Anticancer and radiosensitizing evaluation of novel sulfonamides with quinoline and pyrimidoquinoline groups

Article abstract of DOI:10.1007/s11164-013-1218-9

Because of the reported anticancer activity of quinolines and pyrimidoquinolines containing the biologically active sulfonamide moiety, a new series of quinoline and pyrimidoquinoline derivatives were synthesized and tested for in-vitro anticancer activit

Full text of DOI:10.1007/s11164-013-1218-9

Res Chem Intermed
DOI 10.1007/s11164-013-1218-9
Anticancer and radiosensitizing evaluation of novel
sulfonamides with quinoline and pyrimidoquinoline
groups
Mostafa M. Ghorab
Helmy I. Heiba Ashraf Zaher
•
•
Mohamed A. Shaaban
•
•
Amal A. Hamed
Received: 24 January 2013 / Accepted: 18 April 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Because of the reported anticancer activity of quinolines and pyrimi-
doquinolines containing the biologically active sulfonamide moiety, a new series of
quinoline and pyrimidoquinoline derivatives were synthesized and tested for in-
vitro anticancer activity against liver-cancer cells. Reaction of 5,5-dimethylcyclo-
hexane-1,3-dione 1 with sulfanilamide 2 in ethanol yielded the corresponding
enaminone 3. Treatment of enaminone 3 with 2-(4-methylbenzylidene)malononit-
rile 4 gave the corresponding strategic starting material quinoline 6. The quinoline-
o-aminocarbonitrile 6 was used to synthesize new series of quinolines 8, 11, 15–20
and pyrimidoquinolines 7, 10, 12–14. The structures of the synthesized compounds
1
13
were confirmed by microanalysis, IR, H NMR, and C NMR spectroscopy, and
use of mass spectral data. Almost all the compounds had significant activity against
human cancer cell line HEPG2 compared with doxorubicin as a positive control.
The most potent compounds, 7, 10, and 20, were also evaluated for their ability to
enhance the killing effect of c-radiation.
Keywords Quinolines ꢀ Pyrimidoquinolines and sulfonamides ꢀ Anticancer
activity
M. M. Ghorab (&)
Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy,
King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
e-mail: mmsghorab@yahoo.com
M. M. Ghorab ꢀ H. I. Heiba ꢀ A. A. Hamed
Department of Drug Radiation Research, National Center for Radiation Research and Technology,
Nasr City, Cairo, Egypt
M. A. Shaaban ꢀ A. Zaher
Department of Organic Chemistry, Faculty of Pharmacy, Cairo University, Giza, Cairo, Egypt
123

M. M. Ghorab et al.
Introduction
Much attention has recently been devoted to synthesis of new derivatives of
quinolines and pyrimidoquinolines, because of their reported biological activity [1–5].
According to the literature, several methods have been described for synthesis of
substituted quinolines and pyrimidoquinolines [6, 7], classes reported to have
anticancer and antileukemic activity. Different mechanisms account for the cytotoxic
effect of these compounds. The most prominent mechanism is inhibition of carbonic
anhydrase (CA) isozymes. Sulfonamides, also, have many types of biological activity
and representatives of these pharmacological agents are widely used clinically as
antibacterial, diuretic, anti-carbonic anhydrase, and antithyroid agents [8–12], among
other activity. Recently, many structurally novel sulfonamide derivatives have been
reported to have substantial anticancer activity in vitro and/or in vivo [13–17]. For
these reasons, and in continuation of our investigations on the synthesis of
biologically active heterocyclic compounds [18–21], we were prompted to synthesize
new quinoline and pyrimidoquinoline derivatives containing the biologically active
sulfonamide group, to evaluate their potential anticancer activity. We also wished to
evaluate these promising new compounds for their in-vitro anticancer activity and to
evaluate their ability to enhance the cytotoxic activity of c-radiation.
Experimental
Chemistry
Melting points are uncorrected and were determined on a Stuart Scientific (Redhill, UK)
melting-point apparatus. Elemental analysis (C, H, N) was performed on a Perkin–Elmer
(Norwalk, CT, USA) 2400 analyzer at the micro analytical laboratories of the Faculty of
Science, Cairo University. For all compounds, results were within ± 0.4 % of the
theoretical values. IR spectra (KBr) were measured on Shimadzu (Kyoto, Japan) IR 110
1
spectrophotometer. H and C NMR spectra were obtained on a Bruker (Munich,
13
Germany) proton NMR-Avance 300 (300 MHz), in DMSO-d as a solvent, using
6
tetramethylsilane(TMS)asinternalstandard. MassspectrawereacquiredonanHPmodel
MS-5988 (Hewlett Packard, Palo, Alto, California, USA). All reactions were monitored
by thin-layer chromatograph (TLC) on aluminium sheets precoated with Merck
(
Darmstadt, Germany)silicagel60F254, withvisualizationbyuseofaUVlamp(Merck).
-(5,5-Dimethyl-3-oxocyclohex-1-enylamino) benzenesulfonamide (3)
This compound was prepared as reported elsewhere [18].
4
4
1
-(2-Amino-3-cyano-7,7-dimethyl-5-oxo-4-p-tolyl-5,6,7,8-tetrahydroquinolin-
(4H)-yl)benzenesulfonamide (6)
A mixture of compound 3 (2.94 g, 0.01 mol) and 2-(4-methylbenzylidene)malono-
nitrile 4 (1.7 g, 0.01 mol) in ethanol (20 ml) containing three drops of triethylamine
1
23

