NMR (DMSOd6): ꢀ 1.01 (s, 6H, 2CH3), 1.22
(t, J ¼ 2.7 Hz, 3H, CH3), 1.91 (s, 2H, CH2), 2.30 (s, 2H, CH2),
4.27 (q, J ¼ 3.2, Hz, 2H, CH2), 4.57 (s, 1H, CH), 5.41 (s, 2H,
2OH), 6.10 (s, 2H, SO2NH2), 6.79–7.56 (m, 7H, Ar-H), 8.34
(s, 2H, NH2). 13C NMR: ꢀ 14.7, 25.3, 34.5, 38.7, 43.9, 52.1,
62.5(CH, CH2, CH3), 82.7, 112.0, 114.3, 116.1, 116.6, 124.4,
130.1, 130.5, 136.6, 143.5, 144.2, 145.9, 152.1, 159.5 (Ar-C),
166.2, 192.3 (2C¼O). MS m/z (Rel. Int.): 527 (M+, 34). Anal.
(C26H29N3O7S), Calcd/Found: C, 59.19 (58.93); H, 5.54 (5.80);
N,7.96 (8.14); S, 6.08 (5.86).
4-[2-Amino-3-(ethoxycarbonyl)–(3,4-dihydroxyphenyl)-
5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl]benzenesulfo-
namide (12)
Yield: 27%, M.P.:4300 ꢀC. IR, u (cmꢁ1): 3454, 3383, 3267 (OH,
NH2, SO2NH2), 3063 (Ar-CH), 2967 (Aliph. CH), 2224 (CꢂN),
1
1752 (C¼O). H NMR (DMSOd6): ꢀ 1.38 (m, 2H, CH2), 1.89
4-[2-Amino-3-(aminocarbonyl)-4-(4-hydroxyphenyl)-
5-oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl]benzenesulfo-
namide (8)
(t, J ¼ 2.3 Hz, 2H, CH2), 2.94 (t, 2H, J ¼ 2.6 Hz, CH2), 4.46
(s, 1H, CH), 5.44 (s, 3H, 3OH), 5.96 (s, 2H, Ar-H), 6.15 (s, 2H,
SO2NH2), 6.79–7.63 (m, 4H, Ar-H), 8.39 (s, 2H, NH2). 13C NMR:
ꢀ21.0, 26.8, 36.5, 38.9 (CH, CH2), 58.1 (C-CN), 109.1, 111.3,
116.5, 117.1, 128.2, 129.4, 133.5, 137.2, 144.5, 148.7, 153.5,
163.7 (Ar-C), 196.1 (C¼O). MS m/z (Rel. Int.): 468 (M+, 47).
Anal. (C22H20N4O6S), Calcd/Found: C, 56.40 (56.69); H, 4.30
(4.52); N, 11.96 (12.19); S, 6.84 (6.59).
Yield: 24%, M.P.: 252–54 ꢀC. IR, u (cmꢁ1): 3451, 3380, 3266
(OH, NH2, SO2NH2), 3063 (Ar-CH), 2966 (Aliph. CH), 1752,
1
1740 (2C¼O). H NMR (DMSOd6): ꢀ0.99 (s, 6H, 2CH3), 1.87
(s, 2H, CH2), 2.34 (s, 2H, CH2), 4.51 (s, 1H, CH), 5.43 (s, 2H,
2OH), 6.11 (s, 2H, SO2NH2), 6.79–7.58 (m, 9H, Ar-H, NH2), 8.32
(s, 2H, NH2). 13C NMR: ꢀ 26.4, 33.3, 38.2, 44.5, 52.6(CH, CH2,
CH3), 82.5, 111.3, 115.5, 116.3, 117.0, 123.0, 130.3, 130.7,
137.1, 144.3, 144.8, 146.0 153.3, 159.1 (Ar-C), 173.8, 192.8
(2C¼O). MS m/z (Rel. Int.): 498 (M+, 55). Anal. (C24H26N4O6S),
Calcd/Found: C, 57.82 (57.61); H, 5.26 (5.58); N, 11.24 (11.54);
S, 6.43 (6.65).
