Synthesis and antiproliferative activity of new cytotoxic azanaphthoquinone pyrrolo-annelated derivatives: Part II

Article abstract of DOI:10.1016/j.bmcl.2011.03.013

A series of 6-azanaphthoquinone pyrrolo-annelated derivatives carrying different basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines with Mitoxantrone as reference compound. Cytotoxic effects and DNA intercalation behavior were investigated.

Full text of DOI:10.1016/j.bmcl.2011.03.013

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3117–3121
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiproliferative activity of new cytotoxic azanaphthoquinone
pyrrolo-annelated derivatives: Part II q
Karem Shanab a, Eva Schirmer a, Eva Wulz a, Barbara Weissenbacher a, Sigrid Lassnig a, Rita Slanz a,
b
b
Germana Fösleitner a, Wolfgang Holzer a, Helmut Spreitzer a, , Peter Schmidt , Babette Aicher ,
⇑
Gilbert Müller b, Eckhard Günther b
a Department of Drug and Natural Product Synthesis, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
b AeternaZentaris GmbH, Weismuellerstrasse 50, 60314 Frankfurt, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 6-azanaphthoquinone pyrrolo-annelated derivatives carrying different basic side chains have
been synthesized. The antiproliferative activities of all compounds were evaluated on at least four differ-
ent cell lines with Mitoxantrone as reference compound. Cytotoxic effects and DNA intercalation behav-
ior were investigated.
Received 12 January 2011
Revised 2 March 2011
Accepted 3 March 2011
Available online 9 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keyword:
Anticancer compounds
Mitoxantrone is one of the most widely used therapeutics in
combating a variety of cancerous diseases.2,3 Due to cardiotoxicity4
another less cardiotoxic compound, namely aza-anthracene-9,10-
dione BBR2778 (Pixantrone) was developed, which is currently in
phase III of clinical trials in patients with non-Hodgkin’s lym-
phoma.5 Based on this type of compounds we synthesized a series
of new potential cytotoxic derivatives. In these compounds the bis-
amino phenyl ring was replaced by a mono- or bis-substituted pyr-
role ring. As reported previously by the authors, the position of the
nitrogen in the annelated pyridine1 and pyrrole6 ring has also dras-
tic effects on the antitumor activity. Hence, we investigated a ser-
ies of new 6-azanaphthoquinone pyrrolo-annelated compounds
derived from Pixantrone with position 3 of the pyrrole ring either
unsubstituted (1), or dimethylaminoethyl or -propyl substituted
(2), respectively. In this paper, we discuss the influence of different
side chains on the antiproliferative effects, which are attached to
the pyrrole nitrogen in position 1 and 3 leading to key structures
1 and 2 (Fig. 1). The side chains attached to the tricyclic nucleus
were predominantly provided with alkylating groups (oxiranyl,
aziridinyl, mesylate) and/or amino groups. As a consequence, alkyl-
ation should lead to irreversible drug–DNA bonds. Furthermore,
side chains with amino groups can enhance binding to the dou-
ble-helical DNA by interaction with its phosphate ‘back bone’.
Main core 1 was prepared according to a method previously re-
ported by the authors.7 The first step of the synthesis of com-
H
N
NH2
O
O
HN
HN
OH
OH
O
O
HN
HN
OH
OH
N
N
H
NH2
Mitoxantrone
BBR2778 (Pixantrone)
O
R
O
R
N
N
N
N
N(CH3)2
O
O
n
2
1
n = 2 or 3
Figure 1.
pounds 3–5 consisted of the alkylation of 1 with the according
bromoalkoxy-tert-butyl-diphenylsilanes to give 15–17. Deprotec-
tion to obtain alcohols 18–20 (n = 2, 4, 7) was carried out by treat-
ment with tetrabutylammoniumfluoride (TBAF) in THF. Alcohols
18–20 were reacted with mesylchloride to afford the compounds
3–5, which were converted into aziridines 6–8 by treatment with
aziridine and triethylamine in DCM. Compounds 9–11 were ob-
tained by deprotonation of compound 1 with NaH and reaction
with the corresponding haloalkyloxirane. The synthesis of products
12–14 was accomplished by treatment of oxiranes 9–11 with azi-
ridine in a solution of triethylamine (1%) in absolute ethanol
(Scheme 1).
q
See Ref. 1.
⇑
Corresponding author. Tel.: +43 1427755621; fax: +43 142779556.
E-mail address: helmut.spreitzer@univie.ac.at (H. Spreitzer).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.013

3118
K. Shanab et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3117–3121
O
O
O
O
R
N
R
N
1. NaH
2. RBr
1. NaH
2. RBr
Cl(CH2)3N(CH3)2
N
N
15-17: R = (CH2)nOTBDPS
35-37: R =
(CH2)nOTBDPS
28: R =
(CH2)3N(CH3)2
TBAF
2a b:
,
R = H
1
1. NaH
2. Cl(CH2)3N(CH3
: R = H
TBAF
N(CH3)2
n'
)
2
1. NaH
2. X
18-20: R = (CH2)nOH
21-23: R = (CH2)nOH
27: R = (CH2)2N(CH3)2
34: R = (CH2)3N(CH3)2
O
n
MsCl/TEA
MsCl/TEA
O
9-11:
R = (CH2)n
R = (CH2)n
NH(CH3)2
OSi
38: R =
H2N
H
24-26
: R = (CH2)nOMs
(CH2)2NH(CH2)2OSi(CH3)3
SiO2
3-5
: R = (CH2)nOMs
N
NH2CH3
/ TEA
N
H
H
N
N
/ TEA
/ TEA
12-14:
31-33:
29: R = (CH2)2NHCH3
30: R = (CH2)2NH(CH2)2OH
2b 34
R = (CH2)n
N
OH
6-8:
R = (CH2)n
N
2a 27-30
,
22 25 32 36
n' = 2:
n' = 2, n = 4:
,
,
,
n' = 3:
,
n' = 2, n = 2: 21,24,31,35
n' = 2, n = 7: 23,26,33,37
9 12
,
10 13
,
11 14
n = 6: ,
n = 7: 5,8,17,20
n = 1:
n = 2: 3,6,15,18
n = 3:
n = 4: 4,7,16,19
Scheme 3.
Scheme 1.
prepared directly by alkylation of 2a or 2b with N,N-dimethyl chlo-
ropropylamine (Scheme 3).
OMe
O
O
O
H
H
N
N
Pyrrole annelated 6-azanaphthoquinones (except the instable
mesylates 25 and 26) were screened for antiproliferative activity
against different cancer cell lines KB/HeLa (cervical carcinoma),
SKOV-3 (ovarian carcinoma), SF-268 (CNS, glioma), NCI-H460
(non-small cell lung carcinoma (NSCLC)), and of RKOp27 (colon
adenocarcinoma).8
NH2
MeO
Cl
H3C CH3
N
N
n
2a,b
n = 2 or 3
n = 2: 39
40
Cl
O
n
n = 3:
Scheme 2.
The concentration of the compound that inhibits 50% (EC50) of
cell proliferation after 48 h was calculated by nonlinear regression
using the data of at least two independent XTT cytotoxicity as-
says.9,10 Results of the cytotoxicity assays are shown in detail in Ta-
ble 2 together with Mitoxantrone as reference.
7-Aminoisoquinoline-5,8-dione7 was reacted with either chlo-
robutyraldehyde-dimethylacetal or 5-chloro-1,1-dimethoxypen-
tane yielding 39 and 40, respectively, which afforded 2a and 2b
upon treatment with N,N-dimethylamine (Scheme 2).
