Synthesis and antitumor activity of some new substituted quinolin-4- one and 1,7-naphthyridin-4-one analogs

Article abstract of DOI:10.1002/(SICI)1521-4184(19991)332:1<19::AID-ARDP19>3.0.CO;2-M

The synthesis of some new analogs of quinolin-4-one and 1,7- naphthyridin-4-one is described. The prepared compounds were tested for their in vitro antitumor and cdc2 kinase or cdc25 phosphatase inhibitory activity. Compound ethyl 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][2,3- b]pyrido-1,4-thiazine-6-carboxylate (6b) showed antitumor activity against CNS SNB-75, breast T-47D, and lung NCI-H522 cancer cell lines with GI₅₀ values of 8.3, 17.6, and 22.7 μM, respectively. Meanwhile, the compounds ethyl 4-oxo-8-phenylthio-1H,4H-quinoline-3-carboxylate (11a) and 4-oxo-8- phenylthio-1H,4H-1,7-naphthyridine-3-carboxylic acid (12b) have proved to be cdc25 phosphatase inhibitors at IC₅₀ values of 11 and 5 μM, respectively.

Full text of DOI:10.1002/(SICI)1521-4184(19991)332:1<19::AID-ARDP19>3.0.CO;2-M

Quinolin-4-one and 1,7-Naphthyridin-4-one Analogs
19
Synthesis and Antitumor Activity of Some New Substituted
Quinolin-4-one and 1,7-Naphthyridin-4-one Analogs
H.I. El-Subbagh*, A.H. Abadi, I.E. Al-Khawad, and K.A. Al-Rashood
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Key Words: Synthesis; quinolin-4-one; 1,7-naphthyridin-4-one; antitumor testing; cdc kinase; phosphatase
Summary
The synthesis of some new analogs of quinolin-4-one and 1,7-
naphthyridin-4-one is described. The prepared compounds were
tested for their in vitro antitumor and cdc2 kinase or cdc25 phos-
phatase inhibitory activity. Compound ethyl 7-oxo-2,3-dihydro-
7H-pyrido [1,2,3-de][2,3-b]pyrido-1,4-thiazine-6-carboxylate
(6b) showed antitumor activity against CNS SNB-75, breast T-
47D, and lung NCI-H522 cancer cell lines with GI50 values of 8.3,
17.6, and 22.7 µM, respectively. Meanwhile, the compounds ethyl
4-oxo-8-phenylthio-1H,4H-quinoline-3-carboxylate (11a) and 4-
oxo-8-phenylthio-1H,4H-1,7-naphthyridine-3-carboxylic acid
(12b) have proved to be cdc25 phosphatase inhibitors at IC50
values of 11 and 5 µM, respectively.
Introduction
Quinolinones and their isosteric counterpart, naphthyridin-
ones are known for their antimicrobial and antitumor activ-
[1–9]
ity.
Nalidixic acid (A), the first prototypic “quinolinone”
and its modified analoge ofloxacin (B) were believed to exert
their activities through DNA intercalation and alteration of
the normal functions of bacterial gyrase and its corresponding
[7,10,11]
enzyme in human, namely topoisomerase II
. Quino-
linones and naphthyridinones were also found to inhibit tubu-
lin polymerization resulting in the disruption or the
suppression of both microtubule structure and normal func-
Figure 1
approach for the discovery of new and selective antitumor
agents.
In a previous paper
tions of the eukaryotic cells with consequent arrest of mito-
[12]
sis
. Several natural flavones e.g. 5,3′-dihydroxy-
[20]
, we reported the antitumor potency
3,6,7,8,4′-pentamethoxy-flavone (C) isolated from Polanisia
[13]
of some diaryl sulfide analogs; the activity of this type of
compound, e.g. F (Figure 1), was attributed to the presence
of the thioether function. In the present study, a new series of
quinolinone and its isosteric congeners, naphthyridinone,
were synthesized. The thioether function was introduced to
those heteroaromatic nuclei either in the form of a fused
tricyclic ring structure as in the pyrido[1,2,3-de]-1,4-ben-
zothiazine and its 10-aza isostere (6a,b and 7a,b) or as a
phenylthio substituent at position 8 of both heterocycles
(quinolinone and naphthyridinone) as in 11a,b and 12a,b.