Anticancer and radiosensitizing evaluation
was heated under reflux for 5 h. The reaction mixture was filtered while hot and the
solid obtained was recrystallized from dioxane to give 6. Yield: 64 %; mp:
-
1
2
82–284 °C; FT-IR (KBr, cm ): 3,458, 3,344, 3,200 (2NH ), 3,066 (CH-arom.),
2
1
2
,968, 2,954 (CH-aliph.), 2,172 (C:N), 1,636 (C=O), 1,336,1,162 (SO ), H NMR
2
(
DMSO-d , d, ppm): 0.7, 0.8 [2s, 6H, 2CH cyclo], 1.7–2.1 [m, 4H, 2CH cyclo], 2.2
6
3
2
[
s, 3H, CH , tolyl], 4.8 [s, 1H, CH], 5.3 [s, 2H, NH , D O- exchangeable], 7.1–8.0
3 2 2
1
3
[
m,10H, Ar–H ? SO NH ]; C NMR (DMSO-d , d, ppm): 25.4, 28.6 (2), 31.9,
2
2
6
3
6.5, 42.0, 52.7, 56.9, 110.7, 117.3 (2), 118.8, 127.3 (2), 128.6 (2), 128.9 (2), 130.4,
?
36.8, 141.0, 146.1, 152.8, 169.2, 199.7. MS (m/z): 462 [M ] (15.98), 65 (100);
1
Analysis for C H N O S Calcd. C, 64.91; H, 5.67; N, 12.11 %: Found: C, 64.66; H,
2
5 26 4 3
5
.39; N 12.42 %.
4
1
-(8,8-Dimethyl-4,6-dioxo-5-p-tolyl-3,4,6,7,8,9-hexahydropyrimido[4,5-b]quinolin-
0(5H)-yl)benzenesulfonamide (7)
A solution of compound 6 (4.6 g, 0.01 mol) in formic acid (30 ml) was heated under
reflux for 5 h. The reaction mixture was then cooled and poured on to cold water, the
solid obtained was crystallized from ethanol to give compound 7. Yield: 87 %; mp:
-
1
1
2
78–180 °C; FT-IR (KBr, cm ): 3,344, 3,256 (NH, NH ), 3,100 (CH-arom.), 2,958,
2
1
,945 (CH-aliph.), 1,708, 1,654 (2C=O), 1,312, 1,168 (SO ), H NMR (DMSO-d , d,
2
6
ppm): 0.9, 1.0 [2s, 6H, 2CH cyclo], 1.9–2.1 [m, 4H, 2CH cyclo], 2.3 [s, 3H, CH ,
3
3
2
tolyl], 4.5 [s, 1H, CH], 5.1 [s, 1H, NH, D O- exchangeable], 7.1–7.9 [m, 10H, Ar–
2
1
3
H ? SO NH ], 8.0 [s, 1H, N=CH]. C NMR (DMSO-d , d, ppm): 22.6, 26.4 (2),
2
2
6
3
3.5, 38.9, 39.2, 52.8, 102.3, 112.7, 117.8 (2), 127.2 (2), 128.4 (2), 128.8 (2), 129.9,
?
33.6, 138.9, 146.1, 149.7, 153.2, 155.0, 161.9, 200.3. MS (m/z): 490 [M ] (0.69), 68
1
(
100); Analysis for C H N O S Calcd. C, 63.66; H, 5.34; N, 11.42 %: Found: C,
26 26 4 4
6
3.84; H, 5.61; N 11.75 %.
N-(3-Cyano-7,7-dimethyl-5-oxo-1-(4-sulfamoylphenyl)-4-p-tolyl-1,4,5,6,7,
- hexahydroquinolin-2-yl)acetamide (8)
8
A solution of compound 6 (4.6 g, 0.01 mol) in acetic anhydride (20 ml) was heated
under reflux for 10 min. The reaction mixture was then concentrated. The solid
which separated was crystallized from ethanol to give 8. Yield: 63 %; mp:
-
1
1
84–186 °C; FT-IR (KBr, cm ): 3,255, 3,180, 3,140 (NH, NH ), 3,093 (CH-
2
arom.), 2,953, 2,946 (CH-aliph.), 2,209 (C:N), 1,674, 1,650 (2C=O), 1,345, 1,161
SO ), H NMR (DMSO-d , d, ppm): 0.7, 0.9 [2s, 6H, 2CH cyclo], 1.9–2.1 [m, 4H,
1
(
2
6
3
2
CH cyclo], 2.2 [s, 3H, COCH ], 2.3 [s, 3H, CH tolyl], 5.0 [s, 1H, CH], 7.0–8.0
2 3 3
1
m, 10H, Ar–H ? SO NH ], 9.8 [s, 1H, NH, D O- exchangeable]. C NMR
3
[
(
(
2 2 2
DMSO-d , d, ppm): 24.5, 25.6, 26.8 (2), 31.4, 40.0, 41.2, 52.6, 60.1, 113.2, 117.8
2), 118.5, 127.8 (2), 127.9, 128.1 (2), 129.9, 133.8, 140.5, 143.6, 152.7, 155.4,
?
65.7, 197.6. MS (m/z): 504 [M ] (1.95), 78 (100) Analysis for C H N O S
6
1
Calcd. C, 64.27; H, 5.59; N, 11.10 %: Found: C, 64.55; H, 5.67; N, 11.26 %.
2
7 28 4 4
123

