Synthesis and anticancer activity of 13-membered cyclic enediynes

Article abstract of DOI:10.1002/ardp.201000309

We herein describe the synthesis of 15 novel 13-membered cyclic enediyne derivatives using simple and straightforward approach. Representative examples were screened for their anticancer activities on 60 different human tumor cell lines representing various histologies viz. leukemia, melanoma, and cancers of lung, colon, kidney, ovary, breast, prostate, and central nervous system. The enediyne derivatives with halogen substitutions, especially fluorides were found to be active against most of the cell lines. The initial results indicates marginal to good inhibition for the growth of tumor cells for several cell lines, which shows the potential of these class of compound towards anticancer application. 15 novel 13-membered cyclic enediyne derivatives using a simple and straightforward approach are synthesized. The initial results show the potential of this class of compounds towards anticancer application. Copyright

Full text of DOI:10.1002/ardp.201000309

564
Arch. Pharm. Chem. Life Sci. 2011, 344, 564–571
Full Paper
Synthesis and Anticancer Activity of 13-Membered Cyclic
Enediynes
Mukul Sharma1, Mukesh C Joshi1, Vineet Kumar2, Sanjay V. Malhotra2, and Diwan S. Rawat1
1 Department of Chemistry, University of Delhi, Delhi, India
2 Laboratory of Synthetic Chemistry, SAIC, Frederick Inc, National Cancer Institute at Frederick, Frederick,
MD, USA
We herein describe the synthesis of 15 novel 13-membered cyclic enediyne derivatives using simple
and straightforward approach. Representative examples were screened for their anticancer activities
on 60 different human tumor cell lines representing various histologies viz. leukemia, melanoma,
and cancers of lung, colon, kidney, ovary, breast, prostate, and central nervous system. The enediyne
derivatives with halogen substitutions, especially fluorides were found to be active against most of the
cell lines. The initial results indicates marginal to good inhibition for the growth of tumor cells for
several cell lines, which shows the potential of these class of compound towards anticancer
application.
Keywords: Anticancer / Cell lines / Enediyne
Received: October 16, 2010; Revised: January 21, 2011; Accepted: January 24, 2011
DOI 10.1002/ardp.201000309
Introduction
exhibit excellent anticancer activity but due to their modest
selectivity for cancer cells, clinical use of this class of com-
pounds has been limited. In order to improve the selectivity
of the enediynes, efforts are being made to synthesize anal-
ogous compounds with better efficacy [21–26]. Very recently
we have reported the synthesis and antibacterial activity of
thermally stable 13-membered cyclic enediynes [19]. To this
end, we report herein synthesis and anticancer activity of
various 13-membered cyclic enediynes.
Enediyne class of compounds is considered to be one of the
most powerful anti-tumor and antibiotic agents [1–5]. First
discovered in late 1980’s, these compounds captured immedi-
ate attention of the chemists and biologists throughout the
world due their complex molecular framework and novel
biological activity profile [6]. All the natural enediynes such
as calicheamicin [7], esperamicin [8], dynamicin [9, 10]
maduroptin [1], and more recently uncialamycin [11] possess
highly strained enediyne unit, a triggering device and deliv-
ery agent and under biological conditions these compounds
forms diradical which is responsible for their anticancer
activity [12, 13]. Some of the enediynes such as neocarzino-
statin, and mylotary (a bioconjugate of monoclonal antibody
and calcheamicin g1) [14] have also been approved by FDA for
the treatment of acute myeloid leukemia [15, 16]. Apart from
anticancer activity, synthetic enediynes are known to exhibit
cytotoxicity against various cell lines [1, 17], protein degra-
dation activity [18], antibacterial activity [19], and topoiso-
merase inhibitory activity [20]. Although these compounds
Results and discussion
Chemistry
The synthesis of 13-membered cyclic substituted enediyne
amines is outlined in Scheme 1 and Scheme 2 illustrates the
synthesis of ester analogues of these cyclic enediynes. The
multi step procedure was accomplished by using cis-dichloro-
ethene 1 as starting material. The two arms of cis-dichloro-
ethene were extended to form compound 3 [27] using
protected propargyl alcohol via Sonagashira coupling.
Compound 3 was converted to 1,8-dibromo-oct-4-ene-2,6-
diyne 4 [27] using PPh3 and Br2. The mechanism of this
reaction is depicted in Scheme 3. In the first step, triphenyl
phosphine and bromine forms triphenylphosphinedibro-
mide, which is very reactive and it replaces OTHP group
Correspondence: Professor Diwan S. Rawat, Department of Chemistry,
University of Delhi, Delhi 110007, India.
E-mail: dsrawat@chemistry.du.ac.in
Fax: 91-11-27667501
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2011, 344, 564–571
Synthesis and Anticancer Activity of 13-Membered
565
OTHP
OTHP
Br
Br
Cl
Pd(0), CuI, n-BuNH2,
Br2, PPh3, CH2Cl2,
RT, 1 h
+
Benzene
OTHP
Cl
R
3
4
1
2
R
NH2
R
OH
OH
O
N
4,K2CO3, DMF
CHO
MeOH, Mol. Seives, RT
N
+
HO
O
HO
8 a-d
7 a-d
5
6 a-d
R
R
O
O
9a, R = Cl
9b, R = Br
9c, R = H
9d, R = F
N
O
O
N
NaBH4, MeOH
H
8 a-d
Scheme 1. Synthesis of 13-membered cyclic substituted enediyne amines.
CHO
CHO
CH2OH
O
O
Br
Br
O
O
HO
K2CO3, DMF
NaBH4, MeOH
RT, 2 h
+
OH
4
11
5
10
CHO
R
COOH
COOH
COOH
O
O
Piperidine, Pyridine,
60-120 oC, 3-4 h
11, CDI, DBU, THF
O
+
45 oC, 24 h
R
R
12 a-o
13 a-o
O
14a, R = 4-H
14b, R = 4-CH3
14c, R = 3-CH3
14d, R = 2-CH3
14e, R = 4-Cl
14f, R = 3-Cl
14g, R = 2-Cl
14h, R = 3-F
14i, R = 4-iso-Pr
14j, R = 4-C2H5
14k, R = 1- Naphthyl
14l, R = 3-NO2
14m, R = 4-Br
14n, R = 3-Br
14o, R = 2-Br
Scheme 2. Synthesis of ester analogues of 13-membered cyclic substituted enediyne amines.
