Identification of antitumor activity of pyrazole oxime ethers

Article abstract of DOI:10.1016/j.bmcl.2005.03.082

A series of pyrazole oxime ether derivatives were prepared and examined as cytotoxic agents. In particular, 5-phenoxypyrazole was comparable to doxorubicin, while exhibiting very potent cytotoxicity against XF 498 and HCT15.

Full text of DOI:10.1016/j.bmcl.2005.03.082

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3307–3312
Identification of antitumor activity of pyrazole oxime ethers
Hyun-Ja Park, Kyung Lee, Su-Jin Park, Bangle Ahn, Jong-Cheol Lee,
HeeYeong Cho and Kee-In Lee*
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107,
Yusong, Taejon 305-600, Republic of Korea
Received 17 January 2005; revised 15 March 2005; accepted 22 March 2005
Available online 26 May 2005
Abstract—A series of pyrazole oxime ether derivatives were prepared and examined as cytotoxic agents. In particular, 5-phenoxypyr-
azole was comparable to doxorubicin, while exhibiting very potent cytotoxicity against XF 498 and HCT15.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
number of conformations by heterocyclic core and hin-
dered rotation by substituents. This prompted us to syn-
thesize pyrazole oxime ether derivatives and evaluate
their inhibitory potential against tumor cell lines.
The pyrazole ring is a prominent structural motif found
in numerous pharmaceutically active compounds. Due
to the easy preparation and rich biological activity, pyr-
azole framework plays an essential role in biologically
active compounds and therefore represents an interest-
ing template for combinatorial1 as well as medicinal
chemistry.2–4 Indeed, pyrazole-based derivatives have
shown several biological activities as seen in COX-2,2
p38 MAP kinase,3 and CDK2/Cyclin A inhibitors.4
Many of them are currently being tested and/or clini-
cally evaluated for new drug discovery.
In order to find structural types, we needed a systematic
replacement with a wide range of substituents within
pyrazole moiety. We envisioned that the Vilsmeier–
Haack chloroformylation of pyrazolone would offer a
quite straightforward and easy access to a number of
multi-functionalized pyrazole oxime ethers, as shown
in Figure 1. Thus, the starting pyrazolone could be pre-
pared by the condensation of the corresponding b-keto-
ester with hydrazines, according to the well-known
procedure. The remaining synthesis included (a) Vilsme-
ier–Haack chloroformylation of pyrazolone A, (b) intro-
duction of nucleophile into 5-chloropyrazole B to
produce 5-substituted pyrazole C by nucleophilic aro-
matic substitution, and (c) oximation of 4-formylpyraz-
ole C and (d) the subsequent Williamson synthesis to
In the search for antitumor agents, a certain number of
in-house-stock pyrazole oxime compounds exhibited
promising antiproliferative properties against several
kinds of human tumor cell lines. Our attention was
focused on the pyrazole scaffold, which produces a
number of compounds that are constrained to a limited
O
N
R4
O
O
R2
N
R2
N
R2
N
R2
N
a
b
c
H
R3
H
H
O
Cl
R3
N
R1
N
R1
N
R1
N
R1
A
B
C
D
Figure 1. Easy access to a number of multi-functionalized pyrazole oxime ethers.
Keywords: Pyrazolone; Chloroformylation; Pyrazole oxime ether; Cytotoxicity.
*
Corresponding author. Tel.: +82 42 860 7186; fax: +82 42 860 7160; e-mail: kilee@krict.re.kr
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.082

3308
H.-J. Park et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3307–3312
give pyrazole oxime ether D. Here, we would like to re-
port the generation of multi-functionalized pyrazole
oxime ethers and their preliminary biological results.
mixture of 5-chloropyrazole, phenol, and KOH in
DMF and gave 5-phenoxypyrazole derivatives 3a–f,
respectively, without any problem. Finally, many pyr-
azole oxime ethers were generated by the oximation of
4-formylpyrazoles with hydroxylamine and the subse-
quent Williamson synthesis of 5-phenoxypyrazole oxi-
mes with various alkyl halides, as shown in Scheme 1.