M. M. Ghorab et al.
4
[
-(3-Acetyl-2,8,8-trimethyl-4,6-dioxo-5-p-tolyl-3,4,6,7,8,9-hexahydropyrimido
4,5-b]quinolin-10(5H)-yl)benzenesulfonamide (10)
A solution of compound 6 (4.6 g, 0.01 mol) in acetic anhydride (20 ml) was heated
under reflux for 10 h and the reaction mixture was concentrated. The solid which
separated was crystallized from ethanol to give compound 10. Yield: 60 %; mp:
-
1
2
30–232 °C; FT-IR (KBr, cm ): 3,395, 3,116 (NH ), 3,100 (CH-arom.), 2,976,
2
2
1
,945 (CH-aliph.), 1,702, 1,697, 1,639 (3C=O), 1,558 (C=N), 1,338, 1,156 (SO2),
H NMR (DMSO-d , d, ppm): 0.8, 0.9 [2s, 6H, 2CH cyclo], 1.0 [s, 3H, CH ],
6
3
3
1
1
2
.9–2.1 [m, 4H, 2CH cyclo], 2.4 [s, 3H, COCH ], 2.46 [s, 3H, CH tolyl], 4.8 [s,
2 3 3
1
3
H, CH], 7.2–8.0 [m, 10H, Ar–H ? SO NH ]. C NMR (DMSO-d , d, ppm): 19.4,
2
2
6
0.6, 22.9, 26.8 (2), 30.8, 39.2, 39.7, 50.8, 101.6, 109.5, 115.8 (2), 127.4 (2), 128.1
(
MS (m/z): 546 [M ] (26.8), 455 (100), Analysis for C H N O S Calcd. C, 63.72;
2), 128.8 (2), 130.3, 134.8, 138.9, 142.7, 151.6, 152.5, 164.3, 166.2, 176.8, 201.2.
?
2
9 30 4 5
H, 5.53; N, 10.25 %: Found: C 63.92; H, 5.77; N 10.58 %.
2
1
-Chloro-N-(3-cyano-7,7-dimethyl-5-oxo-1-(4-sulfamoylphenyl)-4-p- tolyl-
,4,5,6,7,8-hexahydroquinolin-2-yl)acetamide (11)
A mixture of compound 6 (4.6 g, 0.01 mol) and chloroacetylchloride (0.8 g,
.01 mol) in dimethylformamide (10 ml) was heated under reflux for 5 h. The
reaction mixture was poured on to ice-cold water and the solid obtained was
0
crystallized from dioxane to give 11. Yield: 63 %; mp: 158–160 °C; FT-IR (KBr,
-
cm ): 3,456, 3,341, 3,205 (NH, NH ), 3,063 (CH-arom.), 2,958, 2,940 (CH-aliph.),
1
2
1
2
,173 (C:N), 1,670, 1,651 (2C=O), 1,374, 1,159 (SO ), 780 (C–Cl). H NMR
2
(
[
DMSO- d , d, ppm): 0.7, 0.9 [2s, 6H, 2CH cyclo], 2.0–2.2 [m, 4H, 2CH cyclo], 2.4
6
3
2
s, 3H, CH tolyl], 4.4 [s, 2H, CH Cl], 4.5 [s, 1H, CH], 7.1–7.8 [m, 10H, Ar–
3
2
1
3
H ? SO NH ]; 8.0 [s,1H, NH, D O- exchangeable]. C NMR (DMSO-d , d, ppm):
2
2
2
6
2
1
5
1
2.9, 25.8 (2), 31.7, 40.0, 41.3, 44.2, 52.6, 60.1, 112.6, 115.7 (2), 116.9, 127.6 (2),
28.2 (2), 128.4 (2), 128.9, 134.7, 140.3, 143.6, 152.9, 155.8, 165.7, 200.7. MS (m/z):
?
39 [M ] (21.1), 93 (100), Analysis for C H ClN O S Calcd. C, 60.16; H, 5.05; N
0.39 %: Found: C, 60.34; H, 5.30; N, 10.51 %.
2
7
27
4 4
Ethyl 2-(8,8-dimethyl-4,6-dioxo-10-(4-sulfamoylphenyl)-5-p- tolyl-6,7,8,
-tetrahydropyrimido[4,5-b]quinolin-3(4H,5H,10H)-yl)acetate (12)
9
A mixture of compound 7 (4.9 g, 0.01 mol) and ethyl bromoacetate (1.6 g, 0.01 mol)
in dry acetone (50 ml) containing (2 g) anhydrous K CO was heated under reflux for
2
3
2
4 h. The reaction mixture was filtered while hot and the solid obtained was
crystallized from dioxane to give 12. Yield: 64 %; mp: 140–142 °C; FT-IR (KBr,
-
cm ): 3,424, 3,329 (NH ), 3,060 (CH-arom.), 2,958, 2,874 (CH-aliph.), 1,729, 1,650,
1
2
1
1
,630 (3C=O), 1,338,1,165 (SO ), H NMR (DMSO-d , d, ppm): 0.9, 1.0 [2s, 6H,
2
6
2
CH tolyl], 4.2 [q, 2H, CH , J = 6.8 Hz], 4.8 [s, 1H, CH], 7.1–7.9 [m, 10H, Ar–
CH cyclo], 1.2 [t, 3H, CH , J = 7.1 Hz], 1.9–2.3 [m, 4H, 2CH cyclo], 2.4 [s, 3H,
3
3
2
3
2
1
3
H ? SO NH ], 8.4 [s, 1H, N=CH pyrimidine]. C NMR (DMSO-d , d, ppm): 13.6,
2
2
6
2
2.8, 26.7 (2), 30.6, 41.4, 41.8, 44.3, 53.0, 62.7, 101.4, 110.6, 116.9 (2), 127.3 (2),
1
23