CH2Cl2, 0 oC, 15 min
via SN2 mechanism. Compound 3 is added to the mixture of
PPh3 and Br2 only after the formation of triphenylphosphine-
dibromide, so double or triple bonds remains unaffected. The
cyclic enediyne imines (8a–d) were prepared by the coupling
of compound 4 with imines 7a–d in dry DMF in the presence
of K2CO3 as a base [19]. Reduction of compounds 8a–d
by sodium borohydride in dry methanol affords compounds
9a–d in good to moderate yield [19]. The key alcohol 11 for
the synthesis of enediyne ester was synthesized by literature
method as shown in Scheme 2 [19]. 3-Phenyl-acrylic acids
13a–o were prepared by Knoevenagel condensation, followed
by coupling with 11 to afford esters 14a–o using CDI and DBU
as coupling reagents in THF. All the synthesized compounds
were characterized by IR, 1H-NMR, 13C-NMR, HRMS, and
elemental analyses.
PPh3Br2
PPh3
+ Br2
+
PPh3
OTHP
O
O
PPh3Br2
Br-
+
+
O
Br
OTHP
+
PPh3
+
Br-
PPh3
O
Br
+
O
PPh3
O
Br
PPh3
Br-
+
Scheme 3. Mechanism of the conversion of compound 3 to 1,8-
dibromo-oct-4-ene-2,6-diyne 4 using PPh3 and Br2.
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M. Sharma et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 564–571
Anticancer activity
having fluoro substitution on aromatic ring, showed
marginal activity against most of the cell lines. It showed
activity in all leukemia cell lines where significant
inhibition was observed for cell line MOLT-4 (40%). This
compound showed maximum activity for leukemia cell
lines HL-60 (43%). The ester analogous 14f and 14h, both
having halogen substitution on aromatic rings showed
inhibition for most of the cell lines compared to naphthyl
and nitro substituted 14k and 14l, respectively. Compounds
14k and 14l were totally inactive in all of the melanoma,
ovarian and renal cancer cell lines, however marginal
activity was observed in few cell lines in other panels.
Compound 14h with fluoro substitution on aromatic ring
was marginally active in most of the cell lines including
all the leukemia, ovarian and renal cell lines showed
significant inhibition for leukemia cell lines K-562 (52%),
SR (71%), colon cell line HT29 (37%), melanoma cell line
LOX IMVI (37%), and breast cancer cell line MDA-MB-468
(48%). The compound 14f was also active in all the
leukemia cell lines with highest activity for cell line
SR with 32% inhibition in tumor cell growth.
Interestingly, all the five cyclic enediynes showed
inhibition for MDS-MB-468 breast cancer cell line
(Table 1). The One-dose data of the compounds 9d, 14f,
14h, 14k, 14l is reported as a mean graph of the percent
growth of treated cells. The number reported for the One-
dose assay is growth relative to the no-drug control, and
relative to the time zero number of cells. This allows detec-
tion of both growth inhibition (values between 0 and 100)
and lethality (values less than 0). For example, a value of
100 means no growth inhibition. A value of 40 would mean
60% growth inhibition. A value of 0 means no net growth
over the course of the experiment. A value of ꢀ40 would
mean 40% lethality. A value of ꢀ100 means all cells are
dead. The one-dose data of all the screened compounds is
given in Figs. S1–S5 (see Supporting Information).
The anticancer activities of selective compounds were eval-
uated using 60 different human tumor cell lines representing
various histologies viz. leukemia, melanoma, and cancers of
lung, colon, kidney, ovary, breast, prostate, and central ner-
vous system. The cyclic enediyne 9d and its ester analogues
14f, 14h, 14k, and 14l were screened at the concentration of
10 mM on all the cell lines. A brief summary of the results on
selective cell lines is described in Table 1. Compound 9d,
Table 1. Single dose screening of selected compounds at 10 mM
on various tumor cell lines.
Panel/Cell lines
Compounds (% Inhibition)
9d
14f
14h
14k
14l
Leukemia
CCRF-CEM
HL-60(TB)
K-562
19
43
16
18
18
27
16
37
29
10
52
27
20
71
MOLT-4
RPMI-8226
SR
40
32
17
12
16
11
Non-Small Cell Lung Cancer
A549/ATCC
HOP-62
10
10
12
20
HOP-92
NCI-H226
NCI-H23
NCI-H522
Colon Cancer
HCT-116
HT29
13
12
34
10
11
17
15
14
10
11
10
11
11
29
37
CNS Cancer
SF-268
SF-539
18
17
SNB-19
SNB-75
U251
13
12
37
12
19
12
29
18
Melanoma
LOX IMVI
MALME-3M
SK-MEL-2
SK-MEL-5
UACC-257
UACC-62
Ovarian Cancer
IGROV1
15
20
31
12
22
Conclusion
11
11
We have successfully synthesized 15 novel cyclic enediyne
derivatives using straightforward and well established syn-
thetic protocols. The selective compounds were screened for
their anticancer activity which showed marginal to good
inhibition for the growth of tumor cells for several cell lines.
To the best of our knowledge, this the first report where such
an extensive screening for this class of compounds has been
done on diversified human tumor cell lines. These initial
results show the potential of this class of compound towards
anticancer application. However, extensive screening and
SAR needs to be done in this direction which is underway
in our group.
12
24
18
10
15
15
25
10
OVCAR-3
OVCAR-4
OVCAR-8
SK-OV-3
Renal Cancer
A498
UO-31
23
20
17
12
29
Breast Cancer
MCF7
T-47D
29
18
22
17
21
MDA-MB-468
48
14
25
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Arch. Pharm. Chem. Life Sci. 2011, 344, 564–571
Synthesis and Anticancer Activity of 13-Membered
567
2856, 2106, 1586, 1440, 1336, 1247, 1161, 1099; 1H-NMR
(300 MHz, CDCl3) d ¼ 4.12 (s, 4H, CH2Br), 5.96 (s, 2H,
260.8883(Mþ þ H), 262.2472 (Mþ þ 2), 264.7164 (Mþ þ 4).
Experimental
2
CH CH); ESI-HRMS calculated for C H Br : 259.8836. Found:
–
–
8
6
2
Chemistry
All of the chemicals used in the synthesis were purchased from
Sigma-Aldrich and were used as such. Thin layer chromatog-
raphy was used to monitor the progress of the reactions. All
the compounds were purified over silica gel column. Solvents
were distilled before using for purification purposes. IR spectra
were recorded using Perkin-Elmer FT-IR spectrophotometer and
the values are expressed as lmax cmꢀ1. Mass spectral data were
recorded on a Jeol (Japan) JMS-DX303 and micromass LCT, Mass
Spectrometer/Data system. The 1H-NMR was recorded on Bruker
Spectrospin spectrometer at 300 MHz, while 13C-NMR was
recorded on Bruker Spectrospin spectrometer at 75.5 MHz and
Jeol ECX at 100 MHz using TMS as an internal standard. The
chemical shift values are recorded on d scale and the coupling
constants (J) are in Hz. Elemental analysis were performed on a
Carlo Erba Model EA-1108 elemental analyzer and data of C, H
and N is within ꢁ0.4% of calculated values.