9 is the most antiproliferative compound (EC50(KB/HeLa)b:
Alcohols 21–23 were prepared by reaction of TBAF with the
appropriate tert-butyldiphenylsilyl (TBDPS) protected precursors
35–37 which were obtained by treating deprotonated 2a,b with
the according bromoalkoxy-tert-butyldiphenylsilanes. Mesylation
of alcohols 21–23 gave compounds 24–26 which served as precur-
sors for aziridines 31–33, dimethylamines 27, monomethylamine
29, and trimethylsilyloxyethylamine 38. Deprotection of 38 oc-
curred spontaneously during column chromatography on silica
gel to afford hydroxyethylamine 30. Compounds 28 and 34 were
0.062 lg/ml) that has been reported on the series of Mitoxan-
trone derived azanaphtho-chinones so far.5,7 Its activity profile
is significantly different as EC50 values are 8–12 times higher than
for the next best new compound, 7. Activity is better or in the
same range compared to reference compound Mitoxantrone. This
antiproliferative property is assigned to the oxiran group con-
nected by a C1-spacer. Compounds 10 and 11 contain also oxi-
rane groups, but are linked through longer spacers and show no
activity.
Table 1
O
R
O
R
N
N
N
N
O
O
N(CH3)2
n
O
1: R = H
n = 2
2a:R = H
27:R = (CH2)2N(CH3)2
28:R = (CH2)3N(CH3)2
10
11
: R = (CH2)3
O
3: R = (CH2)2OMs
21:R = (CH2)2OH
22:R = (CH2)4OH
: R = (CH2)6
N
4: R = (CH2)4OMs
5: R = (CH2)7OMs
29:R = (CH2)2NHCH3
12: R = CH2
OH
N
23:R = (CH2)7OH
24:R = (CH2)2OMs
30:R = (CH2)2NH(CH2)2OH
13: R = (CH2)3
OH
31: R = (CH2)2
N
N
6: R = (CH2)2
N
14
: R = (CH2)6
OH
7
25:R = (CH2)4OMs
26:R = (CH2)7OMs
32: R = (CH2)4
33: R = (CH2)7
N
N
: R = (CH2)4
N
8
: R = (CH2 )7
N
O
n = 3
2b:R = H
34:R = (CH2)3N(CH3)2
9
: R = CH2

K. Shanab et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3117–3121
3119
Table 2
In vitro cytotoxicity of compounds 2a–14, 21–34, 39 and 40 towards different cell lines
Cells (origin)/compound
Compound activity (EC50 [l
g/mL]a)
KB/HeLab (cervix)
SKOV-3 (ovarian)
SF-268 (CNS)
NCI-H460 (NSCLC)
RKOp27 (colon)
RKOp27IND (colon)
2a, 5, 11, 22–24, 27
2b
3
No inhib.c
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
No inhib.
Moderated
Moderate
4
Moderate
No inhib.
Moderate
Moderate
Moderate
No inhib.
6
7
8
9
Moderate
0.549 0.23 (5)
Moderate
0.062 0.01 (5)
Moderate
0.747 (1)
Moderate
Moderate
Not tested
Moderate
Moderate
No inhib.
Moderate
1.894 0.22 (5)
Moderate
0.2 0.041 (5)
No inhib.
Moderate
No inhib.
No inhib.
Not tested
No inhib.
Moderate
Moderate
0.727 0.28 (5)
Moderate
0.062 0.005 (5)
Moderate
2.213 (1)
Moderate
Moderate
Not tested
No inhib.
Moderate
No inhib.
Moderate
0.722 0.43 (3)
Moderate
Moderate
Moderate
0.299 0.05 (5)
1.194 (1)
0.026 0.006 (5)
Moderate
0.899 (1)
Moderate
Moderate
Not tested
Moderate
Moderate
Moderate
2.231 (1)
Moderate
1.3 0.846 (4)
No inhib.
Moderate
No inhib.
No inhib.
Not tested
No inhib.
Moderate
No inhib.
2.365 0.86 (3)
1.35 0.97 (3)
No inhib.
2.185 0.52 (3)
Moderate
0.265 0.03 (5)
No inhib.
Moderate
No inhib.
No inhib.
Not tested
No inhib.
Moderate
No inhib.
2.739 (1)
1.510 0.15 (3)
Moderate
No inhib.
10
12
13
14
25,26e
21
28, 29
30
31
32
33
34
Moderate
Moderate
Moderate
0.972 0.09 (2)
0.512 0.09 (3)
Moderate
2.411 0.44 (2)
1.392 0.49 (3)
No inhib.
0.784 0.3 (3)
0.205 0.13 (3)
Moderate
No inhib.
No inhib.
Moderate
No inhib.
Mitoxantrone
0.3550 0.137 (5)
0.1207 0.042 (3)
0.3150 0.206 (3)
0.1224 0.013 (3)
0.0865 0.005 (3)
0.7629 0.200 (2)
a
b
c
EC50 values <3
EC50(KB) denotes the activity for KB/HeLa cell line, which is used to compare compound activities.
No inhib. = no inhibition, that is, <30% inhibition in the highest concentration (3.16 g/ml) during EC50 determination.
‘Moderate’ activity describes compound activity, that showed at least 30% inhibition in the highest concentration (3.16
lg/ml are given as mean values standard deviation with number of replicates given in round brackets.
l
d
lg/ml) during EC50 determination. Since a
sigmoidal inhibition-concentration curve is not available, compound activity can only be given as EC50 >3.16
l
g/ml.
e
Not tested due to instability.
The difference in activity could be explained by an oxirane ring
opening mechanism, that is, alkylation.
Table 3
SAR for linker chain lengths within compound series containing alkylating groups
Aziridine derivative 32 (EC50(KB/HeLa): 0.512
an interesting antiproliferative activity profile. Compared to 7
(EC50(KB/HeLa): 0.549 g/ml), the additional dimethylaminoethyl
lg/ml) shows also
Series
Optimum
Key structure 1e
Oxirane deriv.
Aziridin deriv.
OH-aziridin deriv.
Key structure 2e
Aziridin deriv.
l
9 (C1)–10 (C3)–11 (C6)
6 (C2)–7 (C4)–8 (C7)
12 (C2)–13 (C3)–14 (C6)
9 (C1)
7 (C4)
12 (C2)
group slightly enhances activity. This activity enhancementby a sec-
ond side chain is more visible when comparing dimethyl aminoethyl
containing compound 31 with
>3.16
g/mlc, respectively), though the overall activity of this pair
is fair to moderate.
6 (EC50(KB/HeLa): 0.972 and
l
31 (C2)–32 (C4)–33 (C7)
32 (C4)
e
Key structure 1 (pyrrole ring unsubstituted) and 2 (pyrrole ring substituted by
dimethylaminoethyl) refer to Figure 1. Column ‘Series’ denotes compound
Interestingly, when changing the aziridine group in 31 to a
dimethylamino group as in 27, activity disappears completely.
While exposing similar hydrogen bonding properties, the main dif-
ferences between a dimethyl amino and an aziridine group are alkyl-
ation properties of the latter. As with the oxiran 9, the results could
be explained by alkylation as the underlying mechanism of action,
which would be contrasting to the mechanism of action of Mitoxan-
trone. Moreover since tumor environments are known to be acidic
the stability of the epoxy moiety (9–11) was checked by exposing
compounds 9–11 to a pH 5.5 buffer system (KH2PO4/Na2HPO4
according to European Pharmacopoea) at 37 °C. Even after 6 h
NMR analysis did not show any signs of decomposition.
a
according to Table 1 and its chain length given in round brackets. Column ‘Opti-
mum’ denotes the best chain length within the series.
tive activity, which could be explained by an alkylating mechanism
of action. Oxirane 9 showed remarkable activity, and series of azirid-
inyl derivatives including compounds 7 and 32 cover an activity
range from very good to moderate. For the aziridine series, C4 linker
chains revealed the highest activity. These studies provide useful
information for further studies and for the development of an ex-
tended compound library.
Strangely enough, mesylates (e.g., 3 or corresponding dimethyl-
aminoethyl containing compound 24) do not show antiproliferative
activity in our hands. However, the chemical stability of mesylates
under (aqueous) assay conditions (48 h incubation before read
out) should be considered before mesylates are regarded as inactive.