4-[2-Amino-3-(aminocarbonyl)-(3,4-dihydroxyphenyl)-5-
oxo-5,6,7,8-tetrahydroquinolin-1(4H)-yl]benzenesulfona-
mide (13)
Yield: 28%, M.P.: 212–214 ꢀC. IR, u (cmꢁ1): 3453, 3381, 3265
(OH, NH2, SO2NH2), 3062 (Ar-CH), 2966 (Aliph. CH), 1760,

4
A. M. Alafeefy
J Enzyme Inhib Med Chem, Early Online: 1–6
1
1741 (2C¼O). H NMR (DMSOd6): ꢀ 1.01 (s, 6H, 2CH3), 1.22 (s, 1H, CH), 5.45 (s, 1H, OH), 6.13 (s, 2H, SO2NH2), 6.75–7.62
(t, J ¼ 2.6 Hz, 3H, CH3), 1.92 (s, 2H, CH2), 2.31 (s, 2H, CH2), (m, 10H, Ar-H, NH2), 8.50 (s, 2H, NH2). 13C NMR: ꢀ 20.7, 26.4,
3.78 (s, 3H, OCH3) 4.28 (q, J ¼ 2.9 Hz, 2H, CH2), 4.54 (s, 1H, 36.6, 39.2, (CH, CH2), 82.1, 111.6, 115.6, 116.9, 128.1, 129.5,
CH), 5.41 (s, 1H, OH), 6.11 (s, 2H, SO2NH2), 6.79–7.57 (m, 7H, 130.6, 135.2, 145.6, 153.3, 155.1, 159.5 (Ar-C), 174.7, 195.5
Ar-H), 8.35 (s, 2H, NH2). 13C NMR: ꢀ 14.6, 27.3, 33.4, 39.8, 41.0, (2C¼O). MS m/z (Rel. Int.): 454 (M+, 61). Anal. (C22H22N4O5S),
51.6, 57.1, 61.6 (CH, CH2, and CH3), 81.6, 112.0, 114.7, 116.3, Calcd/Found: C, 58.14 (57.83); H, 4.88 (4.63); N, 12.33 (12.06);
116.5, 123.4, 128.1, 129.4, 135.6, 142.5, 144.9, 150.9, 153.0, S, 7.06 (6.75).
159.8 (Ar-C), 166.5, 196.3 (2C¼O). MS m/z (Rel. Int.): 541 (M+,
34). Anal. (C27H31N3O7S), Calcd/Found: C, 59.87 (60.08); H, 4-[2-Amino-3-(aminocarbonyl)-4-(3,4,5-trihydroxyphenyl)-
5.77 (6.02); N, 7.76 (7.50); S, 5.92 (6.17).