Anticancer and radiosensitizing evaluation
1
1
28.1 (2), 128.6 (2), 129.9, 134.8, 138.6, 142.9, 149.1, 154.3, 155.6, 162.7, 168.0,
?
96.8. MS (m/z): 576 [M ](3.9), 76 (100), Analysis for C H N O S Calcd. C, 62.48;
3
0 32 4 6
H, 5.59; N, 9.72 %: Found: C, 62.61; H, 5.63; N, 9.90 %.
4
9
-(3-(2-Hydrazinyl-2-oxoethyl)-8,8-dimethyl-4,6-dioxo-5-p-tolyl-3,4,6,7,8,
-hexahydropyrimido [4,5-b]quinolin-10(5H)-yl)benzenesulfonamide (13)
A mixture of compound 12 (5.76 g, 0.01 mol) and hydrazine hydrate (0.50 g,
.01 mol) was heated under reflux in ethanol (20 ml) for 2 h. The reaction mixture
was poured on to ice water and the solid formed was crystallized from ethanol to
0
-
1
give 13. Yield: 76 %; mp: 160–162 °C; FT-IR (KBr, cm ): 3,450, 3,380, 3,241
(
NH, NH ), 3,045 (CH-arom.), 2,924, 2,861 (CH-aliph.), 1,680, 1,658, 1,630
1
2
(3C=O), 1,326, 1,155 (SO ), H NMR (DMSO-d , d, ppm): 0.9, 1.01 [2s, 6H, 2CH
cyclo], 2.2 [s, 3H, CH tolyl], 1.9–2.7 [m, 4H, 2CH cyclo], 4.2 [s, 2H, NH , D O-
2
6
3
3
2
2
2
exchangeable], 4.3 [s, 2H, CH O], 4.6 [s, 1H, CH], 6.9–7.9 [m, 10H, Ar–
2
H ? SO NH ], 8.1 [s, 1H, CH pyrimidine], 9.8 [s, 1H, NH, D O- exchangeable].
2
2
2
1
3
C NMR (DMSO-d , d, ppm): 25.1, 26.3 (2), 30.6, 39.8, 41.2, 51.2, 52.6, 98.4,
6
1
1
01.4, 109.9, 115.8 (2), 126.9 (2), 127.8 (2), 128.1 (2), 128.9, 134.6, 138.8, 146.0,
?
49.6, 150.9, 152.4, 162.7, 172.0, 196.9. MS (m/z): 562 [M ] (0.82), 108 (100),
Analysis for C H N O S: Calcd. C, 59.77; H, 5.37; N, 14.94 %. Found: C, 59.90;
2
8 30 6 5
H, 5.45; N, 15.21 %.
4
[
-(4-Amino-8,8-dimethyl-6-oxo-5-p-tolyl-6,7,8,9-tetrahydropyrimido
4,5-b]quinolin-10(5H)-yl)benzenesulfonamide (14)
A solution of compound 6 (4.6 g, 0.01 mol) in formamide (30 ml) was heated under
reflux for 5 h. The reaction mixture was cooled and then poured on to cold water.
The obtained solid was crystallized from dioxane to give 14. Yield: 62 %;
-
1
mp [ 300 °C; FT-IR (KBr, cm ): 3,334, 3,200 (NH ), 3,075 (CH-arom.), 2,928,
2
1
2
1
4
,900 (CH-aliph.), 1,646 (C=O), 1,350, 1,158 (SO ), H NMR (DMSO- d , d, ppm):
.0, 1.02 [2s, 6H, 2CH cyclo], 2.3 [s,3H, CH tolyl], 1.8–2.9 [m, 4H, 2CH cyclo],
.3 [s, 1H, CH], 6.8 [s, 2H, NH , D O- exchangeable], 6 9–8.0 [m, 10H, Ar–
2
6
3
3
2
2
2
1
3
H ? SO NH ], 8.2 [s, 1H, CH pyrimidine]. C NMR (DMSO-d , d, ppm): 23.6,
2
2
6
2
6.8 (2), 32.6, 34.7, 39.6, 52.1, 103.7, 110.1, 117.3 (2), 119.6, 127.7 (2), 128.6 (2),
28.9 (2), 129.8, 134.5, 136.2, 146.7, 155.2, 166.3, 173.4, 201.7. MS (m/z): 489
1
?
M ] (4.11), 184 (100), Analysis for C H N O S: Calcd. C, 63.78; H, 5.56; N,
[
2
6 27 5 3
1
4.30 %. Found: C, 63.43; H, 5.74; N, 14.61 %.
N-(3-Cyano-7,7-dimethyl-5-oxo-1-(4-sulfamoylphenyl)-4-p-tolyl-1,4,5,6,7,
-hexahydroquinolin-2-yl)-3-oxobutanamide (15)
8
A mixture of compound 6 (4.6 g, 0.01 mol) and ethyl acetoacetate (10 ml) was
fused in an oil bath at 200–220 °C for 1 h. The sticky mass formed was triturated
with ethanol. The solid obtained was crystallized from ethanol to give 15. Yield:
-
1
5
6 %; mp 216–218 °C; FT-IR (KBr, cm ): 3,358, 3,210 (NH, NH ), 3,095 (CH-
2
123

M. M. Ghorab et al.
arom.), 2,960, 2,904 (CH-aliph.), 2,211 (C:N), 1,710, 1,704, 1,653 (3C=O), 1,342,
1
1
,164 (SO ), H NMR (DMSO-d , d, ppm): 0.7, 1.1 [2s, 6H, 2CH cyclo], 2.0–2.2
2
6
3
[
COCH ], 5.3 [s, 1H, CH], 7.0–8.0 [m, 10H, Ar–H ? SO NH ], 10.2 [s, 1H, NH,
m, 4H, 2CH cyclo], 2.3 [s,3H, CH tolyl], 2.5 [s, 3H, COCH ], 4.8 [s, 2H,
2 3 3
2
2
2
1
3
D O- exchangeable]. C NMR (DMSO-d , d, ppm): 25.2, 27.9 (2), 28.9, 31.8, 39.7,
2
6
4
1
1
2.4, 49.6, 52.3, 61.2, 112.7, 115.6 (2), 116.8, 127.6 (2), 128.3 (2), 128.8 (2), 129.6,
?
34.5, 141.2, 146.6, 152.8, 155.6, 166.4, 200.6, 204.0. MS (m/z): 546 [M ] (12.2),
21(100), Analysis for C H N O S: Calcd. C, 63.72; H, 5.53; N, 10.25 %. Found:
2
9 30 4 5
C, 63.90; H, 5.88; N, 10.56 %.
2
1
-Cyano-N-(3-cyano-7,7-dimethyl-5-oxo-1-(4-sulfamoylphenyl)-4-p-tolyl-
,4,5,6,7,8-hexahydroquinolin-2-yl)acetamide (16)
A mixture of compound 6 (4.6 g, 0.01 mol) and ethyl cyanoacetate (10 ml) was
fused at 200–220 °C in an oil bath for 5 h. The sticky mass formed was triturated
with ethanol and the solid obtained was crystallized from ethanol to give 16. Yield:
-
1
5
5 %; mp 237–239 °C; FT-IR (KBr, cm ): 3,367, 3,250 (NH, NH ), 3,064 (CH-
2
arom.), 2,961, 2,930 (CH-aliph.), 2,213 (C:N), 1,658, 1,630 (2C=O), 1,371, 1,163
SO ), H NMR (DMSO-d , d, ppm): 0.9, 1.0 [2s, 6H, 2CH cyclo], 1.9–2.8 [m, 4H,
1
(
2
6
3
2
CH cyclo], 2.2 [s,3H, CH tolyl], 4.0 [s, 2H, CH CN], 4.5 [s, 1H, CH], 6.8–8.0
1
2 3 2
3
[
m, 10H, Ar–H ? SO NH ], 8.6 [s, 1H, NH, D O- exchangeable]. C NMR
2 2 2
(
DMSO-d , d, ppm): 23.4, 24.8, 26.7 (2), 31.6, 37.3, 39.7, 50.6, 61.0, 110.4, 114.8,
6
1
15.5 (2), 116.7, 127.6 (2), 128.4 (2), 128.6 (2), 131.1, 134.8, 140.8, 142.9, 152.8,
?
56.7, 165.6, 199.5. MS (m/z): 529 [M ] (12.9), 64 (100), Analysis for
1
C H N O S: Calcd. C, 63.50; H, 5.14; N, 13.22 %. Found: C, 63.63; H, 5.33;
N, 13.46 %.
2
8 27 5 4
(
1
E)-Ethyl N-3-cyano-7,7-dimethyl-5-oxo-1-(4-sulfamoylphenyl)-4-p- tolyl-
,4,5,6,7,8-hexahydroquinolin-2-ylformimidate (17)
A solution of compound 6 (4.6 g, 0.01 mol) in triethyl orthoformate (10 ml) was
heated under reflux for 5 h. The solid obtained was crystallized from dioxane to
-
1
give 17. Yield: 71 %; mp 158–160 °C; FT-IR (KBr, cm ): 3,452, 3,374 (NH2),
3
1
2
,010 (CH-arom.), 2,955, 2,930 (CH-aliph.), 2,184 (C:N), 1,645 (C=O),
1
,593(C=N) 1,374, 1,154 (SO ), H NMR (DMSO-d , d, ppm): 0.8, 0.9 [2s, 6H,
2
6
CH cyclo], 1.3 [t, 3H, CH , J = 7.0 Hz], 2.0–2.1 [m, 4H, 2CH cyclo], 2.3 [s, 3H,
3
3
2
CH tolyl], 4.5 [q, 2H, CH , J = 7.3 Hz], 4.8 [s, 1H, CH], 7.1–8.1 [m, 10H, Ar–
3
2
1
3
H ? SO NH ], 8.5 [s, 1H, N=CH]. C NMR (DMSO-d , d, ppm): 14.6, 23.5, 26.6
2
2
6
(
2), 30.8, 41.0, 42.1, 50.6, 62.5, 78.4, 113.7, 115.7 (2), 116.8, 127.4 (2), 128.0 (2),
28.2 (2), 128.8 (2), 136.7, 138.3, 146.1, 152.6, 154.8, 162.6, 201.2. MS (m/z): 518
1
?
[
M ] (0.9), 55 (100), Analysis for C H N O S: Calcd. C, 64.84; H, 5.83; N,
28 30 4 4
1
0.80 %. Found: C, 64.94; H, 5.54; N, 10.61 %.
1
23