Relating linker chain lengths to antiproliferative activity reveal
a clear trend to shorter chains, but differ from series to series
(Table 3).
In conclusion, series of new 6-azanaphthoquinone pyrrolo-ann-
elated compounds containing various linkers to alkylating groups
(oxiranyl, aziridinyl, mesylate) and/or dimethylaminoalkyl groups
have been synthesized and analytically characterized.11 The result-
ing compounds were tested for antiproliferative activity against dif-
ferent cell lines. Exchange of amino groups (from inactive
compounds) to oxiranyl and aziridinyl groups led to antiprolifera-
References and notes
1. Shanab, K.; Schirmer, E.; Knafl, H.; Wulz, E.; Holzer, W.; Spreitzer, H.; Schmidt,
P.; Aicher, B.; Müller, G.; Günther, E. Bioorg. Med. Chem. Lett. 2010, 20, 3950.
2. Vuimo, T. A.; Kulikova, E. V.; Sinauridze, E. I.; Yurkevich, A. M.; Kravchenko, S.
K.; Ataullakhanov, F. I. In New Research on Biotechnology and Medicine; Egorov,
A. M., Zaikov, G., Eds.; Nova Science Publishers: New York, 2006.
3. Wiseman, L. R.; Spencer, C. M. Drugs Aging 1997, 10, 473.
4. Frishman, W. H.; Sung, H. M.; Yee, H. C.; Liu, L. L.; Keefe, D.; Einzig, A. I.;
Dutcher, J. J. Curr. Probl. Cancer 1997, 21, 301.
5. Tomillero, A.; Moral, M. A. Methods Find Exp. Clin. Pharmacol. 2009, 31, 661.
6. Pongprom, N.; Bachitsch, H.; Bauchinger, A.; Ettefagh, H.; Haider, T.; Hofer, M.;
Knafl, H.; Slanz, R.; Waismeyer, M.; Wieser, F.; Spreitzer, H. Monatsh. Chem.
2010, 141, 53.
7. Shanab, K.; Pongprom, N.; Wulz, E.; Holzer, W.; Spreitzer, H.; Schmidt, P.;
Aicher, B.; Müller, G.; Günther, E. Bioorg. Med. Chem. Lett. 2007, 17, 6091.
8. Schmidt, M.; Lu, Y.; Liu, B.; Fang, M.; Mendelsohn, J.; Fan, Z. Oncogene 2000, 19,
2423.

3120
K. Shanab et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3117–3121
9. Scudiero, D. A.; Shoemaker, R. H.; Paull, K. D.; Monks, A.; Tierney, S.; Nofziger, T.
H.; Currens, M. J.; Seniff, D.; Boyd, M. R. Cancer Res. 1988, 48, 4827.
10. The XTT assay9 quantifies cellular metabolic activity which correlates with
cellular viability and/or cell number. This cytotoxicity assessment has been
conducted with five diverse tumor cell lines, namely KB/HeLa (ATCC CCL17,
human cervix carcinoma), SKOV3 (ATCC HTB-77, human ovarian carcinoma),
SF268 (NCI 503138, CNS cancer glioma), NCI-H460 (NCI 503473, large cell lung
cancer) and RKOp27 (human colon adenocarcinoma). For the assay the cells are
seeded on 96 well MTPs (Greiner) with an Eppendorf Multipette with a 2.5 ml
Combitip as described below:
211 (10), 79 (7), 45 (100). Anal. Calcd for C15H13N3O2: C, 67.40; H, 4.90; N,
15.72. Found: C, 67.47; H, 5.12; N, 15.44.
Compound 7: Mp = 74–75 °C. 1H NMR (CDCl3): d (ppm): 1.01 (m, 2H), 1.51–1.64
(m, 4H), 1.90 (m, 2H), 2.16 (t, J = 6.9 Hz, 2H), 4.42 (t, J = 7.2 Hz, 2H), 6.68 (d,
J = 2.8 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 5.0 Hz, 1H), 8.90 (d, J = 5.0 Hz,
1H), 9.26 (s, 1H). 13C NMR (CDCl3): d (ppm): 26.6, 27.1, 28.8, 49.4, 61.0, 108.0,
118.6, 126.6, 128.5, 129.6, 131.3, 139.0, 148.3, 154.7, 175.1, 179.4. IR (KBr):
mmax 1675, 1657, 1590, 1388, 1251, 1197 cmÀ1. MS: m/z (% relative intensity)
295 (M+, 7), 252 (24), 225 (12), 221 (18), 97 (37), 69 (41), 56 (100). Anal. Calcd
for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23. Found: C, 69.05; H, 5.95; N, 14.17.
Compound 8: Mp = 94 °C. 1H NMR (CDCl3): d (ppm): 0.98 (m, 2H), 1.31 (m, 6H),
1.47 (m, 2H), 1.62 (m, 2H), 1.80 (m, 2H), 2.09 (t, J = 6.8 Hz, 2H), 4.38 (t,
J = 7.3 Hz, 2H), 6.69 (d, J = 2.8 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 4.9 Hz,
1H), 8.92 (d, J = 4.9 Hz, 1H), 9.29 (s, 1H). 13C NMR (CDCl3): d (ppm): 26.3, 27.0,
27.1, 29.0, 29.5, 30.8, 49.6, 61.8, 108.0, 118.6, 126.6, 128.5, 129.6, 131.3, 139.0,
Cell line Number
per well
Volume (
per well
ll) Media
148.3, 154.7, 175.1, 179.4. IR (KBr): mmax 1657, 1586, 1498, 1371, 1243 cmÀ1
.
KB/
HeLa
SKOV3
2500
3750
5000
1000
125
125
125
125
125
RPMI 1640 + 10%
FCSi + 2% PSG
RPMI 1640 + 10%
FCSi + 2% PSG
RPMI 1640 + 10%
FCSi + 2% PSG
RPMI 1640 + 10%
FCSi + 2% PSG
DMEM + 10% FCSi + 2%
PSG + 1% Hepes
MS: m/z (% relative intensity) 337 (M+, 18), 266 (11), 200 (14), 98 (14), 71 (15),
57 (62), 56 (100). Anal. Calcd for C20H23N3O2: C, 71.19; H, 6.87; N, 12.45.
Found: C, 70.94; H, 6.98; N, 12.21.
Compound 9: Mp = 128 °C. 1H NMR (CDCl3): d (ppm): 2.57 (dd, J = 2.5 Hz,
4.8 Hz, 1H), 2.90 (m, 1H), 3.41 (m, 1H), 4.29 (dd, J = 6.3 Hz, 14.5 Hz, 1H), 5.13
(dd, J = 2.5 Hz, 14.5 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 7.95
(dd, J = 0.8 Hz, 5.0 Hz, 1H), 9.00 (d, J = 5.0 Hz, 1H), 9.36 (d, J = 0.8 Hz, 1H). 13C
NMR (CDCl3): d (ppm): 45.4, 50.6, 50.8, 108.6, 118.9, 126.6, 128.5, 128.9, 132.3,
139.2, 148.4, 155.1, 175.7, 179.6. IR (KBr): mmax 1677, 1652, 1586, 1498, 1374,
1251 cmÀ1. MS: m/z (% relative intensity) 254 (M+, 16), 212 (87), 211 (81), 155
(29), 77 (42), 51 (78), 50 (100). Anal. Calcd for C14H10N2O3 Á 0.2 H2O: C, 65.21;
H, 4.07; N, 10.86. Found: C, 65.37; H, 4.35; N, 10.80.