4-[(4-Chloro-phenylimino)-methyl]-benzene-1,3-diol (7a)
To
a stirred solution of 2,4-dihydroxybezaldehyde (1.0 g,
7.24 mmol) in (MeOH or EtOH, 20 mL), 4-chloroaniline (0.92 g,
7.24 mmol) was added and reaction mixture was stirred at 65–
758C. Progress of reaction was monitored by TLC. After com-
pletion of reaction, excess of solvent was removed from the
reaction mixture and product thus obtained was purified by
crystallization or over SiO2 column. All dihydroxy imines (7b–
d) were synthesized similarly. Yield: 75%; mp 129–1308C; IR (KBr,
cmꢀ1): 3421, 2924, 1624, 1495; 1H-NMR (300 MHz, DMSO-d6)
d ¼ 6.31 (s, 1H) 6.60 (d, 2H, J ¼ 8.3 Hz), 7.04 (d, 2H,
J ¼ 8.2 Hz), 7.43–7.48 (m, 2H), 8.79 (s, 1H), 13.20 (s, 2H); ESI-
HRMS calculated for C13H10ClNO2: 247.0400. Found: 248.0475
(Mþ þ H), 250.0361 (Mþ þ 2).
Compounds 10 and 11 were prepared by previously reported
method [24]. 3-Phenyl-acrylic acid derivatives 13a, 13b, 13d, 13e,
13i, 13j, 13k [28] 13m [29], and 13o [30] were synthesized by
literature method. Rests of acids were prepared by condensation
of malonic acid with corresponding benzaldehydes following the
literature procedure.
4-[(4-Bromo-phenylimino)-methyl]-benzene-1,3-diol (7b)
Yield: 73%; mp 1358C; IR (KBr, cmꢀ1): 3436, 2950, 1624, 1491;
1H-NMR (300 MHz, DMSO-d6) d ¼ 6.28 (s, 1H, Ar-H) 6.50 (d, 2H,
J ¼ 8.3 Hz, Ar-H), 7.11 (d, 2H, J ¼ 8.3 Hz, Ar-H), 7.50–7.59 (m, 2H,
–
Ar-H), 8.78 (s, 1H, CH N), 13.68 (s, 2H, 2 OH); ESI-HRMS calculated
–
for C13H10BrNO2: 290.9895. Found: 291.9865 (Mþ þ H), 293.9860
1,8-Bis-(tetrahydropyran-2-yloxy)-oct-4-ene-2,6-diyne (3)
[27]
(Mþ þ 2).
The title compound was prepared by literature method [27].
A
4-Phenyliminomethyl-benzene-1,3-diol (7c)
Yield: 60%; mp 106–1088C; IR (KBr, cmꢀ1): 3374, 2872, 1627,
1498; 1H-NMR (300 MHz, DMSO-d6) d ¼ 6.30 (s, 1H, Ar-H) 7.25–
mixture of Pd(PPh3)4 (0.95 g, 0.82 mmol), CuI (0.78 g,
4.12 mmol), n-butylamine (7.5 mL, 100 mmol), anhydrous
benzene (5 mL), and 2-prop-2-ynyloxy-tetrahydro-pyran (2)
(6.06 g, 43.2 mmol) was stirred at room temperature for
15 min under inert atmosphere. A solution of cis-dichloroethene
(2.0 g, 20.8 mmol) (1) in anhydrous benzene (2 mL) was added to
this reaction mixture drop wise (Scheme 1). The resulting reac-
tion mixture was stirred for 15 h at 458C. After the completion of
reaction excess of solvent removed under reduced pressure, and
the crude product thus obtained was purified by SiO2 column
using ethyl acetate/hexane as an eluent. Yield: 91%; Yellow
viscous liquid (Rf ¼ 0.5, 20% ethyl acetate/hexane); DSC:
151.578C; IR (KBr, cmꢀ1): 2942, 2870, 2210, 1440, 1389, 1344,
1201, 1119, 1078, 1023; 1H-NMR (300 MHz, CDCl3) d ¼ 1.42–1.85
(m, 12H, 6 CH2), 3.54 (m, 2H), 3.85 (m, 2H), 4.45 (s, 4H), 4.78 (s, 2H),
5.85 (s, 2H); 13C-NMR (75.5 MHz, CDCl3): 18.60, 25.10, 30.00,
54.30, 61.60, 82.60, 92.60, 96.30, 119.00; ESI-HRMS calculated
for C18H24O4: 304.1675. Found: 305.1682 (Mþ þ H).
–
7.43 (m, 5H, Ar-H), 7.45–7.54 (m, 2H, Ar-H), 8.79 (s, 1H, CH N),
–
13.54 (s, 2H, 2 OH); ESI-HRMS calculated for C13H11NO2: 213.0790.
Found: 214.0778 (Mþ þ H).
4-[(4-Fluoro-phenylimino)-methyl]-benzene-1,3-diol (7d)
Yield: (79.09%), mp 1458C (decomposed); IR (KBr, cmꢀ1): 3425,
2923, 2854, 1629, 1464; 1H-NMR (300 MHz, DMSO-d6) d ¼ 6.31
(s, 1H, Ar-H), 6.42 (d, 2H, J ¼ 7.9 Hz, Ar-H), 7.24 (d, 2H, J ¼ 7.7 Hz,
–
Ar-H), 7.40–7.43 (m, 2H, Ar-H), 8.76 (s, 1H, CH N), 13.36 (s, 2H, 2
–
OH); ESI-HRMS calculated for C13H10FNO2: 231.0696. Found:
232.0687 (Mþ þ H).
4-Chloro-N-[(E)-(6Z)-2,11-dioxabicyclo[10.3.1]hexadeca-
1(16),6,12,14-tetraene-4,8 diyn-13-ylmethyl idene]aniline
(8a) [19]
A mixture of 7a (0.5 g, 2.02 mmol) and K2CO3 (2.79 g, 20.2 mmol)
in 15 mL dry DMF was stirred at room temperature for 25 min
under nitrogen atmosphere. To this suspension 1,8-dibromooct-
4-ene-2,6-diyne (4) (0.53 g, 2.02 mmol) in 10 mL dry DMF was
added drop wise and reaction mixture was stirred at room
temperature under nitrogen atmosphere for 13 h. After com-
pletion of the reaction the reaction mixture was poured in 50 mL
water and product was extracted with CHCl3 (6 ꢂ 20 mL).