2. Results and discussion
2.1. Synthesis of pyrazole oxime ethers
2.2. Antitumor activities of pyrazole oxime ethers
The starting pyrazolone 1a (R1 = Me, R2 = Me) was
easily synthesized by the condensation of ethyl acetoace-
tate with methylhydrazine in a quantitative yield. Also,
the known pyrazolones 1b–e were prepared from the
corresponding two components, respectively.5 The pyr-
azolones 1a–e were then subjected to the Vilsmeier–
Haack chloroformylation using DMF and an excess
POCl3 to yield the corresponding 5-chloro-4-formylpyr-
azoles 2a–e, according to the literature procedures.6
Previously, we studied the facile introduction of nucleo-
philes into 5-chloro-pyrazole, activated by the ortho-for-
myl group, by the nucleophilic aromatic substitution.7
Thus, the reaction was simply carried out by heating a
The antiproliferative potential of the synthesized com-
pounds 5–28 was determined in vitro against several hu-
man tumor cell lines such as HepG2 (liver), MCF7
(breast), MKN45 (stomach), and A549 (lung) by sulfo-
rhodamine B (SBR) assay.8 The cytotoxicity values were
obtained as % inhibition at 1 lM and are summarized in
Table 1 showing different sub-class of structural types.
The table shows pyrazole oxime ether compounds 5–15
with random alkyl or aromatic groups at R1 and R2
positions, still commonly have phenoxy at the R3 and
benzyl group at the R4 position. The results exhibit that
OH
O
N
R2
N
R2
N
O
R2
N
H
R2
N
H
O
H
O
N
R1
ii
iii
i
N
R1
O
Cl
N
R1
N
R1
R3'
R3'
1a-e
2a-e
3a-f
4a-f
O
H
N
R4
R2
N
iv
O
N
R1
R3'
5-28
R2
R1
R1
R2
R3′
1/2
3/4
a
Me
Ph
Ph
Ph
Me
Me
Pri
Me
Me
Ph
Me
Me
Me
Pri
H
a
b
c
Cl
Cl
Cl
Cl
H
b
c
Ph
Ph
d
e
d
e
2-Pya
Me
Ph
Ph
2-Py
Me
f
Scheme 1. Reagents and conditions: (i) POCl3, DMF, 120 °C; (ii) HOPh (for 3a and 3f) or HOPh-p-Cl (for 3b–e), KOH, DMF, 120 °C; (iii) NH2OH,
NaOH, MeOH, 60 °C; (iv) R4-Xb (X = Cl or Br), KOH/DMSO/50 °C or NaH/THF/0 °C. a2-Py = 2-piridinyl. bThe structures of R4 are shown in
Table 1.

H.-J. Park et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3307–3312
Table 1. Cytotoxicity of pyrazole oxime ether
3309
Compd.