Such combination has been designed in order to explore its
effect on antitumor activity as well as antimitotic potency as
cdc2 kinase and cdc25 phosphatase inhibitors.
dodecandra
, its synthetic amino analog NSC 664171 (D),
and its naphthyridinone isostere (E) (Figure 1), showed re-
markable in vitro cytotoxicity against panels of cell lines,
with GI values in the low micromolar or nanomolar con-
50
centration range in most of the human tumor cell lines tested
by the National Cancer Institute (NCI). Also they possess
inhibitory activity against tubulin polymerization compara-
ble to that of the potent antimitotic natural product col-
[9]
chicine
.
The cell division cycle comprises two major phases, the S
phase, during which DNA is replicated, and the M phase,
during which the replicated DNA is equally distributed
among the two daughter cells. These two phases are separated
by the “gap” periods G and G and are controlled by cyclin-
1
2
dependent kinases (cdk’s) such as cdc2 kinase and its activa-
Chemistry
[14–16]
tor cdc25 phosphatase
. Increasing evidence supports
the importance of cdk’s in human tumor development, as
The synthesis of the target compounds ethyl 7-oxo-2,3-di-
manifested by their overexpression which is always associ- hydro-7H-pyrido[1,2,3-de]-1,4-benzothiazine-6-carboxylate
[17–19]
ated with various types of tumors
. Thus, the inhibitions (6a), ethyl 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][2,3-
of cdc2 kinase and cdc25 phosphatase may provide a novel b]pyrido-1,4-thiazine-6-carboxylate (6b) and their corre-
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0365-6233/99/0101/0019 $17.50 +.50/0

20
El-Subbagh, Abadi, Al-Khawad, and Al-Rashood
Scheme 2. i – NaOH, H2O; ii – H2(g), 5% Pd/C, EtOH; iii – EMME, 120 °C,
neat, 2 h; iv – PPA, 160 °C, 1 h; v – 20% aq. NaOH.
yields (15, 30% respectively). The physical and analytical
data of the newly prepared compounds are listed in Table 1.
Scheme 1. i – NaOH, H2O; ii – H2 (g), 5% Pd/C, EtOH; iii – LiAlH4, THF;
iv – EMMF, 120 °C, neat 2h; v – PPA, 160 °C, 1 h; vi – 20% aq. NaOH.
Table 1: Physicochemical properties of compounds 3a–12b.
——————————————————————————————
sponding acids 7a,b are depicted in Scheme 1. Reaction of
2-chloronitrobenzene (1a) or 2-chloro-3-nitropyridine (1b)
with thioglycolic acid (2) in NaOH solution afforded the
corresponding thioethers 3a,b in good yield (84, 80%, respec-
Compd. X
No.
Solvent
Mp
(°C)
Yield Molecular
%
formulaa
——————————————————————————————
3a
CH
N
EtOH/H2O
EtOH
150–152
98–100
172–174
206–208
198–200
Oil
84
80
45
60
86
80
40
60
20
17
79
72
50
45
70
35
15
30
C8H7NO4S
C7H6N2O4S
C8H7NOS
C7H6N2OS
tively). The –NO function of 3a,b was then subjected to a
3b
2
reductive cyclization process using catalytic hydrogenation
4a
CH
N
EtOH/H2O
EtOH
(H , 5% Pd/C) to give the 1,4-thiazinone analogs 4a,b. Me-
2
4b
tallic reduction of 4a,b using LiAlH yielded the 1,4-thiazine
4
.
5a
CH
CH
CH
N
EtOH
C8H9NS HCl
derivatives 5a,b in reasonable yields (86, 80%, respectively).
The secondary amine moiety of 5a,b was further utilized by
allowing its reaction with diethyl(ethoxymethylene) malon-
ate (EMME) and the products were subsequently cyclized
using polyphosphoric acid (PPA) to afford the tricyclic ester
compounds 6a,b. The ester function of 6a,b was then hydro-
lyzed using 20% NaOH to give theircorresponding acids 7a,b
in poor yields (20, 17%, respectively).