Combined organic layer was washed with distilled water
(8 ꢂ 75 mL) and finally dried over anhydrous Na2SO4. After
filtration excess of solvent was removed under reduced pressure.
The crude product was purified over SiO2 column using ethyl
acetate in hexanes as an eluent. Yield: 45%; mp 198–2008C (dec.);
1,8-Dibromo-oct-4-ene-2,6-diyne (4) [27]
The title compound was prepared after [27]. PPh3 (5.176 g,
19.7 mmol) was dissolved in dichloromethane (20 mL) and to
this solution of Br2 (3.153 g, 19.7 mmol) in dichloromethane
(5 mL) was added drop wise under inert atmosphere at 08C.
After 15 min solution of compound 3 (2.0 g, 6.57 mmol) was
added to this reaction mixture at the same temperature
(Scheme 1). After the complete addition reaction mixture was
allowed to stir for 1 h at room temperature. The crude product
was purified over silica gel column using 2% ethyl acetate/hex-
anes as an eluent. Yield: 88%; dark brown liquid (Rf ¼ 0.6, 10%
ethyl acetate/hexane); DSC: 1208C; IR (KBr, cmꢀ1): 3052, 2924,
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568
M. Sharma et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 564–571
DSC: 182.708C; IR (KBr, cmꢀ1): 2924, 2854, 2202, 1606, 1457,
1376, 1266, 1100; 1H-NMR (300 MHz, CDCl3) d ¼ 4.97 (s, 2H,
CH2OAr), 5.01 (s, 2H, CH2OAr), 5.92 (s, 2H), 6.68 (m, 1H, Ar-H),
7.13 (m, 1H, Ar-H), 7.33 (d, 2H, J ¼ 8.5 Hz, Ar-H), 7.37 (m, 1H, Ar-H),
d ¼ 4.01 (br, 1H, NH); 4.22 (s, 2H, NCH2Ph), 4.89 (s, 2H, CH2OAr),
4.97 (s, 2H, CH2OAr), 5.90 (s, 2H), 6.54–6.61 (m, 2H, Ar-H), 7.11
(m, 2H, Ar-H), 7.22 (m, 2H, Ar-H), 7.38 (s, 1H, Ar-H); ESI-HRMS
calculated for C21H16ClNO2: 349.0870. Found: 350.0876
(Mþ þ H), 352.0851 (Mþ þ 2).
–
8.11 (d, 2H, J ¼ 8.6 Hz, Ar-H), 8.75 (s, 1H, CH N); ESI-HRMS
–
calculated for C21H14ClNO2: 347.0713. Found: 348.0724
(Mþ þ H), 350.0676 (Mþ þ 2).
4-Bromo-N-[(6Z)-2,11-dioxabicyclo[10.3.1]hexadeca-
1(16),6,12,14-tetraene-4,8-diyn-13-ylmethyl] aniline
(9b) [19]
4-Bromo-N-[(E)-(6Z)-2,11-dioxabicyclo[10.3.1]hexadeca-
1(16),6,12,14-tetraene-4,8-diyn-13-ylmethyl idene]aniline
Yield: 71%; mp 186–1908C (decomposed); DSC: 149.268C; IR
(KBr, cmꢀ1): 3401, 2921, 2854, 2202, 1593, 1501, 1450, 1268,
1097, 1006; 1H-NMR (300 MHz, CDCl3) d ¼ 4.12 (s, 2H, NCH2Ph),
4.68 (brs, 1H, NH); 5.01 (s, 2H, CH2OAr), 5.12 (s, 2H, CH2OAr),
5.92 (s, 2H), 6.13–6.21 (m, 2H, Ar-H), 6.52 (m, 2H, Ar-H), 7.16
(s, 2H, Ar-H); 7.30 (m, 1H, Ar-H); 13C-NMR (100 MHz, CDCl3)
d ¼ 40.59, 56.71, 57.93, 86.47, 91.27, 91.86, 103.89, 111.49,
112.28, 114.52, 120.86, 121.78, 122.54, 122.75, 130.22, 131.81,
132.01, 147.24, 154.59, 156.78; ESI-HRMS calculated for
C21H16BrNO2: 393.0364. Found: 394.0356 (Mþ þ H), 396.0340
(Mþ þ 2).
(8b) [19]
Yield: 34%; mp 197–2008C (dec.); DSC: 188.928C; IR (KBr, cmꢀ1):
2924, 2861, 2202, 1606, 1579, 1457, 1363, 1265, 1100, 1002;
1H-NMR (300 MHz, CDCl3) d ¼ 4.97 (s, 2H, CH2OAr), 5.07 (s, 2H,
CH2OAr), 5.93 (s, 2H), 6.71 (m, 1H, Ar-H), 7.08 (m, 1H, Ar-H), 7.37
(m, 1H, Ar-H), 7.48 (d, 2H, J ¼ 8.3 Hz, Ar-H), 8.11 (d, 2H, J ¼ 8.7 Hz,
–
Ar-H), 8.74 (s, 1H, CH N); ESI-HRMS calculated for C21H14NO2Br:
–
391.0208. Found: 392.0212 (Mþ þ H), 394.0178 (Mþ þ 2).
N-[(E)-(6Z)-2,11-Dioxabicyclo[10.3.1]hexadeca-1(16),6,
12,14-tetraene-4,8-diyn-13-ylmethyl idene] aniline
N-[(6Z)-2,11-Dioxabicyclo[10.3.1]hexadeca-1(16),6,
(8c) [19]
Yield: 30%; mp 159–1608C (dec.); DSC 141.868C; IR (KBr, cmꢀ1):
2923, 2856, 2202, 1603, 1588, 1503, 1452, 1370, 1264, 1098,
1004; 1H-NMR (300 MHz, CDCl3) d ¼ 4.95 (s, 2H, CH2OAr), 4.99
(s, 2H, CH2OAr), 5.91 (s, 2H,), 6.62–6.70 (m, 2H, Ar-H), 7.17–7.24
12,14-tetraene-4,8-diyn-13-ylmethyl]aniline (9c) [19]
Yield: 45%; mp 159–1628C (decomposed); DSC: 139.198C; 1H-NMR
(300 MHz, CDCl3) d ¼ 4.18 (s, 2H, NCH2Ph); 4.53 (br, 1H, NH), 4.81
(s, 2H, CH2OAr), 4.89 (s, 2H, CH2OAr), 5.82 (s, 2H), 6.56–6.59
(m, 5H, Ar-H), 7.09–7.31 (m, 3H, Ar-H); ESI-HRMS calculated for
C21H17NO2: 315.1259. Found: 316.1270 (Mþ þ H).