4
R4
% Inhibition at 1 lM
MCF7 MKN45
8.4
HepG2
A549
5
4a
CH2Ph-3-OMe
CH2Ph-4-Me
CH2Ph-4-CF3
ꢀ41.2
8.4
5.8
ꢀ19.6
1.0
29.1
6
38.2
30.5
17.9
11.0
7
34.7
39.4
8
CH2Ph-4-NO2
CH2Ph-2-Me-3-Ph
CH2Ph-4-CO2Et
CH2Ph-4-CO2But
CH2Ph-4-CO2But
CH2Ph-4-CF3
ꢀ2.8
24.0
24.4
18.3
9
ꢀ13.2
ꢀ31.8
ꢀ31.1
ꢀ14.7
ꢀ2.2
ꢀ12.1
ꢀ17.8
ꢀ9.9
5.0
10
11
12
13
14
15
16
4c
4d
12.0
ꢀ9.9
ꢀ6.5
ꢀ10.6
ꢀ12.1
ꢀ10.1
ꢀ9.1
ꢀ5.9
ꢀ8.4
ꢀ4.9
ꢀ1.9
ꢀ17.5
ꢀ14.8
8.9
ꢀ27.0
ꢀ15.4
ꢀ15.0
ꢀ9.8
4e
4f
CH2Ph-2-Me-3-Ph
CH2Ph-4-CO2But
(CH2)2NMe2
ꢀ14.8
ꢀ25.1
ꢀ36.1
4a
ꢀ29.0
17
18
19
20
21
22
ꢀ25.0
ꢀ29.0
ꢀ40.5
6.7
7.7
3.2
ꢀ24.2
ꢀ22.5
ꢀ28.0
10.5
ꢀ8.2
ꢀ9.9
ꢀ19.4
28.4
(CH2)2N
(CH2)2N
5.4
(CH2)2N
(CH2)2N
(CH2)2N
(CH2)2N
O
23.4
37.7
32.0
NCH2Ph
14.4
15.4
39.7
NCH2Ph-4-CF3
NCH2Ph-4-CO2But
19.8
19.2
44.7
23
24
25
26
27
28
4b
CH2Ph-4-Me
31.3
13.9
20.6
18.4
20.3
27.4
30.7
37.0
16.4
27.1
33.6
33.9
30.4
28.1
27.6
24.6
26.1
20.9
50.0
43.9
50.9
39.6
49.9
48.2
CH2Ph-4-OMe
CH2Ph-4-CF3
CH2Ph-4-NO2
CH2Ph-4-CO2Me
CH2Ph-4-CO2Et
only three compounds 6–8 (R1, R2 = Me) have moderate
potency of around 30% inhibition at 1 lM against
MCF7 and A549, even though weak cytotoxicity was
observed for other analogues. It is interesting to note
that the compounds (6–7) having electron-withdrawing
groups at the R4 proved to be more active than the com-
pound 5. When the methyl groups on pyrazole had been
replaced by a bigger group (10–13), the detrimental po-
tency was observed even in the presence of the electron-
withdrawing groups. This clearly suggests that next ap-
proach should narrow a scope into the structural pattern
featuring small alkyl groups at R1 and R2 positions.
are also indicated in Table 1. The compounds with
two carbon atoms between the oxime and the side-chain
nitrogen atom (16–19) show a very weak potency com-
paring to those with benzyl group (6–8). Thus, introduc-
tion of flexible spacer or hydrophilic surrounding is not
necessary, presumably, due to moderate out of plane in
certain directions. Interestingly, the compounds with N0-
substituted piperazine moiety (20–22) regained the po-
tency reaching around 40% inhibition at 1 lM against
A549. We believed that, in those cases, electronic char-
acter could be diminished in a bulky hydrophobic
environment.
Thus, starting from 3a and 3b, wide ranges of com-
pounds with benzyl or 2-aminoethyl group at the R4 po-
sition, in principle, possessing a hydrophobic or
hydrophilic character were prepared in good to fair
yield. The structures of the prepared compounds 16–28
The compounds with benzyl group at R4 position show
the potent cytotoxic activities against broad range of tu-
mor cell lines. The benzylic derivatives 23–28 are more
potent than those of 2-aminoethyl derivatives (16–19).
While all of the compounds exhibited moderate activity

3310
H.-J. Park et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3307–3312
against four cell lines, they were strongly effective
against A549 with >40% inhibition at 1 lM. The com-
pounds 25–26 sustained a slightly higher potency than
the parent compounds 7–8, which led us to explore the
modification of the R3 position of the pyrazole skeleton.
phenol. The reaction generously allowed the intro-
duction of a wide range of heterocycles into the pyrazole
ring.7 The remaining steps included oximation of 4-form-
yl-pyrazole derivatives and the subsequent alkylation
with the tert-butyl ester, respectively. The structures of
R3 are depicted in Table 2.