The synthesis of the target compounds ethyl 4-oxo-8-
phenylthio-1H,4H-quinoline-3-carboxylate (11a), ethyl 4-
oxo-8-phenylthio-1H,4H-1,7-naphthyridine-3-carboxylate
(11b) and their corresponding acids 12a,b is outlined in
Scheme 2. Compound 1a or 1b was reacted with thiophenol
(8) to give the nitrothioether analogs 9a,b. Catalytic hydro-
genation of 9a,b afforded the corresponding aminothioether
derivatives 10a,b. The amino function of 10a,b was allowed
to react with EMME and the products were cyclized to afford
the quinolinone 11a and the naphthyridinone 11b. Hydrolysis
of the ester group of 11a,b gave the free acids 12a,b in poor
5b
EtOH
C7H8N2S
6a
EtOH/CHCl3
EtOH/CH2Cl2
DMF
148–150
85–87
C14H13NO3S
C13H12N2O3S
6b
7a
CH
N
195–198
136–137
C
12H9NO3S
C11H8N2O3S
12H9NO2S
C11H8N2O2S
7b
DMF/H2O
9a
CH
N
Toluene/Pet.ether 73–74
Toluene/Pet.ether 90–92
C
9b
.
10a
10b
11a
11b
12a
12b
CH
N
EtOH
213–214
C12H11NS HCl
EtOH/H2O
EtOH
147–148
120–122
105–106
202–204
194–196
C11H10N2S
CH
N
C18H15NO3S
C17H14N2O3S
EtOH/H2O
DMF
CH
N
C
16H11NO3S
DMF/H2O
C15H10N2O3S
——————————————————————————————
aAll compounds were analyzed for their C, H, N contents, results were within
±0.4% of the theoretical values.
Arch. Pharm. Pharm. Med. Chem. 332, 19–24 (1999)

Quinolin-4-one and 1,7-Naphthyridin-4-one Analogs
Biology: Results and Discussion
Antitumor Testing
21
In the present study, only compounds 6a, 6b, 11b, and 12b
showed GI values at concentrations < 100 µM (Table 2).
Those four compounds showed a distinctive potential pattern
of sensitivity against individual cell lines. Compound 6b
proved to be active against non-small cell lung NCI-H522
with GI and TGI values of 22.7 and 74.4 µM, respectively;
CNS SNB-75 with GI value of 8.3 µM and breast cancer
T-47D with GI value of 17.6 µM. Compound 11b proved
50
The prepared compounds were subjected to the NCI in vitro
disease-oriented human cells screening panel assay
[21–24]
.
50
About 60 cell lines of nine tumor subpanels were incubated
with five concentrations (0.01–100µM) for each compound
and were used to create log concentration – % growth inhibi-
tion curves. Three response parameters (GI , TGI, and LC )
50
50
to be active against leukemia cell lines CCRF-CEM (GI
50
22.3 µM), HL-60 (TB) (GI 27.5µM, TGI 83.2 µM), MOLT-
4 (GI 17.8 µM). Compound 11b also proved active against
non-small cell lung NCI-H522 with GI and TGI values of
19.7, 74.0 µM, respectively, and against ovarian IGROV1,
50
50
50
were calculated for each cell line. The GI value corresponds
50
50
to the compound’s concentration causing 50% decrease in net
cell growth, the TGI value is the compound’s concentration
resulting in total growth inhibition and the LC value is the
50
Renal UO-31, breast T-47D cancers with GI values of 21.7,
50
50
13.2, and 18.3, respectively. Compounds 6a and 12b showed
weak to moderate activity against many of the used tumor cell
lines.
Structure activity correlations of the obtained results re-
vealed that the isosteric replacement of CH in the quinoline
ring by N in the naphthyridine analogs increased the antitu-
mor activity as evidenced by the four folds increase in po-
compound’s concentration causing a net 50% loss of initial
cells at the end of the incubation period (48 h).
Table 2: Growth inhibitory concentration (GI50, µM) of some in vitro tumor
cells lines.a
——————————————————————————————
Cell lines
6a
6b
11b
12b
——————————————————————————————
tency of 6b (GI 22.7 µM) against non-small cell lung cancer
50
NCI-H 522 when compared by 6a (GI 91.5 µM). This is
Leukemia
50
b
also noticed in the case of CNS SNB-75 cancer (6b, GI
50
50
CCRF-CEM
HL-60 (TB)
MOLT-4
–
–
–
48.6
–
22.3
46.9
8.3 µM vs 6a, GI > 100µM) and breast T-47D (6b, GI
27.5(83.2c) 78.8
50
17.6 µM vs 6a, GI > 100 µM).
50
–
17.8
–
Comparing the activity of the cyclized thioether analog 6b
to the 8-phenylthio derivative 11b showed that the inclusion
of the S atom in a ring structure shifted the threshold of
Non-Small Cell Lung Cancer
A549/ATCC
HOP-92
–
69.9
66.4
32.1
87.6
46.9
32.3
–
–
–
Table 3: Inhibitory concentration (IC50, µM) of the new compounds on cell
cycle control enzymes.