5-oxo-5,6,7,8-tetrahydro quinolin-1(4H)-yl]benzenesulfo-
namide (18)
4-[2-Amino-3-(ethoxycarbonyl)-4-(3,4,5-trihydroxyphe-
nyl)-5-oxo-5,6,7,8-tetrahydro-7,7-dimethylquinolin-1(4H)-
yl]benzenesulfonamide (14)
Yield: 25%, M.P.: 169–71 ꢀC. IR, u (cmꢁ1): 3453, 3381, 3266
(OH, NH2, SO2NH2), 3069 (Ar-CH), 2972 (Aliph. CH), 1756,
1740 (2C¼O). H NMR (DMSOd6): ꢀ 1.20 (t, J ¼ 3.1 Hz, 3H,
1
Yield: 25%, M.P.: 262–64 ꢀC. IR, u (cmꢁ1): 3415, 3381, 3268 CH3), 1.45 (m, 2H, CH2), 1.98 (t, J ¼ 2.2 Hz, 2H, CH2), 2.95
(OH, NH2, SO2NH2), 3061 (Ar-CH), 2969 (Aliph. CH), 1753, (t, J ¼ 2.8, Hz, 2H, CH2), 4.26 (q, J ¼ 3.1 Hz, 2H, CH2), 4.37 (s,
1
1741 (2C¼O). H NMR (DMSOd6): ꢀ 1.02 (s, 6H, 2CH3), 1.86 1H, CH), 5.46 (s, 2H, 2OH), 6.19 (s, 1H, SO2NH2), 6.76–7.69 (m,
(s, 2H, CH2), 2.34 (s, 2H, CH2), 3.80 (s, 3H, OCH3), 4.52 (s, 1H, 7H, Ar-H), 8.34 (s, 2H, NH2). 13C NMR: ꢀ 15.2, 21.0, 27.5, 36.3,
CH), 5.42 (s, 1H, OH), 6.14 (s, 2H, SO2NH2), 6.79–7.56 (m, 9H, 39.5, 62.4 (CH, CH2, and CH3), 81.0, 112.3, 115.7, 116.1, 128.5,
Ar-H, NH2), 8.33 (s, 2H, NH2). 13C NMR: ꢀ 26.7, 32.6, 39.7, 128.9, 130.6, 134.1, 144.7, 153.6, 156.2, 159.8 (Ar-C), 169.0,
40.3, 51.6, 57.0 (CH, CH2, CH3), 82.6, 111.5, 114.6, 116.3, 116.8, 195.6 (2C¼O). MS m/z (Rel. Int.): 499 (M+, 41). Anal.
122.1, 128.0, 129.6 135.3, 142.4, 144.5, 150.9,153.2, 159.0 (Ar- (C24H25N3O7S), Calcd/Found: C, 57.70 (57.96); H, 5.04 (4.77);
C), 169.9, 196.7 (2C¼O). MS m/z (Rel. Int.): 512 (M+, 62). Anal. N, 8.41 (8.69); S, 6.42 (6.17).
(C25H28N4O6S), Calcd/Found: C, 58.58 (58.32); H, 5.51 (5.28);
N, 10.93 (11.15); S, 6.26 (6.51).
4-[2-Amino-3-(ethoxycarbonyl)-4-(3-methoxy-4-hydroxy-
phenyl)-5-oxo-5,6,7,8-tetrahydro-7,7-dmethyliquinolin-
1(4H)-yl]benzenesulfonamide (19)
4-[2-Amino-3-(aminocarbonyl)-4-(3,4,5-trihydroxyphenyl)-
5-oxo-5,6,7,8-tetrahydro-7,7-dimethylquinolin-1(4H)-
yl]benzenesulfonamide (15)
Yield: 25%, M.P.: 266–68 ꢀC. IR, u (cmꢁ1): 3427, 3390, 3274
(OH, NH2, SO2NH2), 3065 (Ar-CH), 2961 (Aliph. CH), 1756,
Yield: 27%, M.P.:4300 ꢀC. IR, u (cmꢁ1): 3421, 3385, 3263 (OH, 1742 (2C¼O). H NMR (DMSOd6): ꢀ 1.41 (m, 2H, CH2), 1.98
1
NH2, SO2NH2), 3066 (Ar-CH), 2971 (Aliph. CH), 2225 (CꢂN), (t, J ¼ 2.9, Hz, 2H, CH2), 2.95 (t, J ¼ 3.0, Hz, 2H, CH2), 4.47 (s,
1
1752 (C¼O). H NMR (DMSOd6): ꢀ 1.07 (s, 6H, 2CH3), 1.85 1H, CH), 5.45 (s, 2H, 2OH), 6.13 (s, 2H, SO2NH2), 6.74–7.63 (m,
(s, 2H, CH2), 2.65 (s, 2H, CH2), 3.78 (s, 3H, OCH3), 4.44 (s, 1H, 9H, Ar-H, NH2), 8.51 (s, 2H, NH2). 13C NMR: ꢀ 20.8, 26.9, 37.0,
CH), 5.62 (s, 1H, OH), 6.17 (s, 2H, SO2NH2), 6.79–7.63 (m, 7H, 39.8, (CH, CH2), 82.6, 112.2, 116.1, 116.8, 117.1, 124.1, 128.2,
Ar-H), 8.47 (s, 2H, NH2). 13C NMR: ꢀ 27.2, 33.0, 39.2, 40.5, 51.4, 129.4, 136.0, 145.2, 145.6, 147.2, 154.1, 159.4 (Ar-C), 171.7,
55.9 (CH, CH2,CH3), 58.0 (C-CN), 111.4, 115.1, 116.3, 116.5, 194.8 (2C¼O). MS m/z (Rel. Int.): 470 (M+, 67). Anal.