From the results in Table 1, we needed to design the
molecular structures for further study. It is desirable
that the pyrazole skeleton should have smaller groups
at the R1 and R2, and bulky group at the R4 position.
Generally, the results show that the introduction of ben-
zyl group at R4 enhanced the cytotoxic activities and
also suggest that the hydrophobic group is more favor-
able. From this point of view, we eventually chose the
benzyl group hanging tert-butyl ester at para position
of the phenyl ring. Next, we readily undertook a modi-
fication of the remaining R3 position of the pyrazole
skeleton.
The growth suppressing potential of pyrazol oxime ether
derivatives was investigated by determining their IC50
values by SBR assay against human solid tumor cell
lines: A549 (non-small cell lung), SKOV-3 (ovarian),
SKMEL-2 (melanoma), XF 498 (CNS), and HCT15
(colon). The cytotoxic activities of the compounds pre-
pared including cisplatin and doxorubicin are summa-
rized in Table 2. In general, the amine derivatives 29–
35 commonly show decreased cytotoxicity compared
to the oxygen derivatives, but are still comparable to cis-
platin. The compounds 36–38 that contain phenyl resi-
due at the R3 position show relatively potent activity.
Interestingly, the compound 36 was known as fenpyroxi-
mate, one of the most important insecticides acting at
proton-translocating NADH:ubiquinone oxidoreduc-
tase.9 The compounds 36 and 37 were proved to be less
or more active than doxorubicin depending on the cell
The compounds 29–38 were similarly prepared as de-
picted in Scheme 1. Starting from 2a, we extended the
nucleophilic aromatic substitution to the readily avail-
able heteroatom-containing nucleophiles such as di-
methylamine, pyrrolidine, imidazole, indole, and thio-
Table 2. Antitumor activity of 3-substituted pyrazole oxime ether
Compound
R3
Cytotoxicity IC50 (lg/mL)
A549
2.76
SKOV-3
9.06
SKMEL-2
23.94
XF498
3.87
HCT15
6.22
29
30
NMe2
N
0.13
0.39
1.64
3.19
8.87
3.91
14.44
16.71
24.90
0.12
1.04
2.67
0.10
1.83
2.48
31
32
N
N
O
N
N
33
34
2.49
5.93
9.63
28.78
9.35
5.51
8.15
3.63
8.67
N
14.08
N
N
35
0.43
2.07
26.51
1.61
1.57
36
37
O
O
S
0.12
0.10
0.21
0.28
13.27
18.78
0.04
0.02
0.02
0.01
Cl
38
0.13
0.92
4.91
0.28
0.26
Cisplatin
Doxorubicin
—
—
3.09
0.05
3.42
0.09
3.28
0.07
3.47
0.09
6.91
0.28

H.-J. Park et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3307–3312
3311
lines, while exhibiting very potent cytotoxicity against
XF 498 and HCT15. In this regard, the phenoxy deriva-
tive could be a promising lead candidate, although its
molecular target remains to be determined by further
studies.
The residue was purified by flash chromatography on
silica gel (hexane/EtOAc = 6:1) to give 6 (189 mg,
56%); H NMR (DMSO–d6) d 7.71 (s, 1H), 7.41–7.36
(m, 2H), 7.18–7.08 (m, 5H), 6.96–6.93 (m, 2H), 4.85 (s,
2H), 3.54 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H); MS
(70 eV) m/z (rel intensity) 335 (M+, 3), 227 (8), 128 (9),
105 (100), 77 (23); Anal. Calcd for C20H21N3O2: C,
71.62; H, 6.31; N, 12.53; O, 9.54. Found: C, 71.58; H,
6.78; N, 12.97; O, 9.75.
1
In summary, a number of multi-functionalized pyrazole
oxime ethers 5–38 were conveniently prepared from pyr-
azolones utilizing Vilsmeier–Haack chloroformylation.