(m, 5H, Ar-H), 7.36 (m, 1H, Ar-H), 8.13 (s, 1H, CH N); 13C-NMR
–
–
(100 MHz, CDCl3): 56.85, 56.97, 86.72, 86.99, 90.62, 91.06,
102.24, 111.95, 112.29, 115.06, 121.01, 122.56, 122.96, 123.04,
129.00, 129.24, 15.65, 157.53, 162.45; ESI-HRMS calculated for
C21H15NO2: 313.1103. Found: 314.1118 (Mþ þ H).
4-Fluoro-N-[(6Z)-2,11-dioxabicyclo[10.3.1]hexadeca-
1(16),6,12,14-tetraene-4,8-diyn-13-ylmethyl] aniline
(9d) [19]
4-Fluoro-N-[(E)-(6Z)-2,11-dioxabicyclo[10.3.1]hexadeca-
1(16),6,12,14-tetraene-4,8-diyn-13-ylmethyl idene]aniline
Yield: 65%; mp 157–1608C (decomposed); DSC: 124.318C; IR
(KBr, cmꢀ1): 3400, 2922, 2871, 2202, 1605, 1507, 1454, 1266,
1216, 1099, 1003; 1H-NMR (300 MHz, CDCl3) d ¼ 4.21 (s, 2H,
NCH2Ph), 4.89 (s, 2H, CH2OAr), 4.97 (s, 2H, CH2OAr), 5.02 (brs,
1H, NH); 5.92 (s, 2H), 6.55–6.62 (m, 2H, Ar-H), 7.89 (m, 2H, Ar-H),
7.24 (m, 2H, Ar-H), 7.38 (s, 1H, Ar-H); 13C-NMR (100 MHz, CDCl3)
d ¼ 43.59, 56.83, 57.89, 86.45, 86.67, 91.34, 91.87, 103.99, 111.50,
113.84, 115.40, 115.62, 122.45, 129.12, 130.30, 130.60, 148.82,
154.61, 155.38; ESI-HRMS calculated for C21H16FNO2: 333.1165.
Found: 334.1156 (Mþ þ H).
(8d) [19]
Yield: 32%; mp 180–1828C (dec.); DSC: 188.908C; IR (KBr, cmꢀ1):
3354, 2922, 2861, 2211, 1580, 1467, 1371, 1270, 1090; 1H-NMR
(300 MHz, CDCl3) d ¼ 5.00 (s, 2H, CH2OAr), 5.05 (s, 2H, CH2OAr),
5.96 (s, 2H), 6.71 (dd, 1H, J ¼ 8 Hz, 1.5 Hz, Ar-H), 7.10 (d, 2H,
J ¼ 6 Hz, Ar-H), 7.18 (d, 2H, J ¼ 6 Hz, Ar-H), 7.36 (d, 1H,
J ¼ 1.5 Hz, Ar-H), 8.12 (d, 1H, J ¼ 6.6 Hz, Ar-H), 8.78
(s, 1H, CH N); 13C-NMR (100 MHz, CDCl3) d ¼ 56.87, 57.13,
–
–
86.74, 87.03, 90.98, 91.07, 102.11, 112.29, 115.55, 115.78,
119.09, 122.29, 122.38, 122.57, 122.69, 129.14, 155.39, 157.51,
160.06; ESI-HRMS calculated for C21H14FNO2: 331.1009. Found:
332.1013 (Mþ þ H).
3-m-Tolyl-acrylic acid (13c)
To a stirred solution of malonic acid (1.29 g, 12.5 mmol) in
pyridine (7 mL) at room temperature was added m-tolualdehyde
(1.0 g, 8.32 mmol) in pyridine (7 mL). Piperidine (2 mL) was
added to the solution. The reaction mixture was heated at
118–1208C for 4 h and was cooled to 08C. Then 3 N HCl was
added to adjust the pH value to 3, and the mixture was stirred at
08C for another 1 h. After suction filtration, the filtrate was
crystallized in acetone to yield the title compound. Yield: 88%;
mp: 115–1188C; IR (KBr, cmꢀ1): 2923, 2832, 2545, 1683, 1624,
4-Chloro-N-[(6Z)-2,11-dioxabicyclo[10.3.1]hexadeca-
1(16),6,12,14-tetraene-4,8-diyn-13-ylmethyl] aniline
(9a) [19]
To a solution of 8a (0.20 g, 0.57 mmol) in 10 mL dry methanol or
dry THF, NaBH4 (0.065 g, 1.71 mmol) was added at room
temperature and reaction mixture was stirred for 2 h. After
completion of reaction excess of solvent was removed under
reduced pressure and crude product was purified by SiO2 column
using ethyl acetate/hexane as an eluent. Yield: 60%; mp 185–
1878C; DSC: 143.278C; IR (KBr, cmꢀ1): 3383, 2920, 2864, 2211,
1593, 1502, 1460, 1270, 1098, 1006; 1H-NMR (300 MHz, CDCl3)
1
1423, 1312, 987, 812, 495; H-NMR (300 MHz, DMSO-d6) d ¼ 2.3
(s, 3H, PhCH3), 6.38 (d, 1H, J ¼ 15 Hz), 7.22 (m, 3H, Ar-H), 7.67
(d, 1H, J ¼ 8 Hz), 7.78 (d, 1H, J ¼ 15 Hz), 12.43 (brs, 1H, COOH)
ESI-HRMS calculated for C10H10O2: 162.0681. Found: 163.0651
(Mþ þ H).
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Arch. Pharm. Chem. Life Sci. 2011, 344, 564–571
Synthesis and Anticancer Activity of 13-Membered
569
Anal. Calcd for C29H17FO4: C, 74.22; H, 4.41. Found: C, 74.33;
H, 4.57.
3-(3-Chloro-phenyl)-acrylic acid (13f)
Yield: 83%; mp: 176–1778C; IR (KBr, cmꢀ1): 2969, 2826, 2715,
2607, 1686, 1633, 1586, 1489, 1419, 1251; 1H-NMR (300 MHz,
DMSO-d6) d ¼ 6.57 (d, 1H, J ¼ 15 Hz), 7.38–7.45 (m, 2H, Ar-H),
7.53 (d, 1H, J ¼ 15 Hz), 7.63–7.65 (m, 1H, Ar-H), 7.78 (s, 1H, Ar-H),
12.50 (brs, 1H, COOH); ESI-HRMS calculated for C10H7ClO2:
182.0135. Found: 183.0181 (Mþ þ H), 185.4398 (Mþ þ 2).
3-Phenyl-acrylic acid 2,11-dioxa-bicyclo[10.3.1]hexadeca-
1(15),6,12(16),13-tetraene-4,8-diyn-13-ylmethyl ester
(14a)
Yield: 50%; IR (KBr, cmꢀ1): 2926, 1708, 1638, 1612, 1591, 1510,
1
1270, 1168; H-NMR (300 MHz, CDCl3) d ¼ 4.84 (s, 2H, CH2OAr),
3-(2-Chloro-phenyl)-acrylic acid (13g)
–
4.91 (s, 2H, CH OAr), 5.17 (s, 2H, ArCH O), 5.83 (s, 2H, CH CH),
2
–
2
Yield: 80%; mp: 209–2108C; IR (KBr, cmꢀ1): 2924, 2835, 2525,
1686, 1621, 1590, 1470, 1440, 1278; 1H-NMR (300 MHz, DMSO-d6)
d ¼ 6.57 (d, 1H, J ¼ 15 Hz), 7.35–7.45 (m, 2H, Ar-H), 7.51 (d, 1H,
J ¼ 15 Hz), 7.84–7.92 (m, 2H, Ar-H), 12.65 (brs, 1H, COOH);
ESI-HRMS calculated for C10H7ClO2: 182.0135. Found: 183.0132
(Mþ þ H), 185.6241 (Mþ þ 2).
6.63 (d, 1H, J ¼ 15 Hz, CHCOO), 6.56–6.60 (m, 1H, Ar-H), 7.18 (s,
1H, Ar-H), 7.29–7.31 (m, 3H, Ar-H), 7.34 (d, 1H, J ¼ 3 Hz), 7.42–7.45
(m, 2H, Ar-H), 7.60 (d, 1H, J ¼ 15 Hz, CH-Ar); 13C-NMR (100 MHz,
CDCl3) d ¼ 57.21, 57.54, 61.50, 86.58, 86.70, 91.46, 91.56, 103.84,
111.58, 118.58, 118.44, 122.12, 122.23, 128.05, 128.83, 130.23,
131.80, 134.40, 144.86, 155.38, 157.68, 166.98; ESI-HRMS calcu-
lated for C24H18O4: 370.1205. Found: 371.1219 (Mþ þ H); Anal.
cacld for C24H18O4: C, 77.82; H, 4.90. Found: C, 77.99; H, 4.70.
3-(3-Fluoro-phenyl)-acrylic acid (13h)
Yield: 85%; mp: 1678C; IR (KBr, cmꢀ1): 2969, 2826, 2715, 2607,
1686, 1633, 1586, 1489, 1419, 1251; 1H-NMR (300 MHz, DMSO-d6)
d ¼ 6.57 (d, 1H, J ¼ 15 Hz), 7.20–7.26 (m, 1H), 7.43–7.60 (m, 4H),
12.65 (brs, 1H, COOH); ESI-HRMS calculated for C10H7FO2:
166.0433. Found: 167.0642 (Mþ þ H).
3-p-Tolyl-acrylic acid 2,11-dioxa-bicyclo[10.3.1]hexadeca-
1(15),6,12(16),13-tetraene-4,8-diyn-13-ylmethyl ester
(14b)
Yield 40%; DSC: 167.188C; IR (KBr, cmꢀ1): 2924, 1709, 1609, 1509,
1
1271, 1165, 1003, 821, 752; H-NMR (300 MHz, CDCl3) d ¼ 2.29
3-(3-Nitro-phenyl)-acrylic acid (13l)
(s, 3H, PhCH3), 4.83 (s, 2H, CH2OAr), 4.91 (s, 2H, CH2OAr), 5.16
–
Yield: 75%; mp: 2038C; IR (KBr, cmꢀ1): 3082–2539, 1689, 1631,
1523, 1418, 1361, 1306, 1224; 1H-NMR (300 MHz, DMSO-d6)
d ¼ 6.52 (d, 1H, J ¼ 15 Hz), 7.45 (d, 2H, J ¼ 9 Hz), 7.54 (d, 1H,
J ¼ 15 Hz), 7.70 (d, 2H, J ¼ 9 Hz), 12.46 (s, 1H, COOH); ESI-HRMS
calculated for C9H7NO4: 193.0374. Found: 194.0358 (Mþ þ H).
(s, 2H, ArCH O), 5.83 (s, 2H, CH CH), 6.32 (d, 1H, J ¼ 15 Hz,
–
2
CHCOO), 6.56–6.59 (m, 1H, Ar-H), 7.09–7.11 (m, 2H, Ar-H), 7.18
(s, 1H, Ar-H), 7.29–7.34 (m, 3H, Ar-H), 7.58 (d, 1H, J ¼ 15 Hz,
CH-Ar); 13C-NMR (100 MHz, CDCl3) d ¼ 21.44, 57.24, 57.55,
61.40, 86.57, 86.69, 91.49, 91.56, 103.90, 111.59, 116.98,
118.56, 122.11, 122.19, 128.05, 129.56, 131.67, 131.76, 140.64,
144.87, 155.36, 157.64, 167.17; ESI-HRMS calculated for
C25H20O4: 384.1362. Found: 385.1592 (Mþ þ H); Anal. cacld for
C25H20O4: C, 78.11; H, 5.24. Found: C, 78.29; H, 5.44.
3-(3-Bromo-phenyl)-acrylic acid (13n)
Yield: 83%; mp: 1748C; (KBr, cmꢀ1): 2921–2604, 1686, 1630, 1420,
1318, 1221, 978, 783; 1H-NMR (300 MHz, DMSO-d6) d ¼ 6.67
(d, 1H, J ¼ 15 Hz), 7.38–7.42 (m, 2H, Ar-H), 7.67 (d, 1H,
J ¼ 15 Hz), 7.70–7.72 (m, 1H, Ar-H), 7.78–7.90 (s, 1H, Ar-H),
12.50 (brs, 1H, COOH); ESI-HRMS calculated for C10H7BrO2:
225.9629. Found: 226.9631 (Mþ þ H), 228.6247 (Mþ þ 2).
3-m-Tolyl-acrylic acid 2,11-dioxa-bicyclo[10.3.1]-
hexadeca-1(15),6,12(16),13-tetraene-4,8-diyn-13-
ylmethyl ester (14c)
Yield: 43%; IR (KBr, cmꢀ1): 3054, 2924, 2854, 1707, 1636, 1610,
1275, 1235, 1158, 1008; 1H-NMR (300 MHz, CDCl3) d ¼ 2.35
(s, 3H, PhCH3), 4.91 (s, 2H, CH2OAr), 4.98 (s, 2H, CH2OAr), 5.23
3-(3-Fluoro-phenyl)-acrylic acid 2,11-dioxa-bicyclo-
[10.3.1]hexadeca-1(15),6,12(16),13-tetraene-4,8-
diyn-13-ylmethyl ester (14h)
–
(s, 2H, ArCH O), 5.90 (s, 2H, CH CH), 6.43 (d, 1H, J ¼ 15 Hz,
–
2
To a stirred solution of acid 13h (100 mg, 0.56 mmol) in dry THF
(10 mL), CDI (130 mg, 8.42 mmol) was added in dry THF under
inert atmosphere. The mixture was stirred at 458C for 15 min.