Anticancer and radiosensitizing evaluation
0
(
E)-N -(3-Cyano-7,7-dimethyl-5-oxo-1-(4-sulfamoylphenyl)-4-p-tolyl-1, 4, 5, 6, 7,
-hexahydroquinolin-2-yl)-N-(4-sulfamoylphenyl)formimidamide (18)
8
A mixture of compound 17 (5.18 g, 0.01 mol) and sulfanilamide (1.7 g, 0.01 mol)
in dimethylformamide (10 ml) containing a catalytic amount of triethylamine was
heated under reflux for 8 h. The reaction mixture was poured on to ice-cold water
and the solid obtained was crystallized from ethanol to give 18. Yield: 58 %; mp
-
1
2
26–228 °C; FT-IR (KBr, cm ): 3,290, 3,192, 3,102 (NH, NH ), 3,095 (CH-
2
arom.), 2,963, 2,926 (CH-aliph.), 2,191 (C:N), 1,630 (C=O), 1,579 (C=N), 1,321,
,162 (SO ), H NMR (DMSO-d , d, ppm): 0.7, 0.9 [2s, 6H, 2CH cyclo], 2.0–2.2
1
1
2
6
3
[
H ? SO NH ], 7.9 [s, 1H, NH, D O- exchangeable] 8.1 [s, 1H, N=CH]. C NMR
m, 4H, 2CH cyclo], 2.2 [s, 3H, CH tolyl], 4.5 [s, 1H, CH], 7.1–7.8 [m, 16H, Ar–
2 3
1
3
2
2
2
(
DMSO-d , d, ppm): 25.3, 27.8 (2), 30.6, 38.7, 41.3, 53.0, 74.8, 110.6, 115.6 (2),
6
1
15.7 (2), 116.4, 127.1 (2), 127.3 (2), 128.4 (2), 128.6 (2), 128.9 (2), 133.8, 141.0,
?
43.6, 149.0, 152.4, 160.6, 165.8, 197.3. MS (m/z): 649 [M ] (0.1), 427 (100),
1
Analysis for C H N O S : Calcd. C, 59.61; H, 5.00; N, 13.03 %. Found: C, 59.81;
H, 5.12; N, 13.36 %.
3
2 32 6 5 2
N-(3-Cyano-7,7-dimethyl-5-oxo-1-(4-sulfamoylphenyl)-4-p-tolyl-1,4,5,6,7,
8
5
4
-hexahydroquinolin-2-yl)benzenesulfonamide (19) and N-(3-cyano-7,7-dimethyl-
-oxo-1-(4-sulfamoylphenyl)-4-p-tolyl-1,4,5,6,7,8-hexahydroquinolin-2-yl)-
-methylbenzenesulfonamide (20)
A mixture of compound 6 (4.6 g, 0.01 mol) and benzenesulfonyl chloride or
toluenesulfonyl chloride (0.01 mol) in benzene (15 ml) containing three drops of
pyridine was heated under reflux for 4 h. The reaction mixture was concentrated and
the solid obtained was crystallized from ethanol to give 19 and 20, respectively.
-
1
1
9: Yield: 61 %; mp 157–159 °C; FT-IR (KBr, cm ): 3,349, 3,322, 3,245 (NH,
NH ), 3,063 (CH-arom.), 2,960, 2,927 (CH-aliph.), 2,180 (C:N), 1,644 (C=O),
,340,1,163 (SO ), H NMR (DMSO-d , d, ppm): 0.9, 1.0 [2s, 6H, 2CH cyclo],
.0–2.8 [m, 4H, 2CH cyclo], 2.3 [s, 3H, CH tolyl], 4.4 [s, 1H, CH], 6.8–8.0 [m,
1
5H, Ar–H ? SO NH ], 8.9 [s, 1H, NH, D O- exchangeable]. C NMR (DMSO-
2
1
1
2
1
2
6
3
2
3
3
2
2
2
d6, d, ppm): 24.8, 26.6 (2), 34.4, 39.9, 41.6, 52.5, 58.6, 114.0, 115.8 (2), 116.7,
1
26.8 (2), 127.6 (2), 127.9 (2), 128.0 (2), 129.7 (2), 130.6, 133.3, 136.1, 140.8,
?
41.0, 143.6, 155.0, 166.5, 197.6. MS (m/z): 602 [M ] (42.3), 183 (100), Analysis
1
for C H N O S : Calcd. C, 61.77; H, 5.02; N, 9.30 %. Found: C, 61.93; H, 5.24;
3
1 30 4 5 2
N, 9.54 %.
0: Yield: 52 %; mp 185–187 °C; FT-IR (KBr, cm ): 3,458, 3,345, 3,219 (NH,
NH ), 3,067 (CH-arom.), 2,960, 2,873 (CH-aliph.), 2,175 (C:N), 1,633 (C=O),
-
1
2
2
1
1
2
1
,338,1,163 (SO ), H NMR (DMSO-d , d, ppm): 0.7, 0.9 [2s, 6H, 2CH cyclo],
2
6
3
.1–2.3 [m, 4H, 2CH cyclo], 2.5 [s, 6H, 2CH tolyl], 4.4 [s, 1H, CH], 7.1–8.0 [m,
2
3
1
3
4H, Ar–H ? SO NH ], 8.4 [s, 1H, NH, D O- exchangeable]. C NMR (DMSO-
2
2
2
d6, d, ppm): 23.6 (2), 25.9 (2), 33.6, 37.4, 41.2, 52.6, 56.8, 109.8, 115.8 (2), 116.7,
1
28.0 (2), 128.3 (2), 128.9 (2), 129.0 (2), 129.8 (2), 131.0, 136.3, 138.8, 141.1,
?
42.6, 146.7, 155.0, 168.9, 201.6. MS (m/z): 616 [M ] (9.3), 68 (100), Analysis for
1
123