Investigation of structure–activity relationships has
identified 5-phenoxypyrazole as a promising scaffold
showing potent cytotoxicity against various human tu-
mor cell lines. The compounds 36 and 37 were proved
to be less or more active than doxorubicin depending
on the cell lines, while exhibiting very potent cytotoxi-
city against XF 498 and HCT15. Further modification
of the structure and identification of its molecular target
are under investigation.
7. 53% (yield); 1H NMR (DMSO–d6) 7.80 (s, 1H), 7.66–
7.63 (m, 2H), 7.45–7.34 (m, 4H), 7.16–7.11 (m, 1H),
6.94–6.92 (m, 2H), 5.00 (s, 2H), 3.54 (s, 3H), 2.21 (s,
3H); MS (70 eV) m/z (rel intensity) 389 (M+, 20), 214
(90), 199 (91), 144 (44), 77 (44).
1
8. 58% (yield); H NMR (CDCl3) 8.14–8.12 (m, 2H),
7.84 (s, 1H), 7.40–7.37 (m, 2H), 7.32–7.25 (m, 1H),
7.12–7.07 (m, 1H), 6.87–6.84 (m, 2H), 5.06 (s, 2H),
3.59 (s, 3H), 2.32 (s, 3H); MS (70 eV) m/z (rel intensity)
366 (M+, 40), 258 (15), 214 (38), 199 (58), 128 (42), 77
(100); Anal. Calcd for C19H18N4O4: C, 62.29; H, 4.95;
N, 15.29; O, 17.47. Found: C, 62.10; H, 5.21; N,
16.00; O, 17.21.
3. Experimental
3.1. Preparation of 5-pyrazolones (1a–e)
The starting pyrazolones were readily prepared by the
reactions of the appropriate hydrazines with b-ketoest-
ers according to the literature procedures.5
1
20. 30% (yield); H NMR (CDCl3) 7.69 (s, 1H), 7.24–
7.16 (m, 7H), 7.02–7.01 (m, 1H), 6.80 (d, 2H,
J = 9.0 Hz), 4.02 (t, 2H, J = 6.0 Hz), 3.52 (s, 3H), 3.42
(s, 2H), 2.50 (t, 2H, J = 6.0 Hz), 2.29 (s, 3H); MS
(70 eV) m/z (rel intensity) 433 (M+, 5), 216 (16), 203
(37), 189 (100), 91 (71); Anal. Calcd for C25H31N5O2:
C, 69.26; H, 7.21; N, 16.15; O, 7.38. Found: C, 68.08;
H, 7.91; N, 18.24; O, 9.06.
3.2. Preparation of 5-chloro-4-formylpyrazoles (2a–e)
The known 5-chloro-4-formylpyrazoles were prepared
from the 5-pyrazolones employing Vilsmeier–Haack
chloroformylation.6 Thus, 5-pyrazolones were heated
with an excess phosphorus oxychloride in DMF to af-
ford the corresponding 5-chloro-4-formylpyrazoles.
1
21. 44% (yield); H NMR (CDCl3) 7.78 (s, 1H), 7.58–
7.56 (m, 2H) 7.46–7.43 (m, 2H), 7.34–7.28 (m, 2H),
7.11–7.06 (m, 1H) 6.91–6.88 (m, 2H), 4.14–4.09 (m,
2H), 3.55 (s, 2H), 2.59 (t, 2H, J = 3.0 Hz), 2.48 (s,
8H); MS (70 eV) m/z (rel intensity) 501 (M+, 8), 271
(15), 257 (100), 216 (22), 159 (33).
3.3. Preparation of 5-substituted-4-formylpyrazoles (3a–f)
The nucleophilic aromatic substitution was conveniently
carried out by heating a mixture of 5-chloro-4-formylpyr-
azole and the corresponding nucleophile with pow-
dered KOH in DMF to give 5-substituted pyrazole
according to the previously described procedure.7
22. 58% (yield); oil; 1H NMR (CDCl3) 7.78 (d, 2H,
J = 8.1 Hz), 7.62 (s, 1H), 7.23–7.12 (m, 4H), 6.96–6.91
(m, 1H), 6.75–6.72 (m, 2H), 4.01–3.94 (m, 2H), 2.47 (s,
4H), 2.36 (s, 4H), 3.39 (s, 2H), 1.49 (m, 2H), 1.44 (s,
9H); MS (70 eV) m/z (rel intensity) 533 (M+, 3), 342
(30), 233 (58), 135 (100), 57 (85); Anal. Calcd for
C30H39N5O4: C, 67.52; H, 7.37; N, 13.12; O, 11.99.