–
NCI-H23
NCI-H522
–
——————————————————————————————
91.5
22.7(74.4c) 19.7(74.0c) 76.7
Compound
cdc2 kinase
cdc25 phosphatase
——————————————————————————————
Colon Cancer
a
3a
–
300
300
KM12
–
40.9
44.6
39.9
3b
–
a
4a
400
280
–
–
CNS Cancer
SNB-75
U251
–
–
8.3
71.1
44.4
–
–
4b
–
–
43.8
5a
5b
–
–
Melanoma
LOX IMVI
UACC-62
6a
500
550
350
–
–
–
–
57.4
51.7
31.0
36.7
44.2
–
6b
30
–
7a
7b
–
Ovarian Cancer
9a
220
350
350
400
130
300
ntb
–
55
310
310
300
11
120
ntb
5
IGROV1
–
40.5
57.6
21.7
13.2
–
–
9b
Renal Cancer
10a
10b
11a
11b
12a
12b
UO-31
77.7
Breast Cancer
BT-549
42.8
–
62.2
17.6
30.7
18.3
33.0
–
T-47D
——————————————————————————————
a
——————————————————————————————
a – , IC50 value of > 1000 µM. b nt, compound was not tested.
Data obtained from NCI’s in vitro disease-oriented human tumor cell
screen. b –, GI50 value > 100 µM. c TGI values in µM.
Arch. Pharm. Pharm. Med. Chem. 332, 19–24 (1999)

22
El-Subbagh, Abadi, Al-Khawad, and Al-Rashood
Acknowledgement
The authors are deeply grateful to the authority of the National Cancer
Institute, USA, for the antitumor screening and the Centre National de la
Recherche Scientifique, Station Biologique, Roscoff, France, for carrying
out the inhibitory effect of the prepared compounds on cdc2 kinase and cdc25
phosphatase.
Experimental Part
Synthesis
Melting points were determined in open capillaries on an Electrothermal
melting-point apparatus and are uncorrected. 1H-NMR spectra were recorded
on Varian XL-400 MHz spectrometer, chemical shifts are given in δ (ppm)
values down field from Me4Si as an internal standard. Elemental analyses
(C,H,N) were carried out by the Central Laboratory of the College of
Pharmacy, King Saud University, on Perkin-Elmer 2400 elemental analyzer,
results were within ± 0.4% of the theoretical values. Thin layer chromatog-
raphy (TLC) was performed on Merck 5 × 10 cm plates, precoated with silica
gel GF254. Chromatographic separations were carried out on Chromatotron
model No. 7924 T, Harrison Research, Palo Alto, CA.
Figure 2
potency from the inactive side towards activity particularly
against the leukemia cell lines CCRF-CEM, HL-60 (TB), and
MOLT-4 (6b, GI 48.6, >100 and >100 µM vs 11b, GI
50
50
22.3, 27.5, and 17.8 µM, respectively) (Table 2). This is also
found in case of Renal UO-31 (6b, GI 57.6 µM while 11b,
S-(2-Nitrophenyl)-thioglycolic Acid (3a) and S-(3-Nitropyridin-2-yl)-thio-
glycolic Acid (3b)
50
GI 13.2 µM). Hydrolysis of the ester function of 11b
50
produced the free acid 12b with an appreciable decrease in
the antitumor activity.
A solution of NaOH (1.76 g, 0.44 mol) in water (15 ml) was cooled to
10 °C and stirred. Thioglycolic acid (2, 2.0 g, 0.022 mol) was then added
followed by a solution of either 2-chloro-nitrobenzene (1a) or 2-chloro-3-ni-
tropyridine (1b) (0.022 mol) in ethanol (100 ml) while temperature was
maintained below 20 °C. The mixture was then refluxed for 1 h then cooled
and poured into ice water. The precipitated solid obtained upon acidification
with dilute HCl was collected by filtration, dried and recrystallized (Table 1).
1H-NMR (DMSO-d6), 3a: δ 4.75 (S, 2H, CH2), 8.50–9.00 (m, 4H, ArH),
11.80 (s, 1H, COOH). 3b: δ 4.0 (S, 2H, CH2), 7.40–8.80 (m, 3H, pyridine-H),
12.10 (s, 1H, COOH).