117.1, 122.5, 128.1, 129.4, 134.5, 142.7, 144.6, 152.0, 153.6, (C22H22N4O6S), Calcd/Found: C, 56.16 (55.92); H, 4.71 (5.04);
162.3 (Ar-C), 196.2 (C¼O). MS m/z (Rel. Int.): 494 (M+, 54). N, 11.91 (12.16); S, 6.82 (7.08).
Anal. (C25H26N4O5S), Calcd/Found: C, 60.71 (60.94); H, 5.30
(5.54); N, 11.33 (11.05); S, 6.48 (6.75).
4-[2-Amino-3-(aminocarbonyl)-4-(3methoxy-4-hydroxy-
phenyl)-5-oxo-5,6,7,8-tetrahydro-7,7-dimethylquinolin-
1(4H)-yl]benzenesulfonamide (20)
4-[2-Amino-3-cyano-4-(3,4,5-trihydroxyphenyl)-5-oxo-
5,6,7,8-tetrahydro-7,7-dimethyl quinolin-1(4H)-yl]benze-
nesulfonamide (16)
Yield: 24%, M.P.: 221–23 ꢀC. IR, u (cmꢁ1): 3450, 3381, 3265
(OH, NH2, SO2NH2), 3067 (Ar-CH), 2972 (Aliph. CH), 1756,
Yield: 22%, M.P.: 165–67 ꢀC. IR, u (cmꢁ1): 3450, 3382, 3266 1743 (2C¼O). H NMR (DMSOd6): ꢀ 1.19 (t, J ¼ 3.0 Hz, 3H,
1
(OH, NH2, SO2NH2), 3068 (Ar-CH), 2973 (Aliph. CH), 1755, CH3), 1.42 (m, 2H, CH2), 1.96 (t, J ¼ 2.7 Hz, 2H, CH2), 2.91
1
1742 (2C¼O). H NMR (DMSOd6): ꢀ 1.21 (t, J ¼ 3.0 Hz, 3H, (t, J ¼ 2.6, Hz, 2H, CH2), 4.27 (q, J ¼ 3.6 Hz, 2H, CH2), 4.38 (s,
CH3), 1.43 (m, 2H, CH2), 1.97 (t, J ¼ 2.5 Hz, 2H, CH2), 2.93 1H, CH), 5.43 (s, 3H, 3OH), 5.97 (s, 2H, Ar-H), 6.18 (s, 1H,
(t, J ¼ 2.8, Hz, 2H, CH2), 4.29 (q, J ¼ 3.5 Hz, 2H, CH2), 4.36 (s, SO2NH2), 6.79–7.65 (m, 4H, Ar-H), 8.36 (s, 2H, NH2). 13C NMR:
1H, CH), 5.40 (s, 1H, OH), 6.17 (s, 1H, SO2NH2), 6.74–7.68 (m, ꢀ 14.56, 20.5, 27.3, 37.1, 39.9, 62.1 (CH, CH2, and CH3), 81.2,
8H, Ar-H), 8.33 (s, 2H, NH2). 13C NMR: ꢀ 14.5, 20.8, 27.1, 36.4, 109.0, 111.4, 116.1, 128.5, 129.3, 134.1, 137.5, 144.7, 148.3,
39.7, 62.6 (CH, CH2, and CH3), 81.1, 112.3, 115.6, 116.0, 128.6, 154.5, 159.6 (Ar-C), 167.2, 194.8 (2C¼O). MS m/z (Rel. Int.):
129.1, 130.7, 134.2, 144.6, 154.0, 155.8, 159.7 (Ar-C), 166.1, 515 (M+, 34). Anal. (C24H25N3O8S), Calcd/Found: C, 55.91
194.2 (2C¼O). MS m/z (Rel. Int.): 483 (M+, 34). Anal. (56.17); H, 4.89 (5.08); N, 8.15 (7.96); S, 6.22 (5.96).