Found: C, 65.19; H, 6.90; N, 12.71; O, 11.88.
3.4. Preparation of pyrazole oximes (4a–f)
The treatment of 4-formylpyrazole with hydroxylamine
hydrochloride in NaOH/EtOH gave the corresponding
pyrazole oxime in good yield. All pyrazole oximes
were isolated as single isomers and assigned as E-
geometry.6a
1
23. 52% (yield); H NMR (CDCl3) 7.70 (s, 1H), 7.25–
7.01 (m, 6H), 6.75–6.70 (m, 2H), 5.36 (s, 2H), 3.53 (s,
3H), 3.42 (s, 3H), 2.19 (s, 3H); MS (70 eV) m/z (rel inten-
sity) 369 (M+, 52), 242 (30), 105 (100), 77 (42), 65 (20);
Anal. Calcd for C20H20ClN3O2: C, 64.95; H, 5.45; N,
11.36; O, 8.65. Found: C, 65.61; H, 5.51; N, 13.10; O,
8.63.
3.5. General procedure for the synthesis of 6
To an ice-cooled solution of 4a (232 mg, 1.0 mmol) in
THF (10 mL) were added NaH (31 mg, 1.3 mmol) and
then 4-methylbenzyl chloride (169 mg, 1.2 mmol) under
the nitrogen atmosphere. The solution was stirred for
overnight at room temperature. The solvent was re-
moved and the resulting residue was partitioned with
EtOAc and water. The organic layer was washed succes-
sively with brine and water and dried over Na2SO4, then
evaporated under reduced pressure to give a residue.
1
25. 88% (yield); H NMR (CDCl3) 7.83 (s, 1H), 7.31–
7.23 (m, 2H), 7.56–7.41 (m, 2H), 7.31–7.23 (m, 2H),
6.84–6.79 (m, 2H), 5.13 (s, 2H), 3.61 (s, 3H), 2.34 (s,
3H); MS (70 eV) m/z (rel intensity) 423 (M+, 60), 248
(100), 233 (62), 159 (90), 123 (47).

3312
H.-J. Park et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3307–3312
1
A.; Grimsey, P.; Hird, N. W.; MacLachlan, W. S.; Vimil,
M. Tetrahedron Lett. 1999, 40, 1405; (c) Grosche, P.;
Holtzel, A.; Walk, T. B.; Trautwein, A. W.; Jung, G.
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28. 47% (yield); H NMR (CDCl3) 7.92–7.89 (s, 2H),
7.74 (s, 1H), 7.22–7.15 (m, 4H), 6.74–6.71 (m, 2H),
4.94 (s, 2H), 4.29 (q, 2H, J = 7.2 Hz), 1.32 (t, 3H,
J = 7.1 Hz), 3.51 (s, 3H), 2.25 (s, 3H); MS (70 eV) m/z
(rel intensity) 427 (M+, 47), 247 (100), 163 (87), 135
(60), 107 (40); Anal. Calcd for C22H22ClN3O4: C,
61.75; H, 5.18; N, 9.82; O, 14.96. Found: C, 59.43; H,
5.19; N, 10.54; O, 14.63.
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5. (a) Khan, M. A.; Ellis, G. P.; Pagotto, M. C. J. Heterocycl.
Chem. 2001, 38, 193; (b) Reiner, K.; Richter, R.; Haupt-
mann, S.; Becher, J.; Hennig, L. Tetrahedron 1995, 51,
13291.