SF268
NCI-
H460
RKOp27 6250
Compound 10: Mp = 103–104 °C. 1H NMR (CDCl3): d (ppm): 1.34 (m, 1H), 1.65
(m, 1H), 1.91 (m, 2H), 2.36 (dd, J = 2.7 Hz, 4.9 Hz, 1H), 2.63 (m, 1H), 2.83 (m,
1H), 4.36 (m, 1H), 6.56 (d, J = 2.8 Hz, 1H), 6.95 (d, J = 2.8 Hz, 1H), 7.73 (d,
J = 5.0 Hz, 1H), 8.81 (d, J = 5.0 Hz, 1H), 9.13 (s, 1H). 13C NMR (CDCl3): d (ppm):
27.3, 28.8, 46.3, 48.7, 51.3, 107.8, 118.3, 126.3, 128.4, 129.3, 131.4, 138.7,
148.0, 154.5, 174.7, 179.0. IR (KBr): mmax 1675, 1654, 1586, 1498, 1374,
1247 cmÀ1. MS: m/z (% relative intensity) 282 (M+, 10), 223 (28), 211 (38), 198
(35), 170 (24), 69 (100), 55 (71). Anal. Calcd for C16H14N2O3: C, 68.08; H, 5.00;
N, 9.92. Found: C, 68.03; H, 5.24; N, 9.74.
Test compounds in 100% DMSO are added to the tumor cell lines in a 10 point
dose response starting at 31.6 g/ml with halflog dilution steps and adjustment
of the final DMSO concentrations to 0.3%. After 45 h of incubation at 37 °C/
5%CO2 1 mg/ml XTT (Serva, cat. no 38450) and 76.6 g/ml PMS (Sigma, cat.
l
l
no P9625) are incubated with the cells for additional 3 h. After 48 h of total
compound incubation cellular metabolic activity is quantified by single point
measurement of absorbance at 490 nm. Non-treated cells and blank controls
w/o cells are set as reference values of 0% and 100% inhibition, respectively.
EC50 determination was carried out employing the regression software Graph-
Pad Prism™.
Compound 11: Mp = 53–55 °C. 1H NMR (CDCl3): d (ppm): 1.37 (m, 8H), 1.82 (m,
2H), 2.40 (dd, J = 2.8 Hz, 5.0 Hz, 1H), 2.68 (m, 1H), 2.83 (m, 1H), 4.40 (t,
J = 7.3 Hz, 2H), 6.71 (d, J = 2.8 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 7.88 (dd,
J = 0.8 Hz, 4.9 Hz, 1H), 8.93 (d, J = 4.9 Hz, 1H), 9.30 (s, 1H). 13C NMR (CDCl3): d
(ppm): 25.7, 26.3, 28.8, 30.7, 32.2, 46.9, 49.5, 52.1, 108.1, 118.6, 126.7, 128.6,
11. All of the final structures were confirmed by 1H NMR, 13C NMR, IR, and MS as
the following.
Compound 2a: Mp = 212 °C. 1H NMR (DMSO): d (ppm): 2.17 (s, 6H), 2.47–2.50
(m, 2H), 2.78–2.93 (m, 2H), 7.15 (s, 1H), 7.79 (d, J = 4.9 Hz, 1H), 7.89 (d,
J = 4.9 Hz, 1H), 8.91 (d, J = 4.9 Hz, 1H), 9.09 (s, 1H). 13C NMR (DMSO): d (ppm):
23.8, 45.0, 59.4, 118.5, 124.7, 126.0, 127.3, 132.9, 136.6, 140.5, 147.0, 154.3,
174.4, 179.2. IR (KBr): mmax 3424, 2924, 2834, 1661, 1585, 1512, 1473, 1433,
1421, 1392, 1340, 1314, 1274, 1249, 1224, 917, 736 cmÀ1. MS: m/z (% relative
intensity) 269 (M+, 1), 254 (8), 211 (7), 111 (6), 97 (10), 83 (11), 71 (16), 58
(100), 43 (22).
129.7, 131.3, 139.1, 148.3, 154.8, 175.1, 179.5. IR (KBr): mmax 1661, 1586, 1498,
1374, 1247 cmÀ1. MS: m/z (% relative intensity) 324 (M+, 23), 293 (14), 225
(24), 212 (69), 211 (100), 199 (24), 55 (91). Anal. Calcd for C19H20N2O3 Á 0.2
H2O: C, 69.58; H, 6.27; N, 8.54. Found: C, 69.60; H, 6.44; N, 8.26.
Compound 12: Mp = 181 °C. 1H NMR (DMSO): d (ppm): 1.16 (m, 2H), 1.63 (m,
2H), 2.17 (dd, J = 6.0 Hz, 12.0 Hz, 1H), 2.34 (dd, J = 5.3 Hz, 12.0 Hz, 1H), 3.97 (m,
1H), 4.24 (dd, J = 8.8 Hz, 13.3 Hz, 1H), 4.77 (dd, J = 3.3 Hz, 13.3 Hz, 1H), 5.04 (d,
J = 5.5 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.85 (d, J = 5.0 Hz,
1H), 9.01 (d, J = 5.0 Hz, 1H), 9.18 (s, 1H). 13C NMR (DMSO): d (ppm): 26.5, 26.7,
53.3, 64.9, 69.5, 107.2, 118.5, 126.5, 128.1, 129.5, 134.2, 138.6, 147.6, 155.1,
Compound 2b: Mp = 173 °C. 1H NMR (DMSO): d (ppm): 1.69 (m, 2H), 2.11 (s,
6H), 2.23 (t, J = 6.9, 2H), 2.70 (t, J = 7.3, 2H), 7.20 (s, 1H), 7.83 (d, J = 4.5 Hz, 1H),
8.99 (d, J = 4.9 Hz, 1H), 9.12 (s, 1H). 13C NMR (DMSO): d (ppm): 23.2, 27.3, 45.2,
58.8, 118.7, 123.8, 126.1, 126.6, 127.1, 132.1, 139.6, 147.1, 155.1, 174.0, 178.0.
IR (KBr): mmax 3426, 3079, 2938, 2756, 1653, 1586, 1393, 1220 cmÀ1. MS: m/z
(% relative intensity) 283 (M+, 3), 223 (1), 212 (4), 84 (1), 78 (2), 58 (100), 42
(8).
174.6, 179.2. IR (KBr): m
max 3117, 1673, 1652, 1498, 1385, 1249 cmÀ1. MS: m/z
(% relative intensity) 297 (M+, 1), 269 (10), 212 (9), 211 (7), 57 (17), 56 (100).
13 1H NMR (CDCl3): d (ppm): 1.18 (m, 2H), 1.47 (m, 2H), 1.74 (m, 2H), 2.01 (m,
4H), 2.47 (dd, J = 8.5 Hz, 11.8 Hz, 1H), 3.78 (m, 1H), 4.47 (t, J = 7.3 Hz, 2H), 6.74
(d, J = 2.8 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 5.0 Hz, 1H), 8.95 (d,
J = 5.0 Hz, 1H), 9.32 (s, 1H). 13C NMR (CDCl3): d (ppm): 26.9, 27.3, 27.5, 31.3,
49.5, 67.3, 70.1, 108.2, 118.7, 126.7, 128.7, 129.7, 131.6, 139.1, 148.4, 154.8,
Compound 3: Mp = 164 °C. 1H NMR (DMSO): d (ppm): 3.10 (s, 3H), 4.59 (t,
J = 4.8 Hz, 2H), 6.72 (d, J = 2.8 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 5.0 Hz,
1H), 8.99 (d, J = 5.0 Hz, 1H), 9.15 (s, 1H). 13C NMR (DMSO): d (ppm): 36.6, 47.8,
68.7, 107.6, 118.5, 126.3, 128.3, 129.4, 133.6, 138.6, 147.5, 155.2, 174.8, 179.2.
IR (KBr): mmax 1671, 1657, 1593, 1502, 1392, 1339, 1176 cmÀ1. MS: m/z (%
relative intensity) 320 (M+, 9), 241 (27), 223 (21), 97 (28), 83 (1), 69 (63), 57
(100).
175.2, 179.5. IR (KBr): mmax 3397, 1671, 1657, 1586, 1500, 1374, 1229 cmÀ1
.