(C24H25N3O6S), Calcd/Found: C, 59.61 (59.35); H, 5.21 (4.99);
N, 8.69 (8.40); S, 6.63 (6.37).
4-[2-Amino-3-cyano-4-(3-methoxy-4-hydroxyphenyl)-5-
oxo-5,6,7,8-tetrahydro-7,7-dimethyl quinolin-1(4H)-
yl]benzenesulfonamide (21)
4-[2-Amino-3-(ethoxycarbonyl)-4-(3,4,5-trihydroxyphe-
nyl)-5-oxo-5,6,7,8-tetrahydro quinolin-1(4H)-yl]benzene-
sulfonamide (17)
Yield: 27%, M.P.:4300 ꢀC. IR, u (cmꢁ1): 3451, 3386, 3263 (OH,
NH2, SO2NH2), 3061 (Ar-CH), 2967 (Aliph. CH), 1757, 1738
Yield: 26%, M.P.: 261–63 ꢀC. IR, u (cmꢁ1): 3416, 3389, 3261 (2C¼O). 1H NMR (DMSOd6): ꢀ 1.40 (m, 2H, CH2), 1.97
(OH, NH2, SO2NH2), 3062 (Ar-CH), 2964 (Aliph. CH), 1754, (t, J ¼ 2.8, Hz, 2H, CH2), 2.94 (t, J ¼ 3.2, Hz, 2H, CH2), 4.46 (s,
1
1739 (2C¼O). H NMR (DMSOd6): ꢀ 1.41 (m, 2H, CH2), 1.98 1H, CH), 5.47 (s, 3H, 3OH), 5.97 (s, 2H, Ar-H), 6.14 (s, 2H,
(t, J ¼ 2.9, Hz, 2H, CH2), 2.95 (t, J ¼ 3.0, Hz, 2H, CH2), 4.47 SO2NH2), 6.84–7.62 (m, 6H, Ar-H, NH2), 8.52 (s, 2H, NH2).

DOI: 10.3109/14756366.2014.899595
Synthesis and in vitro antitumor testing of 20
5
13C NMR: ꢀ 20.5, 26.7, 36.5, 39.9, (CH, CH2, CH3), 82.2, 112.0,
116.7, 128.3, 129.2, 134.4, 138.1, 145.0, 147.6, 153.7, 159.8
(Ar-C), 170.6, 196.3 (2C¼O). MS m/z (Rel. Int.): 486 (M+, 61).
Anal. (C22H22N4O7S), Calcd/Found: C, 54.31 (54.55); H, 4.56
(4.74); N, 11.52 (11.78); S, 6.59 (6.31).
Table 1. In vitro antitumor activity of the designed
tetrahydroquinoline derivatives 4–23.
IC50 (mM)
Cpd no.