M. M. Ghorab et al.
C H N O S : Calcd. C, 62.32; H, 5.23; N, 9.08 %. Found: C, 62.50; H, 5.38; N,
3
2 32 4 5 2
9
.16 %.
In-vitro anticancer screening
The human tumor cell line HEPG2 was available from the National Cancer Institute,
Cairo, Egypt. The anticancer activity of the newly synthesized compounds was
measured by use of the sulforhodamine B stain (SRB) assay [22]. The in-vitro
anticancer screening was performed by the Pharmacology Unit at the National
Cancer Institute, Cairo University. Cells were plated in 96-multiwell plate
(
4
10 cells/well) for 24 h before treatment with the compounds to enable attachment
of cells to the wall of the plate. Tested compounds were dissolved in DMSO and
diluted with saline to the appropriate volume. Different concentrations of the
compounds under test (5, 12.5, 25, or 50 lM) were added to the cell monolayer.
Triplicate wells were prepared for each dose. Monolayer cells were incubated with
the compounds for 48 h at 37 °C in an atmosphere of 5 % CO . After 48 h, the cells
2
were fixed, washed, and stained for 30 min with 0.4 % (w/v) SRB dissolved in 1 %
acetic acid. Excess unbound dye was removed by washing four times with 1 %
acetic acid, and attached stain was recovered with Tris–EDTA buffer. Color
intensity was measured in an ELISA reader. The relationship between surviving
fraction and drug concentration was plotted to construct the survival curve for liver
tumor cell line after the specified time. The concentration required for 50 %
inhibition of cell viability (IC ) was calculated and compared with that for the
5
0
reference drug doxorubicin; the results are listed in Table 1.
Radiosensitizing evaluation
The most potent compounds in in-vitro anticancer screening, compounds 7, 10, and
2
0, were selected for evaluation of their in-vitro anticancer activity alone and in
combination with c-radiation. This study was conducted to evaluate the ability of
these compounds to enhance the cell-killing effect of c-radiation. Cells were subjected
to a single dose of c-radiation at a dose of 8 Gy and a rate of 2 Gy/min. Irradiation was
performed in the National Cancer Institute, Cairo University, using a gamma cell-40
6
0
( Co) source. The surviving fractions were expressed as mean ± standard error. The
results are given in Table 2.
Results and discussion
The synthesized compounds were designed with the purpose of investigating their
anticancer and radiosensitizing activity. The sequence of reactions followed in the
synthesis of the target compounds is illustrated in Schemes 1, 2, and 3.
The paper reports use of enaminone 3 for synthesis of quinoline and pyrimidoquin-
oline derivatives. Compound 3 [18] was obtained by condensation of dimedone 1 with
sulfanilamide 2 in ethanol. The corresponding quinoline derivative 6 was obtained in
good yield by reaction of enaminone 3 with 4-methylbenzylidinemalononitrile 4 in
1
23

Anticancer and radiosensitizing evaluation
Table 1 In-vitro anticancer screening of the synthesized compounds against human liver cell line
HEPG2
Compound
Compound concentration (lM)
5
12.5
25
50
IC50 (lM)
a
Surviving fraction (mean ± SE)
6
7
8
1
1
1
1
1
1
1
2
0.827 ± 0.04
0.546 ± 0.20
0.792 ± 0.03
0.482 ± 0.09
1.14 ± 0.02
0.865 ± 0.06
0.757 ± 0.05
0.68 ± 0.07
0.824 ± 0.03
0.673 ± 0.05
0.552 ± 0.05
0.921 ± 0.02
0.504 ± 0.04
0.635 ± 0.10
0.574 ± 0.03
0.479 ± 0.05
0.544 ± 0.07
0.467 ± 0.06
0.652 ± 0.09
0.623 ± 0.03
0.769 ± 0.03
0.436 ± 0.03
0.499 ± 0.70
0.846 ± 0.02
0.365 ± 0.03
0.365 ± 0.03
0.337 ± 0.09
0.385 ± 0.04
0.268 ± 0.03
0.536 ± 0.04
0.337 ± 0.02
0.426 ± 0.02
0.302 ± 0.04
0.438 ± 0.01
0.286 ± 0.02
0.761 ± 0.01
0.48 ± 0.02
34.50
22.40
28.00
23.66
25.00
46.50
28.60
31.90
27.60
35.00
21.20
38.46
0.202 ± 0.09
0.345 ± 0.09
0.306 ± 0.07
0.156 ± 0.02
0.542 ± 0.05
0.348 ± 0.01
0.357 ± 0.01
0.234 ± 0.04
0.492 ± 0.03
0.283 ± 0.28
0.494 ± 0.03
0
3
4
5
6
7
8
0
Doxorubicin
a
Each value is the mean of three values ± standard error
Table 2 In-vitro anticancer screening of compounds 7, 10, and 20 against human liver cell line (HEPG2)
in combination with c-radiation
Compound Control Irradiated
8 Gy)
Compound concentration (lM) irradiation (8 Gy)
12.5 25
0.23 ± 0.01 0.11 ± 0.01
IC50
(
(lM)
5
50
0.16 ± 0.08
7
1
2
1.000
1.000
1.000
1.000
0.927 ± 0.02*
0.67 ± 0.07
13.20
14.40
7.70
0
0
0.927 ± 0.02* 0.395 ± 0.06
0.259 ± 0.01
0.16 ± 0.02
0.65 ± 0.047
0.346 ± 0.02
0.24 ± 0.05
0.412 ± 0.01
0.21 ± 0.06
0.927 ± 0.02*
0.927 ± 0.02*
0.29 ± 0.010
0.87 ± 0.0012
Dox.
0.38 ± 0.085 0.063 ± 0.111 20.20
*
Significant difference from control group at p \ 0.001
ethanol containing triethylamine as catalyst. Formation of compound 6 proceeded via
formation of the intermediate Michael type product 5, followed by intramolecular
cyclization (Scheme 1).
Compound 6 was prepared by another route involving one-pot condensation of
enaminone 3 with malononitrile and 4-methylbenzaldehyde in the molar ratio 1:1:1,
in ethanol, under reflux, containing triethylamine as catalyst (m.p and m.m.p).
1
13
Compound 6 was identified on the basis of microanalysis, IR, H, and C NMR
spectroscopy, and by use of mass spectral data. Thus, the IR spectrum of 6
contained sharp bands at 3,458, 3,344, 3,200 (2NH ), 2,172 (C:N), and 1,646
2
-
C=O) cm . The H NMR spectrum contained signals at 2.2 ppm from tolyl CH ,
1
1
(
3
4
.8 ppm from CH-4, and 5.3 ppm from the NH group.
2
The pyrimidoquinoline derivative 7 was obtained by heating compound 6 under
reflux in formic acid (Scheme 2). The IR spectrum showed the absence of a C:N
123