1
30. 58% (yield); H NMR (CDCl3) 8.14 (s, 1H), 7.96–
7.99 (d, 2H, J = 8.1 Hz), 7.41–7.44 (d, 2H, J = 8.1 Hz),
5.15 (s, 2H), 3.65 (s, 3H), 3.13–3.18 (t, 2H,
J = 6.6 Hz), 2.26 (s, 3H), 1.87–1.91 (m, 2H), 1.60 (s,
9H); MS (70 eV) m/z (rel intensity) 398 (M+, 3), 325
(36), 191 (100), 174 (38), 134 (33); Anal. Calcd for
C22H30N4O3: C, 66.31; H, 7.59; N, 14.06; O, 12.04.
Found: C, 65.35; H, 8.11; N, 14.67; O, 12.95.
1
36. 79% (yield); H NMR (CDCl3) 7.93–7.90 (d, 2H,
J = 9.0 Hz), 7.82 (s, 1H), 7.26–7.33 (m, 4H), 7.13–7.09
(t, 1H, J = 12.0 Hz), 6.88–6.86 (d, 2H, J = 8.8 Hz),
5.03 (s, 2H), 3.59 (s, 3H), 2.34 (s, 3H), 1.59 (s, 9H);
13C NMR (CDCl3) d 16.0, 29.4, 35.4, 76.6, 82.2, 101.4,
116.5, 124.9, 129.1, 130.7, 131.2, 132.6, 142.3, 143.7,
148.2, 149.0, 158.0, 166.8; Anal. Calcd for
C24H27N3O4: C, 68.39; H, 6.46; N, 9.97. Found: C,
68.10; H, 6.62; N, 9.56; HRMS (EI) calcd for
C24H27N3O4: 421.2002 found: 421.2001.
6. (a) Holzer, W.; Hahn, K. J. Heterocycl. Chem. 2003, 40,
303; (b) Abd El Latiff, F. M. J. Heterocycl. Chem. 2000, 37,
1659; (c) Becher, J.; Toftlund, H.; Olesen, P. H. J. Chem.
Soc., Chem. Commun. 1983, 740; (d) Becher, J.; Jørgensen,
P. L.; Pluta, K.; Krake, N. J.; Fa¨lt-Hansen, B. J. Org.
Chem. 1992, 57, 2127.
1
38. 44% (yield); H NMR (CDCl3) 8.13 (s, 1H), 7.87–
7.90 (d, 2H, J = 8.1 Hz), 7.32–7.35 (d, 2H, J = 8.1 Hz),
7.09–7.18 (m, 3H), 6.89–6.92 (m, 2H), 5.09 (s, 2H),
3.70 (s, 3H), 2.35 (s, 3H), 1.51 (s, 9H); MS (70 eV) m/z
(rel intensity) 437 (M+, 27), 364 (35), 231 (51), 135
(100), 106 (80), 90 (58); Anal. Calcd for C24H27N3O3S:
C, 65.88; H, 6.22; N, 9.60; O, 10.97; S, 7.33. Found:
C, 65.23; H, 6.59; N, 10.42; O, 11.36; S, 7.63.
7. Park, M.-S.; Park, H.-J.; Park, K. H.; Lee, K.-I. Synth.
Commun. 2004, 34, 1541.
8. (a) Rubinstein, L. V.; Shoemaker, R. H.; Paull, K. D.;
Simon, R. M.; Tosini, S.; Skehan, P.; Scudiero, D. A.;
Monks, A.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82,
1113; (b) Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.;
McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.;
Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82,
1107.
References and notes
1. (a) Tietze, L. F.; Steinmetz, A.; Balkenhohl, F. Bioorg.
Med. Chem. Lett. 1997, 7, 1303; (b) Brooking, P.; Doran,
9. (a) Miyoshi, H. Biochim. Biophys. Acta 1998, 1364, 236; (b)
Lummen, P. Biochim. Biophys. Acta 1998, 1364, 287.
¨