MCF-7*
HeLay
HepG2z
4
5
6
7
8
9
0.011
0.012
0.013
0.005
0.015
0.004
0.009
0.011
0.004
0.005
0.008
0.009
0.011
0.005
0.006
0.011
0.009
0.005
0.006
0.006
0.007
0.013
0.012
0.013
0.003
0.013
0.004
0.008
0.011
0.004
0.005
0.008
0.009
0.011
0.005
0.006
0.011
0.009
0.005
0.006
0.007
0.008
0.009
0.011
0.013
0.014
0.014
0.004
0.009
0.011
0.004
0.006
0.009
0.009
0.011
0.006
0.006
0.011
0.008
0.003
0.007
0.006
0.007
4-[2-Amino-3-(ethoxycarbonyl)-4-(3-methoxy-4-hydroxy-
phenyl)-5-oxo-5,6,7,8-tetrahydro quinolin-1(4H)-yl]benze-
nesulfonamide (22)
Yield: 25%, M.P.: 206–208 ꢀC. IR, u (cmꢁ1): 3438, 3374, 3265
(OH, NH2, SO2NH2), 3067 (Ar-CH), 2973 (Aliph. CH), 1758,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
DOX
1
1746 (2C¼O). H NMR (DMSOd6): ꢀ 1.16 (t, J ¼ 3.0 Hz, 3H,
CH3), 1.38 (m, 2H, CH2), 1.93 (t, J ¼ 2.9 Hz, 2H, CH2), 2.88
(t, J ¼ 2.6, Hz, 2H, CH2), 3.77 (s, 3H, OCH3), 4.29 (q, J ¼ 3.7 Hz,
2H, CH2), 4.39 (s, 1H, CH), 5.47 (s, 1H, OH), 6.15 (s, 1H,
SO2NH2), 6.81–7.65 (m, 7H, Ar-H), 8.37 (s, 2H, NH2). 13C NMR:
ꢀ 14.6, 20.3, 27.1, 36.7, 39.4, 57.0, 61.8 (CH, CH2, and CH3),
80.9, 111.5, 114.3, 116.1, 116.5, 122.4, 128.6, 129.1, 136.0,
142.7, 145.1, 151.0, 153.6, 160.1 (Ar-C), 167.0, 195.3 (2C¼O).
MS m/z (Rel. Int.): 513 (M+, 34). Anal. (C25H27N3O7S),
Calcd/Found: C, 58.47 (58.19); H, 5.30 (5.11); N, 8.18 (7.92);
S, 6.24 (5.95).
4-[2-Amino-3-(aminocarbonyl)-4(3-methoxy-4-hydroxy-
phenyl)-5-oxo-5,6,7,8-tetrahydro quinolin-1(4H)-yl]benze-
nesulfonamide (23)
*Human breast cancer cell line (MCF-7).
yHuman cervical cancer cell line (HeLa).
zHuman hepatocellular liver carcinoma cell line (HepG2).
Yield: 27%, M.P.:4300 ꢀC. IR, u (cmꢁ1): 3425, 3374, 3267 (OH,
NH2, SO2NH2), 3064 (Ar-CH), 2968 (Aliph. CH), 1760, 1739
(2C¼O). 1H NMR (DMSOd6): ꢀ 1.40 (m, 2H, CH2), 1.95
(t, J ¼ 2.7, Hz, 2H, CH2), 2.92 (t, J ¼ 3.0, Hz, 2H, CH2), 3.76
(s, 3H, OCH3), 4.47 (s, 1H, CH), 5.45 (s, 1H, OH), 6.15 (s, 2H,
SO2NH2), 6.83–7.63 (m, 9H, Ar-H, NH2), 8.47 (s, 2H, NH2).
13C NMR: ꢀ 20.3, 26.7, 36.4, 39.9, 57.0 (CH, CH2, CH3), 82.1,
112.0, 115.1, 116.5, 116.9, 122.5, 128.3, 129.2, 134.9,
The response parameter calculated was IC50 value (Table 1),
which corresponds to the compound concentration causing 50%
mortality in net cells.