MS: m/z (% relative intensity) 325 (M+, 1), 269 (M+À56, 1), 211 (3), 199 (2), 126
(3), 57 (16), 56 (100). Anal. Calcd for C18H19N3O3: C, 66.45; H, 5.89; N, 12.91.
Found: C, 63.30; H, 5.80; N, 12.02.
Compound 4: Mp = 151 °C. 1H NMR (DMSO): d (ppm): 1.69 (m, 2H), 1.87 (m,
2H), 3.15 (s, 3H), 4.21 (t, J = 6.0 Hz, 2H), 4.45 (t, J = 6.8 Hz, 2H), 7.00 (d,
J = 2.8 Hz, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 4.9 Hz, 1H), 8.98 (d, J = 4.9 Hz,
1H), 9.14 (s, 1H). 13C NMR (DMSO): d (ppm): 25.6, 26.5, 36.5, 48.1, 69.9, 107.6,
118.4, 126.4, 128.0, 129.3, 133.0, 138.6, 147.5, 155.1, 174.5, 179.1. IR (KBr):
mmax 1671, 1661, 1586, 1502, 1342, 1247, 1173 cmÀ1. MS: m/z (% relative
intensity) 348 (M+, 86), 252 (100), 225 (72), 223 (87), 211 (80), 170 (53), 55
(91). Anal. Calcd for C16H16N2O5S: C, 55.15; H, 4.63; N, 8.04. Found: C, 55.42; H,
4.77; N, 7.97.
Compound 14: Mp = 97 °C. 1H NMR (CDCl3): d (ppm): 1.10 (m, 1H), 1.33 (m,
9H), 1.75 (m, 5H), 2.41 (dd, J = 8.7 Hz, 11.9 Hz, 1H), 3.16 (br s, 1H), 3.67 (m, 1H),
4.40 (t, J = 7.3 Hz, 2H), 6.72 (d, J = 2.5 Hz, 1H), 7.12 (d, J = 2.8 Hz, 1H), 7.89 (dd,
J = 0.6 Hz, 4.9 Hz, 1H), 8.94 (d, J = 4.9 Hz, 1H), 9.31 (d, J = 0.6 Hz, 1H). 13C NMR
(CDCl3): d (ppm): 25.3, 26.3, 26.8, 27.4, 29.0, 30.8, 34.5, 49.6, 67.4, 70.5, 108.1,
118.7, 126.7, 128.6, 129.7, 131.4, 139.1, 148.4, 154.8, 175.1, 179.5. IR (KBr):
mmax 3390, 1657, 1586, 1498, 1378, 1247 cmÀ1. MS: m/z (% relative intensity)
367 (M+, 6), 311 (M+À56, 7), 211 (17), 199 (11), 83 (96), 69 (56), 56 (100). Anal.
Calcd for C21H25N3O3 Á 0.3 H2O: C, 67.65; H, 6.92; N, 11.27. Found: C, 67.60; H,
6.99; N, 11.06.
Compound 5: Mp = 92 °C. 1H NMR (CDCl3): d (ppm): 1.34 (m, 6H), 1.76 (m, 4H),
3.00 (s, 3H), 4.17 (t, J = 6.4 Hz, 2H), 4.40 (t, J = 7.3 Hz, 2H), 6.71 (d, J = 2.8 Hz,
1H), 6.99 (d, J = 2.8 Hz, 1H), 7.88 (d, J = 5.0 Hz, 1H), 8.93 (d, J = 5.0 Hz, 1H), 9.29
(s, 1H). 13C NMR (CDCl3): d (ppm): 37.2, 49.4, 69.8, 108.1, 118.6, 126.6, 128.6,
Compound 15: Mp = 145 °C. 1H NMR (CDCl3): d (ppm): 0.99 (s, 9H), 4.04 (d,
J = 4.8 Hz, 2H), 4.56 (t, J = 4.8 Hz, 2H), 6.74 (d, J = 2.8 Hz, 1H), 7.09 (d, J = 2.8 Hz,
1H), 7.22 (m, 6H), 7.42 (m, 4H), 7.95 (d, J = 4.9 Hz, 1H), 8.99 (d, J = 4.9 Hz, 1H),
9.24 (s, 1H). 13C NMR (CDCl3): d (ppm): 18.9, 26.8, 51.9, 62.4, 107.6, 118.6,
126.6, 127.6, 129.0, 129.4, 129.6, 132.5, 133.2, 133.4, 139.2, 148.3, 154.8, 175.1,
129.6, 131.4, 139.0, 148.3, 154.8, 175.1, 179.4. IR (KBr): mmax 1664, 1586, 1498,
1346, 1243, 1162 cmÀ1. MS: m/z (% relative intensity) 390 (M+, 10), 225 (13),
211 (21), 198 (25), 149 (51), 69 (83), 57 (100). Anal. Calcd for C19H22N2O5S: C,
58.45; H, 5.68; N, 7.17. Found: C, 58.19; H, 5.81; N, 6.97.
179.6. IR (KBr): m
max 1671, 1657, 1590, 1505, 1381, 1254, 1106, 710 cmÀ1. MS:
m/z (% relative intensity) 423 (M+À57, 3), 199 (6), 149 (13), 86 (77), 84 (100),
77 (21), 69 (78).
Compound 6: Mp = 174 °C. 1H NMR (CDCl3): d (ppm): 1.06 (m, 2H), 1.69 (m,
2H), 2.46 (t, J = 5.8 Hz, 2H), 4.63 (t, J = 5.8 Hz, 2H), 6.77 (d, J = 2.8 Hz, 1H), 7.15
(d, J = 2.8 Hz, 1H), 7.92 (d, J = 4.9 Hz, 1H), 8.92 (d, J = 4.9 Hz, 1H), 9.33 (s, 1H).
13C NMR (CDCl3): d (ppm): 27.1, 49.8, 60.9, 118.8, 126.6, 128.9, 129.6, 132.6,
139.2, 148.4, 154.9, 175.3, 179.6. IR (KBr): mmax 1664, 1650, 1586, 1502, 1374,
1247 cmÀ1. MS: m/z (% relative intensity) 267 (M+, 7), 239 (M+À28, 8), 222 (8),
Compound 16: 1H NMR (CDCl3): d (ppm): 1.03 (s, 9H), 1.59 (m, 2H), 1.98 (m,
2H), 3.71 (t, J = 6.1 Hz, 2H), 4.45 (t, J = 7.0 Hz, 2H), 6.75 (d, J = 2.8 Hz, 1H), 6.95
(d, J = 2.8 Hz, 1H), 7.38 (m, 6H), 7.66 (m, 4H), 7.92 (dd, J = 0.6 Hz, 5.0 Hz, 1H),
8.96 (d, J = 5.0 Hz, 1H), 9.35 (d, J = 0.6 Hz, 1H). 13C NMR (CDCl3): d (ppm): 19.0,
26.7, 27.3, 29.2, 49.3, 63.0, 108.0, 118.6, 126.6, 127.5, 128.6, 129.5, 129.7,

K. Shanab et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3117–3121
max 1671, 1657, 1586, 97 (4), 83 (4), 71 (6), 58 (100), 44 (40).
3121
131.3, 135.4, 139.0, 148.3, 154.7, 175.0, 179.4. IR (KBr):
m
1502, 1247, 1109 cmÀ1. MS: m/z (% relative intensity) 453 (13), 452 (42), 451
(M+À57, 100), 395 (8), 253 (9), 199 (9), 183 (14), 77 (7).