The solution of 11 (90 mg, 0.56 mmol) and DBU (90 mg,
0.61 mmol) in dry THF (10 mL) was then added quickly. The
resulting mixture was stirred at 458C for 6 h. Excess of solvent
was evaporated to afford a residue, which was subjected to
column chromatography to provide compound 14h. Yield:
55%; DSC: 141.358C; IR (film, cmꢀ1): 3062, 2923, 2853, 2208,
1705, 1639, 1612, 1586, 1510, 1458, 1323; 1H-NMR (300 MHz,
CDCl3) d ¼ 4.92 (s, 2H, CH2OAr), 4.99 (s, 2H, CH2OAr), 5.24 (s, 2H,
CHCOO), 6.64 (m, 1H, Ar-H), 7.17–7.41 (m, 5H, Ar-H), 7.65 (d,
1H, J ¼ 15 Hz, CH-Ar), 7.76 (d, 1H, J ¼ 9 Hz, Ar-H); ESI-HRMS
calculated for C25H20O4: 384.1362. Found: 385.1314 (Mþ þ H);
Anal. cacld. for C25H20O4: C, 78.11; H, 5.24. Found: C, 78.01;
H, 5.04.
3-o-Tolyl-acrylic acid 2,11-dioxa-bicyclo[10.3.1]hexadeca-
1(15),6,12(16),13-tetraene-4,8-diyn-13-ylmethyl ester
(14d)
Yield: 39%; IR (film, cmꢀ1): 2922, 2847, 1709, 1601, 1449, 1261,
1164, 1013, 802; 1H-NMR (300 MHz, CDCl3) d ¼ 2.36 (s, 3H,
PhCH3), 4.84 (s, 2H, CH2OAr), 4.92 (s, 2H, CH2OAr), 5.17 (s, 2H,
–
ArCH O), 5.91 (s, 2H, CH CH), 6.43 (d, 1H, J ¼ 15 Hz, CHCOO),
–
2
6.64 (m, 1H, Ar-H), 7.04–7.10 (m, 1H, Ar-H), 7.18–7.41 (m, 5H,
Ar-H), 7.62 (d, 1H, J ¼ 15 Hz, CH-Ar); 13C-NMR (75.5 MHz, CDCl3)
d ¼ 57.18, 57.56, 61.67, 86.60, 86.74, 91.43, 91.58, 103.81, 111.58,
114.44, 116.92, 117.20, 118.29, 119.57, 122.10, 122.28, 124.00,
130.44, 131.84, 143.42, 155.42, 157.76, 166.57; ESI-HRMS
calculated for C29H17FO4: 388.1111. Found: 389.1642 (Mþ þ H);
–
ArCH O), 5.83 (s, 2H, CH CH), 6.29 (d, 1H, J ¼ 15 Hz, CH-Ar), 6.57
–
2
(m, 1H, Ar-H), 7.13–7.35 (m, 5H, Ar-H), 7.45 (d, 1H, J ¼ 6 Hz, Ar-H),
7.90 (d, 1H, J ¼ 15 Hz, CHCOO); ESI-HRMS calculated for
C25H20O4: 384.1362. Found: 385.1612 (Mþ þ H); Anal. cacld.
for C25H20O4: C, 78.11; H, 5.24. Found: C, 78.50; H, 5.11.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

570
M. Sharma et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 564–571
J ¼ 6 Hz, PhCH2CH3), 2.62 (q, 2H, J ¼ 6 Hz, PhCH2CH3), 4.91
(s, 2H, CH2OAr), 4.95 (s, 2H, CH2OAr), 5.23 (s, 2H, ArCH2O), 5.90
(s, 2H, CH¼CH), 6.40 (d, 1H, J ¼ 15 Hz, CH-Ar), 6.63 (m, 1H, Ar-H),
7.19–7.46 (m, 6H, Ar-H), 7.66 (d, 1H, J ¼ 15 Hz, CHCOO), ESI-HRMS
calculated for C26H22O4: 398.1518. Found: 399.1511 (Mþ þ H);
Anal. cacld. for C26H22O4: C, 78.37; H, 5.57. Found: C, 78.52;
H, 5.71.
3-(4-Chloro-phenyl)-acrylic acid 2,11-dioxa-bicyclo-
[10.3.1]hexadeca-1(15),6,12(16),13-tetraene-4,8-diyn-
13-ylmethyl ester (14e)
Yield: 41%; IR (KBr, cmꢀ1): 2958, 2925, 1708, 1269, 1166, 1000,
822, 750; 1H-NMR (300 MHz, CDCl3) d ¼ 4.91 (s, 2H, CH2OAr), 4.95
(s, 2H, CH2OAr), 5.23 (s, 2H, ArCH2O), 5.90 (s, 2H, CH¼CH), 6.41
(d, 1H, J ¼ 15 Hz, CH-Ar), 6.63–6.67 (m, 5H, Ar-H), 7.32 (d, 1H,
J ¼ 9 Hz, Ar-H), 7.42 (d, 1H, J ¼ 9 Hz, Ar-H), 7.61 (d, 1H, J ¼ 15 Hz,
CHCOO); ESI-HRMS calculated for C24H17ClO4: 404.0815.
Found: 405.0842 (Mþ þ H), 407.9164 (Mþ þ 2); Anal. cacld. for
C24H17ClO4: C, 71.20; H, 4.23. Found: C, 71.05; H, 4.37.
3-Naphthalen-1-yl-acrylic acid 2,11-dioxa-bicyclo-
[10.3.1]hexadeca-1(15),6,12(16),13-tetraene-4,8-diyn-
13-ylmethyl ester (14k)
Yield: 43%; IR (film, cmꢀ1): 3054, 2925, 2852, 1707, 1611, 1508,
1252, 1165, 1111, 1007; 1H-NMR (300 MHz, CDCl3) d ¼ 4.92
(s, 2H, CH2OAr), 5.01 (s, 2H, CH2OAr), 5.29 (s, 2H, ArCH2O), 5.90
(s, 2H, CH¼CH), 6.54 (d, 1H, J ¼ 15 Hz, CH-Ar), 6.66–6.68 (m, 1H,
Ar-H), 7.40–7.57 (m, 5H, Ar-H), 7.73–7.90 (m, 3H, Ar-H), 8.18 (d, 1H,
J ¼ 6 Hz, Ar-H), 8.52 (d, 1H, J ¼ 15 Hz, CHCOO); ESI-HRMS
calculated for C28H20O4: 420.1362. Found: 421.1334 (Mþ þ H).