M. M. Ghorab et al.
O
NH2
O
SO2NH2
EtOH
N
O
H
SO2NH2
1
2
3
NC
EtOH
TEA
3
CN
Ar
4
CN
CN
ArCHO
O
O
Ar
Ar
N
H
H
CN
CN
CN
NH
NH2
SO2NH2
SO2NH2
6
5
Ar = C H CH -4
6
4
3
Scheme 1 Formation of quinoline-carbonitrile derivative 6
group and the presence of sharp bands at 3,344, 3,256 (NH, NH ), 1,708, and 1,654
2
-
2C=O) cm . The H NMR spectrum contained signals at 5.18 ppm from NH and
1
1
(
at 7.12–8.0 ppm from aromatic protons.
When compound 6 was heated under reflux in acetic anhydride for short time
10 min) the monoacetyl derivative 8 was obtained; after reflux for a long time
10 h) the cyclic intermediate 3,1-oxazinoquinoline 9a was obtained, then
(
(
rearrangement occurred to give intermediate 9b followed by acetylation of the
NH group to afford the pyrimidoquinoline derivative 10. The structure of
compounds 8 and 10 was established on the basis of elemental analysis and
spectral data. Thus, the IR spectrum of compound 8 contained sharp bands, at 3,255,
-
1
-1 1
3
spectrum contained a signal at 2.2 ppm from the acetyl group. The IR spectrum of
,180, 3,140 (NH, NH ), 2,209 cm , 1,674, and 1,650 (2C=O) cm . H NMR
2
compound 10 confirmed the absence of a C:N band and contained sharp bands at
-
1
,395, 3,116 (NH ), 1,702, 1,697, and 1,649 (3C=O) cm . The H NMR spectrum
1
3
contained signals at 2.17 ppm from tolyl CH and 2.49 ppm from COCH .
2
3
3
Interaction of compound 6 with chloroacetyl chloride afforded the quinoline
derivative 11. The IR spectrum contained sharp bands at 3,456, 3,341, 3,205 (NH,
-
1
1
NH ), 2,173 (C:N), 1,670, and 1,651 (2C=O) cm . The H NMR spectrum
2
contained a signal at 4.4 ppm assigned to CH Cl.
Compound 12 was obtained by treatment of compound 7 with ethyl
bromoacetate in dry acetone in the presence of anhydrous potassium carbonate.
2
The IR spectrum of 12 contained sharp bands at 3,424, 3,329 (NH ), 1,729, 1,650,
2
1
23

Anticancer and radiosensitizing evaluation
O
Ar
O
N
N H .H O
2
4
2
NHNH
2
N
EtOH
O
N
R
(
13 )
O
Ar
N
O
N
OEt
N
O
Ar
N
O
CN
ClCOCH Cl
2
O
R
(
Cl
12 )
N
H
R
(
11 )
BrCH COOC H
2
2
5
O
Ar
NH
2
O
Ar
O
N
HCONH2
HCOOH
NH
(
6 )
N
N
N
R
N
R
(
14 )
( 7 )
Ac O
2
O
Ar
O
Ar
NH
CN
1
0
min.
10 hr.
O
O
N
N
N
R
N
H
R
(
8 )
( 9a )
Rearangement
O
Ar
O
N
O
O
Ar
O
Ac O
2
N
NH
N
N
R
N
R
(
10 )
( 9b)
O
,
Ar = C H CH - 4
6 4 3
R =
S
NH
2
O
Scheme 2 Synthesis of quinoline and pyrimidoquinoline derivatives 7–14
-
1
1
and 1,630 (3C=O) cm . The H NMR spectrum of 12 contained a triplet at
.2 ppm from CH ester and a quartet at 4.2 ppm from CH ester.
Treatment of ester derivative 12 with hydrazine hydrate in ethanol under reflux
1
3
2
afforded the corresponding hydrazide derivative 13. Its IR spectrum contained sharp
bands at 3,450, 3,380, 3,241, 3,160 (NH, NH ), 1,680, 1,658, and 1,630 (3C=O)
2
-
cm . The H NMR spectrum of 13 contained signals at 4.43 ppm corresponding to
1
1
CH CO and 10.0 ppm for NH.
2
123