Compound 30: 1H NMR(CDCl3):d (ppm): 2.28–2.33 (m, 8H), 2.59 (t,J = 7.1 Hz, 2H),
2.72–2.83 (m, 2H), 3.00 (t, J = 7.0 Hz, 2H), 3.10 (t, J = 5.9 Hz, 2H), 3.57 (t, J = 4.9 Hz,
2H), 4.52 (t, J = 5.9 Hz, 2H), 6.99 (s, 1H), 7.91 (d, J = 5.1 Hz, 1H), 8.96 (d, J = 4.7 Hz,
1H), 9.32 (s, 1H). 13C NMR (CDCl3): d (ppm): 23.7, 45.3, 49.1, 49.7, 50.9, 59.1, 60.9,
118.7, 125.2, 125.7, 126.7, 129.8, 131.2, 139.5, 148.3, 154.8, 175.2, 180.3. IR (KBr):
Compound 17: 1H NMR (CDCl3): d (ppm): 1.04 (s, 9H), 1.34 (m, 6H), 1.56 (m, 2H),
1.84 (m, 2H), 3.66 (t, J = 6.4 Hz, 2H), 4.42 (t, J = 7.3 Hz, 2H), 6.76 (d, J = 2.8 Hz, 1H),
6.98 (d, J = 2.8 Hz, 1H), 7.36 (m, 6H), 7.67 (m, 4H), 7.93 (dd, J = 0.8 Hz, 5.0 Hz, 1H),
8.97 (d, J = 5.0 Hz, 1H), 9.37 (d, J = 0.8 Hz, 1H). 13C NMR (CDCl3): d (ppm): 19.1,
25.5, 26.4, 26.8, 28.7, 30.8, 32.3, 49.6, 63.7, 108.0, 118.6, 126.7, 127.5, 128.6,
129.4, 129.7, 131.3, 133.9, 135.4, 139.1, 148.4, 154.8, 175.1, 179.5. IR (KBr): mmax
1671, 1657, 1586, 1505, 1378, 1247, 1109 cmÀ1. MS: m/z (% relative intensity)
453 (12), 494 (37), 493 (100), 199 (56), 183 (22), 181 (17), 77 (31).
m
max 3375, 2925, 1653, 1585, 1493, 1465, 1420, 1395, 1262, 1055, 933, 734 cmÀ1
.
MS: m/z (% relative intensity) 250 (M+, 2), 204 (2), 149 (7), 97 (8), 84 (79), 58 (100),
44 (48), 30 (22).
Compound 31: 1H NMR (CDCl3): d (ppm): 1.07 (m, 2H), 1.71 (m, 2H), 2.29 (s, 6H),
2.54–2.66 (m, 4H), 3.01 (t, J = 7.3 Hz 2H), 4.58 (t, J = 5.8 Hz, 2H), 7.04 (s, 1H), 7.91
(d, J = 4.9 Hz, 1H), 8.95 (d, J = 4.9 Hz, 1H), 9.31 (s, 1H). 13C NMR (CDCl3): d (ppm):
23.7, 27.1, 45.3, 49.7, 59.2, 60.9, 118.6, 125.1, 125.8, 126.7, 129.6, 131.5, 139.6,
Compound 18: Mp = 163 °C. 1H NMR (DMSO-d6): d (ppm): 3.73 (m, 2H), 4.45 (t,
J = 5.5 Hz, 2H), 4.96 (t, J = 5.4 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 7.41 (d, J = 2.8 Hz,
1H), 7.79 (d, J = 5.0 Hz, 1H), 8.96 (d, J = 5.0 Hz, 1H), 9.10 (s, 1H). 13C NMR (CDCl3):
d (ppm): 51.3, 60.1, 107.2, 118.4, 126.3, 128.0, 129.2, 133.8, 138.5, 147.5, 155.1,
148.2, 154.8, 175.1, 180.4. IR(KBr):mmax 3424,2927, 1653, 1585,1495, 1465, 1420,
1396, 1352, 1266, 1174, 1009, 916, 803, 733 cmÀ1. MS: m/z (% relative intensity)
338 (M+, 1), 295 (1), 211(1), 195(1), 149 (1), 111(1), 97 (2), 81 (2), 69 (4), 58(100).
Compound 32: 1H NMR (CDCl3): d (ppm): 1.02–1.05 (m, 2H), 1.49–1.61 (m, 2H),
1.65–1.67 (m, 2H), 1.83–1.98 (m, 2H), 2.15–2.22 (m, 2H), 2.26 (s, 6H), 2.52 (t,
J = 7.5 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H), 4.39 (t, J = 7.2 Hz, 2H), 6.89 (s, 1H), 7.86 (dd,
J = 4.9 Hz, 0.8 Hz, 1H), 8.91 (dd, J = 4.9 Hz, 1.9 Hz, 1H), 9.28 (s, 1H). 13C NMR
(CDCl3): d (ppm): 23.7, 26.7, 27.2, 28.7, 45.2, 49.3, 59.1, 61.1, 118.5, 125.2, 125.4,
174.5, 179.1. IR(KBr): m .
max 3227, 1657, 1646, 1593, 1502, 1374, 1251, 1070 cmÀ1
MS:m/z (%relative intensity) 242(M+, 15), 241 (100), 222(32), 210(63), 198(36),
169 (51), 78 (39).
Compound 19: Mp = 160 °C. 1H NMR (DMSO-d6): d (ppm): 1.40 (m, 2H), 1.78 (m,
2H), 3.40(m, 2H), 4.43 (m, 3H), 6.69(d, J = 2.8 Hz, 1H), 7.50(d, J = 2.8 Hz, 1H), 7.81
(d, J = 5.0 Hz, 1H), 8.98 (d, J = 5.0 Hz, 1H), 9.14 (s, 1H). 13C NMR (DMSO-d6): d
(ppm): 27.2, 29.4, 48.7, 60.3, 107.5, 118.4, 126.4, 128.0, 129.2, 133.0, 138.6,
147.5, 155.1, 174.4, 179.1. IR (KBr): mmax 3262, 1668, 1657, 1590, 1498, 1374,
1247 cmÀ1. MS: m/z (% relative intensity) 270 (M+, 100), 252 (M+À18, 27), 225
(32), 213 (36), 211 (40), 199 (31), 170 (39).
126.7, 129.6, 130.2, 139.5, 148.2, 154.6, 174.9, 180.2. IR (KBr): mmax 3404, 3061,
2945, 1657, 1583, 1492, 1418, 1392, 1290, 1261, 1216, 1061, 934, 903 cmÀ1. MS:
m/z(%relativeintensity)366(M+, 3), 323(1),225(1), 211(1), 127(1), 98(7),69(2),
58 (100).
Compound 20: Mp = 69 °C. 1H NMR (CDCl3): d (ppm): 1.33 (m, 6H), 1.51 (m, 2H),
1.81 (m, 2H), 2.23 (s, 1H), 3.58 (t, J = 6.4 Hz, 2H), 4.39 (t, J = 7.3 Hz, 2H), 6.71 (d,
J = 2.8 Hz, 1H), 6.98 (d, J = 2.76 Hz, 1H), 7.88 (dd, J = 0.8 Hz, 5.0 Hz, 1H), 8.92 (d,
J = 5.0 Hz, 1H), 9.28 (s, 1H). 13C NMR (CDCl3): d (ppm): 25.5, 26.4, 28.8, 30.7, 32.5,
49.6, 62.5, 108.1, 118.7, 126.7, 128.6, 129.6, 131.4, 139.1, 148.2, 154.7, 175.0,
Compound33:1HNMR(CDCl3):d(ppm):1.02–1.04(m, 2H), 1.35(s, 6H), 1.49–1.55
(m, 2H), 1.66–1.69 (m, 2H), 1.80–1.83 (m, 2H), 2.14 (t, J = 6.8 Hz, 2H), 2.30 (s, 6H),
2.57 (t, J = 7.5 Hz, 2H), 3.01 (t, J = 7.5 Hz, 2H), 4.38 (t, J = 7.3 Hz, 2H), 6.89 (s, 1H),
7.91 (dd, J = 4.9 Hz, 0.8 Hz, 1H), 8.95 (d, J = 4.9 Hz, 1H), 9.33 (s, 1H). 13C NMR
(CDCl3):d(ppm):23.8, 26.5, 27.2, 27.3,29.1, 29.6, 30.8, 45.3, 49.6, 59.2,61.9, 118.6,
125.2, 125.5, 126.8, 129.8, 130.3, 139.6, 148.3, 154.7, 175.0, 180.4. IR (KBr): mmax
3422, 2929, 2855, 1653, 1584, 1492, 1466, 1419, 1395, 1262, 934, 734 cmÀ1. MS:
m/z (% relative intensity) 408 (M+, 4), 363 (1), 322 (1), 225 (1), 211 (1), 127 (1), 83
(2), 69 (2), 58 (100).