142.7, 144.8, 152.0, 153.6, 160.2 (Ar-C), 172.5, 196.8 (2C¼O). Results and discussion
MS m/z (Rel. Int.): 484 (M+, 69). Anal. (C23H24N4O6S),
Chemistry
Calcd/Found: C, 57.01 (56.78); H, 4.99 (5.22); N, 11.56
(11.72); S, 6.62 (6.85).
The synthetic strategies adopted for the synthesis of the target
compounds are depicted in Scheme 1, the key starting material
the enaminone 3 was obtained by condensation of the appro-
priate di-carbonyl compound with sulfanilamide in absolute
ethanol. The structure of the enaminone derivative was con-
firmed by elemental analysis and spectral data which were in
accordance with the proposed structures. The target compounds
4–23 were obtained by one-pot synthesis through base-
catalyzed-condensation reaction of the appropriate enaminone,
active methylene, and aldehyde in absolute ethanol. IR spectra
for all the compounds showed the presence of aliphatic carbons
at around 2950 cmꢁ1, one carbonyl was common and appeared
at around 1700 cmꢁ1 in addition to the SO2NH2 amino group at
around 3250 cmꢁ1. Compounds 4, 7, 9, 12, 14, 17, and 22
showed the presence of an additional OH group absorption band
at around 3400 cmꢁ1. The NMR spectra of these compounds
showed the presence of the required hydrogens and their
carrying carbons in the expected regions. The amide derivatives
5, 8, 10, 13, 15, 18, 20, and 23 were characterized by an
additional NH2 absorption band in the IR spectra and the
corresponding protons in the 1H NMR spectra in addition,
the absence of the characteristic triplet-quartet pattern of the
ethyl ester functionality. The 2-amino-cyano derivatives 6, 11,
16, and 21 were characterized by the presence of the absorp-
tion band at around 2225 cmꢁ1 as an indicative for the cyano
group and its 13C at around 116 ppm. The MS and elemental
analyses were fully in accordance with suggested molecular
structures.
In vitro anticancer screening23,24
The stock solutions of the tested compounds were prepared in
DMSO and were used for serial dilutions in the culture medium
(the final concentration of DMSO was adjusted as not to exceed
0.3%). The three chosen cell lines were grown in RPMI-1640
medium supplemented with 10% calf serum. For growth assays,
exponentially growing cells were suspended in the mentioned
medium at a density of 4 ꢃ 104 cells per mL and were seeded onto
96-well plates well (200 mL/well), and incubated at 37 ꢀC in a
humidified 5% CO2 atmosphere for 24 h. The cell medium in test
wells was then changed to another culture medium containing
different concentrations of the compounds under test. The control
wells were changed to new medium with an equivalent amount of
solvent. After incubation at 37 ꢀC in a humidified 5% CO2
atmosphere for 3 d, 100 mL of MTT (3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide, 0.5 mg/mL) in the serum-free
medium was added to each well and incubated at 37 ꢀC for an
additional 4 h. Subsequently, 200 mL of DMSO was added to each
well and thoroughly mixed. The cell viability was then evaluated
by measuring the optical density at 544 nm using a Microelisa
Reader. The percentage of inhibition of cell growth was calculated
as follows:
%Inhibition ¼ ðMeanODcontrol ꢁ MeanODtestÞ=MeanODcontrol
ꢃ 100%:

6
A. M. Alafeefy
J Enzyme Inhib Med Chem, Early Online: 1–6
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4. Mun˜oz A, Sojo F. Cytotoxic effects of new trans-2,4-diaryl-r-3-
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tumoral drugs gemcitabine and paclitaxel on cellular lines of human
breast cancer. Chem Biol Interact 2011;189:215–21.