Inhibition of cdc2 Kinase and cdc25 Phosphatase
Cyclin-dependent kinases (cdk’s) play an important role in
cell division cycle regulation and human tumor development.
The inhibition of such regulators, e.g., cdc2 kinase and its
activator cdc25 phosphatase, may provide a novel approach
for the discovery of new antitumor agents. A compound is
3-Oxo-3,4-dihydro-2H-1,4-benzothiazine (4a) and 3-Oxo-3,4-dihydro-2H-
pyrido[2,3-b]-1,4-thiazine (4b)
considered an inhibitor to these two enzymes if its IC
<
50
A slurry of 3a or 3b (0.001 mol) and 350 mg of 5% Pd/C in ethanol
(200 ml) was subjected to hydrogenation using a Parr hydrogenator at 50 psi
for 5 h. Catalyst was then removed by filtration and filtrate was evaporated
in vacuo to give crude 4a or 4b. An analytically pure sample was obtained
by recrystallization (Table 1). 1H-NMR (DMSDO-d6) , 4a: δ 3.60 (S, 2H,
CH2), 7.40–7.60 (m, 4H, ArH), 10.60 (brs, 1H, NH). 4b: δ 3.60 (S, 2H, CH2),
7.20–7.40 (m, 2H, pyridine-H), 7.92–8.10 (m, 1H, pyridine-H), 10.60 (brs,
1H, NH).
[25]
50 µM
. Table 3 shows a list of the IC ’s of the prepared
50
compounds. All of the tested compounds showed no inhibi-
tory effect toward cdc2 kinase. On the other hand compounds
6b, 11a, and 12b proved to be cdc25 phosphatase inhibitors
at a concentrations of 30, 11, and 5 µM, respectively. These
results indicate that the antitumor activity of 6b and 12b
might be through an antimitotic mode of action while 11b
may exert its potency through some other mechanism(s). A
close examination of the obtained data suggests that the
3,4-Dihydro-2H-1,4-benzothiazine (5a) and 3,4-Dihydro-2H-pyrido[2,3-b]-
1,4-thiazine (5b)
3-COOH group in 12b (IC , 5 µM) is essential for cdc25
phosphatase inhibition if compared with its ester precursor
50
A solution of 4a or 4b (0.05 mol) in dry THF (100 ml) was added dropwise
to a suspension of LiAlH4 (2.4 g, 0.06 mol) in dry THF (50 ml). The reaction
mixture was stirred at room temperature for 2 h, then dilute HCl was added
to destroy the excess of LiAlH4. The mixture was filtered and the solution
was alkalinized with 10% NaOH and extracted with CHCl3. The chloroform
extract was washed with water, dried, and evaporated. The obtained residue
was chromatographed to provide 5a and 5b (Table 1). 1H NMR (DMSO-d6),
5a: δ 3.38–3.42 (m, 2H, CH2NH), 3.65–3.80 (t, 2H, CH2S), 6.70–8.60 (m,
5H, ArH, and NH). 5b: δ 3.35–3.46 (m, 2H, CH2NH), 3.75–3.82 (t, 2H,
CH2S), 6.80–8.80 (m, 3H, pyridine-H), 9.20 (brs, 1H, NH).
11b (IC , 120 µM).
50
In conclusion, the obtained data suggests that the 1,7-
naphthyridinone series is more potent antitumors than the
quinolinone series (6b > 6a, Figure 2 and Table 2). The
introduction of S atom at position 8 as a thioether function
yielded a more potent analogue rather than its inclusion in the
form of a fused 1,4-thiazine ring (11b > 6b, Figure 2 and
Table 2). The 3-COOEt function seemed to be more contrib-
uting to the antitumor activity than the 3-COOH (11b > 12b,
Figure 2); on the contrary, the 3-COOH seemed to be in the
favor of the cdc25 phosphatase inhibition activity rather than
the 3-COOEt group. Future research efforts will focus on the
derivatization of compounds 11b and 12b as antitumor and
cdc25 phosphatase inhibitor, respectively.