179.5. IR (KBr): m
max 3362, 1675, 1650, 1586, 1498, 1388, 1251 cmÀ1. MS: m/z (%
relative intensity) 200 (39), 199 (100), 181 (11), 139 (9), 88 (35), 77 (31), 55 (28).
Compound 21: Mp = 154 °C. 1H NMR (CDCl3): d (ppm): 2.18 (s, 6H), 2.45 (t,
J = 7.2 Hz, 2H), 2.86 (t, J = 7.2 Hz, 2H), 3.72 (t, J = 5.4 Hz, 2H), 4.43 (t, J = 5.4 Hz, 2H),
5.04 (s, 1H), 7.31 (s, 1H), 7.82(d, J = 4.9 Hz, 1H), 8.99(d, J = 4.9 Hz, 1H), 9.13 (s, 1H).
13C NMR (CDCl3): d (ppm): 23.2, 45.0, 51.2, 58.9, 60.1, 118.4, 123.9, 124.9, 126.4,
Compound34:Mp = 97 °C. 1HNMR(CDCl3):d (ppm):1.72–1.87 (m, 2H), 1.90–2.04
(m, 2H), 2.21–2.29 (m, 16H), 2.83 (t, J = 7.6 Hz, 2H), 4.44 (t, J = 6.9 Hz, 2H), 6.87 (s,
129.0, 132.5, 138.9, 147.4, 155.0, 174.9, 179.9. IR (KBr):
m
max 3419, 2820, 1664,
1H), 7.90 (d, J = 4.9 Hz, 0.8 Hz, 1H), 8.95 (dd, J = 4.0 Hz, 0.9 Hz, 1H), 9.33 (s, 1H). 13
C
1642, 1584, 1490, 1465, 1395, 1263, 1221, 1068, 933 cmÀ1. MS: m/z (% relative
intensity) 313 (M+, 1), 269 (1), 211 (3), 155 (1), 128 (2), 101 (2), 91 (3), 78 (4), 58
(100).
NMR (CDCl3): d (ppm): 23.5, 27.7, 28.4, 47.3, 55.8, 59.3, 45.3, 45.5, 118.6, 126,8,
127.1, 129.8, 130.6, 132.9, 139.6, 148.3, 154.7, 175.0, 180.3. IR (KBr): max 3416,
m
2938, 2763, 1653, 1584, 1490, 1399, 1254, 1041 cmÀ1. MS: m/z (% relative
intensity) 368 (M+, 1), 297 (1), 226 (6), 211 (1), 149 (2), 84 (15), 72 (11), 58 (100).
Compound 35: Mp = 94 °C. 1H NMR (CDCl3): d (ppm): 1.00 (s, 9H), 2.30 (s, 6H), 2.53
(t, J = 7.9 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 4.04 (t, J = 4.9 Hz, 2H), 4.51 (t, J = 4.5 Hz,
2H), 7.00(s, 1H), 7.18–7.21 (m, 6H), 7.39–7.42 (m, 4H), 7.93 (d,J = 4.9 Hz, 1H), 8.98
(d, J = 4.9 Hz, 1H), 9.21 (s, 1H). 13C NMR (CDCl3): d (ppm): 19.0, 23.7, 26.8, 45.3,
51.9, 59.1, 62.5, 118.5, 124.5, 125.8, 126.7, 127.6, 129.3, 129.7, 132.2, 132.6, 135.4,
139.6, 148.2, 154.7, 174.9, 180.4. IR (KBr): mmax 3418, 2927, 2854, 1663, 1652,
1583, 1491, 1464, 1425, 1390, 1265, 1110, 930, 701 cmÀ1. MS: m/z (% relative
intensity)551(M+,1),199(7),167(7),149(23),97(17),81(24),69(45),58(56),44
(100).
Compound 22: 1H NMR (CDCl3): d (ppm): 1.54–1.67 (m, 2H), 1.86–1.97 (m, 2H),
2.29 (s, 6H), 2.56 (t, J = 7.5 Hz, 2H), 2.98 (t, J = 7.4 Hz, 2H), 3.23 (s, 1H), 3.65 (t,
J = 6.3 Hz, 2H), 4.42 (t, J = 7.3 Hz, 2H), 6.92 (s, 1H), 7.87 (dd, J = 4.9 Hz, 0.7 Hz, 1H),
8.92 (d, J = 4.9 Hz, 1H), 9.28 (s, 1H). 13C NMR (CDCl3): d (ppm): 23.6, 27.3, 29.3,
45.1, 49.2, 59.1, 61.6, 118.6, 125.1, 125.5, 126.7, 129.7, 130.4, 139.5, 148.2, 154.7,
175.0, 180.2. IR (KBr): mmax 3378, 2940, 1653, 1585, 1493, 1395, 1261, 1059, 935,
734, 688 cmÀ1. MS: m/z (% relative intensity) 341 (M+, 2), 326 (2), 223 (1), 128 (1),
101 (1), 83 (1), 69 (1), 58 (100).
Compound23:1HNMR(CDCl3):d(ppm):1.37(s, 6H),1.54(t,J = 6.1 Hz, 2H),1.83(t,
J = 6.1 Hz, 2H), 2.06 (s, 1H), 2.30 (s, 6H), 2.57 (t, J = 7.2 Hz, 2H), 3.01 (t, J = 7.4 Hz,
2H), 3.61 (t, J = 6.4 Hz, 2H), 4.39 (t, J = 7.3 Hz, 2H), 6.90 (s, 1H), 7.91 (d, J = 4.9 Hz,
1H), 8.95 (d,J = 5.0 Hz, 1H), 9.33 (s, 1H). 13CNMR(CDCl3):d(ppm):23.7, 25.6, 26.5,
28.8, 30.7, 45.3, 49.5, 59.2, 62.7, 118.6, 125.2, 125.5, 126.8, 129.8, 130.3, 139.6,
Compound36:1HNMR(CDCl3):d(ppm):1.03(s, 9H),1.52–1.66(m,2H), 1.88–2.03
(m, 2H), 2.30(s, 6H), 2.57 (t, J = 7.4 Hz, 2H), 3.01 (t, J = 7.4 Hz, 2H), 3.70 (t, J = 6.0 Hz
2H), 4.41 (t, J = 7.1 Hz, 2H), 6.86 (s, 1H), 7.35–7.38 (m, 6H), 7.62–7.65 (m, 4H), 7.92
(d, J = 4.9 Hz, 1H), 8.96 (d, J = 5.0 Hz, 1H), 9.34 (s, 1H). 13C NMR (CDCl3): d (ppm):
19.1, 23.7, 26.8, 27.4, 29.3, 45.2, 49.3, 59.2, 63.1, 118.6, 125.1, 125.5 126.8, 127.6,
129.6, 129.8, 130.2, 133.6, 135.4, 139.5, 148.3, 154.6, 174.9, 180.4. IR (KBr): mmax
3416, 2928, 2854, 1667, 1653, 1585, 1493, 1396, 1262, 1111, 1086, 937, 823, 733,
704 cmÀ1. MS: m/z (% relative intensity) 199 (100), 181 (8), 152(3), 121 (6), 97 (2),
77 (24), 69 (4), 45 (26).
148.3, 154.7 175.0, 180.4. IR (KBr): mmax 3384, 2931, 1653, 1585, 1492, 1465, 1419,
1395, 1261, 1054, 934 cmÀ1. MS: m/z (% relative intensity) 383 (M+, 2), 368 (12),
325 (1), 254 (1), 237 (1), 225 (2), 211 (6), 141 (1), 128 (1), 97 (1), 58 (100).