5. Jiang C, Yang L, Wu WT, et al. De novo design, synthesis and
biological evaluation of 1,4-dihydroquinolin-4-ones and 1,2,3,4-
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6. Chou LC, Tsai MT, Hsu MH, et al. Design, synthesis, and
preclinical evaluation of new 5,6- (or 6,7-) disubstituted-2-
(fluorophenyl)quinolin-4-one derivatives as potent antitumor
agents. J Med Chem 2010;53:8047–58.
In vitro cytotoxicity screening
The target compounds 4–23 were initially screened at
concentration of 0.06 mM using the colorimetric MTT
[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]
to test their activity against human breast cancer cell line
(MCF-7), human cervix cancer (HeLa), and human hepatocellular
liver carcinoma (HepG2). Doxorubicin was employed as a
reference standard drug. The cytotoxic activity of these com-
pounds was evaluated in terms of percent growth inhibition
compared with the control cells. The candidate compound which
produces ꢄ50% inhibition in the primary dose was retested by
serial dilution from 0.06 to 0.002 mM. The results were expressed
as IC50, and the data are shown in Table 1.
7. Semenza G. HIF-1 and human disease: one highly involved factor.
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Close scrutiny of the cytotoxic data revealed that all the
compounds exhibited significant activity against the three tested
cell lines. Seven compounds were more potent than the standard
drug. The activity of which could be arranged in the following
order: 9 ¼ 12413 ¼ 17418 ¼ 22 ¼ 23. Four compounds were
more or less as active as the standard drug. These compounds may
be also arranged in the following order: 14410 ¼ 20415. It is
also worth to mention that there were no great difference in
activity between those compounds obtained from dimedone and
those obtained from cyclohexandione. Also, compounds (4, 7, 9,
12, 14, 17, 19, and 22) bearing 2-amino ethyl ester side chain and
compounds (5, 8, 10, 13, 15, 18, 20, and 23) bearing 2-amino
amide derivatives, both groups showed almost equal antiproli-
ferative activity against the three tested cell lines without
significant difference. However, compounds (6, 11, 16, and 21)
bearing the 2-amino-cyano group, although retained considerable
activity they were far less active than the preceding two. With
regard to the effect of aldehyde substituents, it was clear that
monohydroxy derivatives were less active compared to the di and
trihydroxy derivatives.
8. Pacchiano F, Carta F, McDonald PC, et al. Ureido-substituted
benzenesulfonamides potently inhibit carbonic anhydrase IX and
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´
´
´
´
12. Svastova E, Hulıkova A, Rafajova M, et al. Hypoxia activates the
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`
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The observation that most of the compounds in this study
showed considerable activity could be attributed to the great
structural similarity and the inherent activity of the current nuclei
where the sulfonamide and catechol are molded in the
tetrahydroquinoline backbone.
´
15. Thiry A, Dogne JM, Masereel B, et al. Targeting tumor-associated
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inhibitors imatinib and nilotinib strongly inhibit several mammalian
alpha-carbonic anhydrase isoforms. Bioorg Med Chem Lett 2009;
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Conclusion
The present work adopted simple chemical procedures to develop
new small molecules comprising sulfonamide functionality,
catechol in a tetrahydroquinoline scafold. The structure of the
obtained compounds was established by different instrumental
analytical techniques. All the obtained very similar derivatives
revealed outstanding close activities against three tested tumor
cell lines at low micromolar concentration.
20. Dubois L, Lieuwes NG, Maresca A, et al. Imaging of CA IX with
fluorescent labelled sulfonamides distinguishes hypoxic and (re)-
oxygenated cells in a xenograft tumour model. Radiother Oncol
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Declaration of interest
This work was supported by a grant from the Graduate Studies and
Scientific Research Agency (Grant no. 4.H.33), Salman Bin Abdulaziz
University, Alkharj, Saudi Arabia. Thanks are extended to Prof. Dr. Sherif
Y. S. Department of Cancer Research, National Cancer Institute, Research
Center, Cairo, Egypt, for carrying out the anticancer activities of the
tested compounds.
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