M. M. Ghorab et al.
O
Ar
O
O
Ar
O
NC
O O
CN
CN
O
O
O
O
O
(
6 )
CN
Fusion
N
R
N
H
N
N
H
R
(
16 )
( 15 )
Ar
O
Ar
CN
R1
SO Cl
CN
N
2
CH(OC H )
2
5 3
O
PhH /Pyridine
N
R
N S
R1
N
O
H
O
R
1
9, R = H
( 17 )
1
2
0, R = CH
1 3
NH2
O
Ar
N
CN
N
SO NH2
2
N
SO NH2
2
R
H
(
18 )
R=
SO NH2
Ar= C H CH - 4
6 4 3
2
Scheme 3 Formation of quinoline derivatives 15–20
The pyrimidoquinoline derivative 14 was obtained in a good yield by reaction of
compound 6 with formamide. The IR spectrum of 14 confirmed the absence of
-
1
C:N and presence of sharp bands at 3,334, 3,200 (NH ), and 1,646 (C=O) cm
.
Fusion of compound 6 with ethyl acetoacetate furnished the corresponding
2
acetamide derivative 15 (Scheme 3). The IR spectrum of compound 15 contained
-
sharp bands at 3,358, 3,210 (NH, NH ), 1,710, 1,704, and 1,653 (3C=O) cm . The
1
2
1
H NMR spectrum contained signals at 2.5 ppm from the COCH group and at
3
1
0.2 ppm from the NH group.
Fusion of compound 6 with ethyl cyanoacetate yielded the quinoline derivative
1
6. The IR spectrum of 16 contained sharp bands at 3,367, 3,250 (NH, NH ), 2,213
2
-
1
1
(C:N), 1,658, and 1,630 (2C=O) cm . The H NMR spectrum contained a signal
at 4.15 ppm corresponding to CH CN.
2
When compound 6 was reacted with triethyl orthoformate the corresponding
quinoline derivative 17 was obtained. Reaction of compound 17 with sulfanilamide
in ethanol yielded the sulfonamide derivative 18. The IR spectrum of compound 17
-
1
contained sharp bands at 3,452, 3,374 (NH ), 2,184 (C:N), and 1,645 (C=O) cm
.
The H NMR spectrum of 17 contained a triplet at 1.38 ppm from ethyl CH , a
2
1
3
quartet at 4.5 ppm from ethyl CH , and a singlet at 8.5 ppm from N=CH. The IR
2
spectrum of compound 18 contained sharp bands at 3,290, 3,192, 3,102 (NH, NH2),
1
23

Anticancer and radiosensitizing evaluation
-
1
-1
1
2
contained signals at 7.1–7.9 ppm from aromatic protons, NH, and SO NH , and
,191 cm (C:N), and 1,630 (C=O) cm . The H NMR spectrum of 18
2
2
at 8.1 ppm from the N=CH group.
The sulfonamide derivatives 19 and 20 were obtained by reaction of compound 6
with benzene or toluene sulfonyl chloride in benzene containing a few drops of
pyridine. The IR spectrum of compound 19 contained sharp bands at 3,349, 3,322,
-
1
3
compound 20 contained sharp bands at 3,458, 3,345, 3,219 (NH, NH ), 2,175
(
,245 (NH, NH ), 2,180 (C:N), and 1,644 (C=O) cm . The IR spectrum of
2
2
-
1
1
C:N), and 1,633 (C=O) cm . The H NMR spectrum contained a multiplet at
7
.1–8.0 ppm from aromatic protons and SO NH .
2 2
In vitro anticancer screening
The newly synthesized compounds were evaluated for in-vitro cytotoxic activity
against the human liver cancer cell line HEPG2. The relationship between surviving
fraction and drug concentration was plotted to obtain the survival curve of the cells.
The variable calculated, the IC50 value, corresponds to the concentration required
for 50 % inhibition of cell viability. Table 1 shows the in-vitro cytotoxic activity of
the compounds. From these results it was apparent that the pyrimidoquinoline 7, the
pyrimidoquinoline with an acetyl group at the 3 position, 10, and the quinoline with
a cyano group at the 3 position and a sulfonamide at the 2 position, 20, were the
most potent compounds (IC50 values 22.40, 23.66, and 21.20 lM, respectively);
they were more potent than doxorubicin (IC50 value 38.46 lM), the reference drug,
(
Fig. 1).
Radiosensitizing activity
The rationale for combining chemotherapy and radiotherapy is based mainly on two
ideas. One idea is spatial cooperation, which is effective if chemotherapy is
sufficiently active to eradicate subclinical metastases and radiotherapy enables
effective treatment of the primary local tumor. In this regard, no interaction between
radiotherapy and chemotherapy is required. The other idea is enhancement of the
effects of radiation.
Fig. 1 In-vitro IC50 of the
synthesized compounds and
doxorubicin against human liver
cell line HEPG2
123

M. M. Ghorab et al.
Fig. 2 In-vitro IC50 of
compounds 7, 10, and 20, in
combination with c-radiation,
against the human liver cell line
HEPG2
25
IC50
2
1
1
0
5
0
5
0
7
10
20
Dox.
Cytotoxic agents can enhance the effects of radiation by direct enhancement of
the initial radiation damage, by incorporation into DNA and thus inhibiting cellular
repair, by accumulating in cells in the radiosensitive phase, by eliminating cells in
the radio-resistant phase, by eliminating hypoxic cells, or by inhibiting accelerated
repopulation of tumor cells. Virtually all chemotherapeutic agents have the ability to
sensitize cancer cells to the lethal effects of ionizing radiation [23].
Consequently, the ability of the most active compounds 7, 10, and 20 to enhance
the cell-killing effect of c-irradiation was studied. The results listed in Table 1 are
indicative of in-vitro cytotoxic activity with IC50 values of 22.40, 23.66, and
2
1.20 lM, respectively. When the cells were subjected to the same concentrations
of compounds and irradiated with a single dose of c-radiation at a level of 8 Gy, the
IC50 values were synergistically reduced to 13.20, 14.40, and 7.70 lM, respectively
(
Table 2).
From these results, we can conclude that combination of the promising syn-
thesized compounds 7, 10, and 20 with ionizing radiation synergistically enhanced
inhibition of the growth of liver cancer cells (Fig. 2).
Conclusions
Because it has been reported that compounds bearing a free sulfonamide group may
have potent carbonic anhydrase inhibition activity, which is believed to be an
interesting target for design of anticancer agents, the objective of this study was to
synthesize new quinoline and pyrimidoquinoline derivatives bearing a free sulfon-
amide moiety. The results obtained from anticancer screening revealed that most of
the synthesized compounds had significant activity, with IC50 ranging from 21.20 to
4
6.50 lM. The most potent compounds, 7, 10, and 20, were further subjected to
anticancer evaluation in combination with c-radiation; substantial decreases of their
IC50 values were observed, indicating the ability of these compounds to sensitize
cancer cells to the lethal effects of ionizing radiation. This showed the potential of
these compounds, in combination with chemoradiotherapy, for cancer treatment.
1
23

Anticancer and radiosensitizing evaluation
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