Compound24:1HNMR(CDCl3):d(ppm):2.32(s, 6H),2.62(t,J = 7.2 Hz, 2H), 2.95(s,
3H), 3.03 (t, J = 7.2 Hz, 2H), 4.60 (t, J = 4.9 Hz, 2H), 4.74 (t, J = 4.7 Hz, 2H), 7.02 (s,
1H), 7.91 (d, J = 4.9 Hz, 1H), 8.98 (d, J = 5.1 Hz, 1H), 9.31 (s, 1H). 13C NMR (CDCl3): d
(ppm): 23.4, 37.4, 45.1, 48.7, 58.8, 67.8, 118.7, 125.2, 126.2, 126.4, 129.5, 131.7,
139.5, 148.2, 155.1, 175.4, 180.3. IR (KBr): mmax 3424, 2927, 2856, 1663, 1585,
1495, 1464, 1420, 1396, 1352, 1266, 1174, 1009, 916, 803 cmÀ1. MS: m/z (%
relative intensity) 391 (M+, 1), 195 (3), 165 (3), 125 (9), 111 (16), 97 (30), 84 (49),
58 (100).
Compound 37: 1H NMR (CDCl3): d (ppm): 1.03 (s, 9H), 1.34 (m, 6H), 1.53 (m, 2H),
1.80 (m, 2H), 2.31 (s, 6H), 2.58 (t, J = 7.5 Hz, 2H), 3.02 (t, J = 6.3 Hz, 2H), 3.64 (t,
J = 6.3 Hz2H), 4.37 (t, J = 7.2 Hz, 2H), 6.89 (s, 1H), 7.32–7.38 (m, 6H), 7.62–7.67(m,
4H), 7.91 (d, J = 4.9 Hz, 1H), 8.95 (d, J = 5.1 Hz, 1H), 9.34 (s, 1H). 13C NMR (CDCl3): d
(ppm): 19.1, 23.7, 25.6, 26.5, 26.8, 28.8, 30.8, 32.3, 45.2, 49.5, 59.1, 63.7, 118.5,
125.1, 125.4 126.7, 127.6, 127.5, 129.4, 129.7, 130.2, 133.9, 135.4, 139.5, 148.2,
Compounds25, 26:Due toinstability, theseCompoundswereusedimmediatelyfor
the next step without spectroscopic characterization.
154.6, 174.9, 180.3. IR(KBr): mmax 3418, 2930, 2856, 1653, 1492, 1465, 1427, 1261,
Compound 27: 1H NMR (CDCl3): d (ppm): 2.28 (s, 12H), 2.52 (t, J = 7.2 Hz, 2H), 2.70
(t, J = 6.6 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H), 4.50 (t, J = 6.4 Hz, 2H), 6.95 (s, 1H), 7.89 (d,
J = 4.9 Hz, 1H), 8.94 (d, J = 5.0 Hz, 1H), 9.31 (s, 1H). 13C NMR (CDCl3): d (ppm): 23.7,
45.3, 45.6, 47.2, 59.1, 59.4, 118.6, 125.2, 125.5, 126.7, 129.7, 130.8, 139.5, 148.2,
1112, 934, 702 cmÀ1. MS:m/z (% relative intensity) 199 (100), 181 (7), 152(3), 137
(7), 121 (6), 97 (6), 69 (21), 45 (32).
Compound 38: During silica gel column chromatography compound 38
decomposes to give target compound 30 in pure form.
154.7, 175.1, 180.3. IR(KBr):
m
max 3415, 2929, 2823, 2778, 1653, 1584, 1493, 1465,
Compound 39: Mp = 235 °C (decomp.). 1H NMR (DMSO): d (ppm): 3.15 (t,
J = 6.7 Hz, 2H), 3.82 (t, J = 7.1 Hz, 2H), 7.27 (d, J = 4.8 Hz, 1H), 7.78 (t, J = 5.3 Hz,
1H), 8.96 (d, J = 8.7 Hz, 1H), 9.08 (d, J = 5.9 Hz, 1H), 12.94 (br s, 1H). 13C NMR
(DMSO): d (ppm): 28.8, 43.9, 118.6, 122.3, 123.8, 125.9, 127.5, 132.1, 139.3, 147.1,
155.2, 174.0, 180.1. IR (KBr): mmax 1652, 1582, 1494, 1418, 1397, 1256, 1232,
1079,927 cmÀ1. MS:m/z (%relativeintensity) 260(M+, 9),224(100), 211 (53), 196
(6), 168 (6), 156 (6), 140 (7), 128 (11), 106 (12), 78 (13).
1420, 1396,1265, 1174, 1042, 934 cmÀ1. MS: m/z (%relativeintensity)326(M+, 2),
240 (7), 212 (4), 97 (4), 83 (4), 71 (6), 58 (100), 44 (40), 30 (20).
Compound 28: 1H NMR (CDCl3): d (ppm): 1.92–2.03 (m, 2H), 2.20–2.30 (m, 14H),
2.56 (t, J = 7.6 Hz, 5.0 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 4.43 (t, J = 6.7 Hz, 2H), 6.94 (s,
1H), 7.89 (d, J = 4.9 Hz, 1H), 8.94 (d, J = 4.9 Hz, 1H), 9.31 (s, 1H). 13C NMR (CDCl3): d
(ppm): 23.7, 28.4, 45.3, 45.5, 47.3, 55.8, 59.2, 118.6, 125.0, 125.5, 126.8, 129.7,
131.0, 139.6, 148.3, 154.7, 174.9, 180.3. IR (KBr): mmax 3429, 2937, 2765, 1652,
1583, 1490, 1394, 1259, 933, 734 cmÀ1. MS: m/z (% relative intensity) 354 (M+, 1),
254 (2), 149 (5), 111 (4), 97 (7), 85 (10), 71 (14), 58 (100).
Compound 40: Mp = 230 °C. 1H NMR (DMSO): d (ppm): 1.97–2.11 (m, 2H), 2.85 (t,
J = 7.1 Hz, 2H), 3.65 (t, J = 6.6 Hz, 2H), 7.23 (s, 1H), 7.83 (d, J = 4.9 Hz, 1H), 8.99 (d,
J = 4.9 Hz, 1H), 9.13 (s, 1H), 12.91 (br s, 1H). 13C NMR (DMSO): d (ppm): 22.7, 31.9,
45.0, 118.7, 123.8, 125.3, 126.0, 126.6, 132.2, 139.5, 147.1, 155.1, 174.0, 180.0. IR
Compound 29: 1H NMR (CDCl3):d (ppm): 2.30 (s, 6H), 2.32(s, 1H), 2.45 (s, 3H), 2.58
(t, J = 7.6 Hz, 2H), 2.98–3.05 (m, 4H), 4.53 (t, J = 5.8 Hz, 2H), 6.96 (s, 1H), 7.91 (d,
J = 4.4 Hz, 1H), 8.97 (d, J = 4.9 Hz, 1H), 9.34(s, 1H). 13C NMR(CDCl3): d (ppm): 23.8,
36.3, 45.3, 49.2, 51.8, 59.1, 118.6, 125.3, 125.7, 126.7, 129.9, 130.9, 139.6, 148.3,
(KBr): m
max 3446, 3080, 2918, 2840, 1659, 1591, 1397, 1247, 1033, 925 cmÀ1. MS:
m/z (% relative intensity) 274 (M+, 29), 239 (61), 225 (47), 212 (42), 211 (100), 197
(2), 183 (4), 155 (6), 140 (3), 128 (11), 106 (27), 78
(22).
154.8, 175.2, 180.4. IR(KBr):
mmax 3415, 2926, 2854, 1653, 1584, 1492, 1465, 1419,
1395, 1263, 933 cmÀ1. MS: m/z (% relative intensity) 326 (M+, 2), 240 (7), 212 (4),