Ethyl 7-Oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzothiazine-6-carbox-
ylate (6a) and Ethyl 7-Oxo-2,3-dihydro-7H-pyrido [1,2,3-de][2,3-b]pyrido-
1,4-thiazine-6-carboxylate (6b)
A mixture of 5a or 5b (0.025 mol) and 10.0 g of diethyl(ethoxymethylene)
malonate (EMME) was heated at 120°C for 2 h. Polyphosphoric acid (35 g)
was added, and the mixture was then gradually heated to 160°C and kept at
that temperature for 1 h. After cooling, the reaction mixture was poured into
Arch. Pharm. Pharm. Med. Chem. 332, 19–24 (1999)

Quinolin-4-one and 1,7-Naphthyridin-4-one Analogs
23
ice-water and the separated solid was collected by filtration, washed with
10% NaHCO3, water and then recrystallized to afford 6a and 6b (Table 1).
1H NMR (DMSO-d6), 6a: δ 1.48–1.50 (t, J = 7.2Hz, 3H, CH3-CH2), 3.40–
3.52 (m, 2H, CH2S), 4.25–4.32 (q, J = 7.2 Hz,2H,CH3CH2), 4.95–5.10 (m,
2H, CH2N), 7.80–8.10 (m, 3H, ArH), 9.20 (s, 1H, N-CH=C). 6b: δ 1.50–
1.53(t, J = 7.3 Hz, 3H, CH3CH2), 3.65–3.70 (m, 2H, CH2S) 4.25–4.30 (q, J =
7.3 Hz, 2H, CH3CH2), 5.10–5.20 (m, 2H, CH2N), 7.10–8.00 (m, 2H, pyri-
dine-H), 9.10 (s, 1H, N-CH=C).
Biological Testing
Antitumor Screening
Compound 3a–12b were subjected to the NCI in vitro screening panel
assays. Sixty different cell lines of nine tumor subpanels were incubated with
five concentrations (0.01–100 µM) of each tested compound for 48 h. Dose
response parameters were calculated as given previously [21–24]
.
Inhibition of cdc2 Kinase and cdc25 Phosphatase
7-Oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzothiazin-6-carboxylic
Acid. (7a) and 7-Oxo-2,3-dihydro-7H-pyrido[1,2,3-de][2,3-b]pyrido-1,4-
thiazine-6-carboxylic Acid (7b)
The cdc2 kinase activity is assayed, in the presence of potential inhibitors,
using histone H1 and 32P-labelled ATP, as described elsewhere [25], highly
purified recombinant glutathione-S-transferase/cdc25 fusion protein, as-
sayed colorimetrically for p-nitrophenylphosphate activity in microtitration
A suspension of 6a or 6b (1.0 g) in 20% NaOH solution (50 ml) was stirred
for 3 h. The cooled mixture was acidified with HCl till pH 5–6 and the
precipitate formed was filtered and washed with water then recrystallized to
afford 7a and 7b (Table 1). 1H NMR (DMSO-d6), 7a: 3.30–3.5 (m, 2H,
CH2S), 4.8–5.0 (m, 2H, CH2N), 7.90–8.20 (m, 3H, ArH), 9.10 (s, 1H,
N-CH=C), 11.10 (s, 1H, COOH). 7b: 3.69–3.75 (m, 2H, CH2S), 5.15–5.30
(m, 2H, CH2N), 7.20–7.9 (m, 2H, pyridine-H), 9.30 (s, 1H, N-CH=C), 11.30
(s, 1H, COOH).
plates [26,27]
.
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[3] L. Li, H. Wang, S. Kuo, T. IUu, D. Lednicer, C. Lin, E. Hame, K. Lee,
2-Phenylthio-nitrobenzene (9a) and 2-Phenylthio-3-nitropyridine (9b)
J. Med. Chem. 1994, 37, 1126.
A solution of NaOH (8.0 g, 0.2 mol) in water (100 ml) was cooled to
10–15 °C and stirred. Thiophenol (8, 11.0 g, 0.1 mol) was then added fol-
lowed by a solution of either 2-chloronitrobenzene (1a) or 2-chloro-3-ni-
tropyridine (1b) (0.1 mol) in ethanol (100 ml) and continued as mentioned
under 3a,b to afford 9a and 9b (Table 1). 1H NMR (DMSO-d6), 9a: δ
7.15–7.48 (m, 5H, ArH), 7.62–8.35 (m, 3H, ArH), 8.56–8.92 (m, 1H, ArH).
9b: δ 7.20–7.52 (m, 5H, ArH), 7.64–8.50 (m, 1H, ArH), 8.73–9.30 (m, 2H,
ArH).
[4] M. Liu, T. Lin, P. Penketh, A. Sartorelli, J. Med. Chem. 1995, 38, 4234.
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B. Stefanska, J. Mazerski, S. Martelli, J. Med. Chem. 1997, 40, 3749.
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Hilliard, J. Barrett, J. Med. Chem. 1997, 40, 3292.
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W. Denny, J. Med. Chem. 1997, 40, 1381.
2-Phenylthio-aniline (10a) and 2-Phenylthio-3-aminopyridine (10b)
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Med. Chem. 1997, 40, 2266.
A slurry of 9a or 9b (0.001 mol) and 350 mg of 5% Pd/C in ethanol
(200 ml) was subjected to catalytic hydrogenation using a Parr hydrogenator
at 50 psi for 3 h, and continued as mentioned under 4a,b to give 10a and 10b
(Table 1). 1H NMR (DMSO-d6), 10a: δ 7.10–7.50 (m, 7H, ArH), 7.55–7.83
(m, 4H, ArH, and NH2). 10b: δ 7.21–7.54 (m, 5H, ArH), 7.56–7.91 (m, 3H,
pyridine-H), 8.10 (brs, 2H, NH2).
[10] T.M. Seay, S. J. Peretsman, P.S. Dixon, J. Urol. 1966, 155, 757.
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Mol. Pharmacol. 1988, 34, 200.
Ethyl 4-oxo-8-phenylthio-1H, 4H-quinoline-3-carboxylate (11a) and Ethyl
4-oxo-8-phenylthio-1H,4H-1,7-naphthyridine-3-carboxylate (11b)
[13] G. Shi, K. Chen, L. Li, J. Chang, C. Autry, M. Kozuka, T. Konoshima,
J. Estes, C. Lin, E. Hamel, A. McPhail, K. Lee, J. Nat. Prod., 1995, 58,
475.
A mixture of 10a or 10b (0.025 mol) and 10 g of diethyl(ethoxymethylene)
malonate (EMME) was heated at 120 °C for 2 h. Polyphosphoric acid (35 g)
was then added, and the mixture was gradually heated to 160°C and kept at
that temperature for 1 h. The reaction mixture was then worked up as
mentioned under 6 a,b to afford 11a and 11b (Table 1). 1H NMR (DMSO-d6),
11a: δ 1.40–1.42 (t, J = 7.2Hz, 3H, CH3CH2), 4.25 –4.30(q, J = 7.2 Hz, 2H,
CH3CH2), 7.20–7.90 (m, 8H, ArH), 8.20 (d, J = 2Hz, 2H, NH-CH=C), 11.4
(brm, 1H, NH). 11b: δ 1.49–1.53 (t, J = 7.3 Hz, 3H, CH3CH2), 4.32–4.37 (q,
J = 7.3 Hz, 2H, CH3CH2), 7.25–8.4 (m, 8H, ArH, and pyridine-H), 11.0 (brm,
1H, NH).
[14] P. Fantes, R. Brooks, The Cell Cycle–A Practical Approach, IRL Press,
Oxford, U.K. 1994.
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Plenum Press, New York 1994.
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4-Oxo-8-phenylthio-1H,4H-quinoline-3-carboxylic acid (12a) and
4-Oxo-8-phenylthio-1H,4H-1,7-naphthyridine-3-carboxylic acid (12b)
Badria, Boll. Chim. Farmaceutico 1995, 134, 80.
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A suspension of 11a or 11b (1.0 g) in 20% NaOH solution (50 ml) was
stirred at r.t. for 3 h, and the procedure continued as mentioned under 7 a,b
to give 12a and 12b (Table 1).1H- NMR (DMSO-d6), 12a: δ 7.3–7.95 (m,
8H, ArH), 8.40 (d, J = 2Hz, 1H,NH-CH=C), 11.0 (brm, 1H, NH), 11.90 (s,
1H, COOH). 12b: δ 6.70 (brm, 1H, NH), 7.4–8.9 (m, 8H, ArH), 12.2 (s, 1H,
COOH).
622.
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Strategies for the NCI Disease-Oriented in vitro Antitumor Drug
Screen, Klaur Academic Publisher, Amsterdam 1992.
Arch. Pharm. Pharm. Med. Chem. 332, 19–24 (1999)

24
El-Subbagh, Abadi, Al-Khawad, and Al-Rashood
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H. Fiebig, A. Makriyannis, J. Med. Chem. 1996, 39, 2609.
Received: September 29, 1998 [FP334]
Arch. Pharm. Pharm. Med. Chem. 332, 19–24 (1999)