3-(3-Chloro-phenyl)-acrylic acid 2,11-dioxa-bicyclo-
[10.3.1]hexadeca-1(15),6,12(16),13-tetraene-4,8-diyn-
13-ylmethyl ester (14f)
Yield: 54%; DSC: 142.228C; IR (film, cmꢀ1): 2924, 2853, 1708,
1609, 1508, 1314, 1267, 1168, 1007, 759; 1H-NMR (300 MHz,
CDCl3) d ¼ 4.91 (s, 2H, CH2OAr), 4.99 (s, 2H, CH2OAr), 5.25
(s, 2H, ArCH2O), 5.90 (s, 2H, CH¼CH), 6.43 (d, 1H, J ¼ 18 Hz,
CH-Ar), 6.64 (m, 1H, Ar-H), 7.23–7.41 (m, 5H, Ar-H), 7.58–7.61
(m, 1H, Ar-H), 8.09 (d, 1H, J ¼ 15 Hz, CHCOO); 13C-NMR
(100 MHz, CDCl3) d ¼ 57.12, 57.52, 61.68, 86.58, 86.72, 91.40,
91.55, 103.71, 111.52, 118.20, 119.06, 122.11, 122.29, 126.16,
127.80, 130.06, 131.84, 134.82, 136.21, 143.18, 155.39, 157.72,
166.52; ESI-HRMS calculated for C24H17ClO4: 404.0815.
Found: 405.0871 (Mþ þ H), 407.8521 (Mþ þ 2); Anal. cacld. for
C24H17ClO4: C, 71.20; H, 4.23. Found: C, 71.45; H, 4.40.
3-(3-Nitro-phenyl)-acrylic acid 2,11-dioxa-bicyclo-
[10.3.1]hexadeca-1(15),6,12(16),13-tetraene-4,8-diyn-
13-ylmethyl ester (14l)
Yield: 52%; DSC: 155.388C; IR (KBr, cmꢀ1): 2964, 1714, 1529, 1354,
1262, 1097, 1020, 800; 1H-NMR (300 MHz, CDCl3) d ¼ 4.85 (s, 2H,
CH2OAr), 5.93 (s, 2H, CH2OAr), 5.19 (s, 2H, ArCH2O), 5.84 (s, 2H,
CH¼CH), 6.49 (d, 1H, J ¼ 15 Hz, CH-Ar), 6.57 (m, 1H, Ar-H), 7.19–
7.35 (m, 4H, Ar-H), 7.47–7.53 (m, 1H, Ar-H), 7.63 (d, 1H, J ¼ 15 Hz,
CHCOOH), 7.72 (d, 1H, J ¼ 6 Hz, Ar-H); ESI-HRMS calculated
for C24H17NO6: 415.1056. Found: 416.1041 (Mþ þ H); Anal. cacld.
for C24H17NO6: C, 69.39; H, 4.12; N, 3.37. Found: C, 69.55; H, 4.01;
N, 3.49.
3-(2-Chloro-phenyl)-acrylic acid 2,11-dioxa-bicyclo-
[10.3.1]hexadeca-1(15),6,12(16),13-tetraene-4,8-diyn-
13-ylmethyl ester (14g)
Yield: 45%; DSC: 132.448C; IR (film, cmꢀ1): 2924, 2853, 1708,
1609, 1508, 1314, 1267, 1168, 1007, 759; 1H-NMR (300 MHz,
CDCl3) d ¼ 4.92 (s, 2H, CH2OAr), 4.99 (s, 2H, CH2OAr), 5.24
(s, 2H, ArCH2O), 5.91 (s, 2H, CH¼CH), 6.44 (d, 1H, J ¼ 15 Hz,
CH-Ar), 6.64 (m, 1H, Ar-H), 7.30–7.41 (m, 5H, Ar-H), 7.49 (s, 1H,
Ar-H), 7.60 (d, 1H, J ¼ 15 Hz, CHCOO); ESI-HRMS calculated for
C24H17ClO4: 404.0815. Found: 405.0817 (Mþ þ H), 406.3182
(Mþ þ 2); Anal. cacld. for C24H17ClO4: C, 71.20; H, 4.23. Found:
C, 71.31; H, 4.03.
3-(4-Bromo-phenyl)-acrylic acid 2,11-dioxa-bicyclo-
[10.3.1]hexadeca-1(15),6,12(16),13-tetraene-4,8-diyn-
13-ylmethyl ester (14m)
Yield: 36%; DSC: 178.838C; IR (KBr, cmꢀ1): 2926, 1715, 1638, 1509,
1
1226, 1163; H-NMR (300 MHz, CDCl3) d ¼ 4.91 (s, 2H, CH2OAr),
4.98 (s, 2H, CH2OAr), 5.23 (s, 2H, ArCH2O), 5.90 (s, 2H, CH¼CH),
6.42 (d, 1H, J ¼ 15 Hz, CH-Ar), 6.63–6.66 (m, 1H, Ar-H), 7.32–7.41
(m, 4H, Ar-H), 7.49–7.52 (m, 2H, Ar-H), 7.60 (d, 1H, J ¼ 15 Hz,
CHCOO); ESI-HRMS calculated for C24H17BrO4: 448.0310. Found:
449.0335 (Mþ þ H), 451.7221 (Mþ þ 2); Anal. cacld. for
C24H17BrO4: C, 64.16; H, 3.81. Found: C, 64.02; H, 3.99.
3-(4-iso-Propyl-phenyl)-acrylic acid 2,11-dioxa-bicyclo-
[10.3.1]hexadeca-1(15),6,12(16),13-tetraene-4,8-diyn-
13-ylmethyl ester (14i)
3-(3-Bromo-phenyl)-acrylic acid 2,11-dioxa-bicyclo-
[10.3.1]hexadeca-1(15),6,12(16),13-tetraene-4,8-diyn-
Yield: 35%; IR (film, cmꢀ1): 2922, 2852, 1709, 1638, 1275, 1165,
1009, 819; 1H-NMR (300 MHz, CDCl3) d ¼ 1.23 (d, 6H, J ¼ 6 Hz,
PhCH(CH3)2), 2.86–2.96 (m, 1H, PhCH(CH3)2), 4.91 (s, 2H, CH2OAr),
4.98 (s, 2H, CH2OAr), 5.23 (s, 2H, ArCH2O), 5.90 (s, 2H, CH¼CH),
6.40 (d, 1H, J ¼ 15 Hz, CH-Ar), 6.63 (m, 1H, Ar-H), 7.21–7.50
(m, 6H), 7.66 (d, 1H, J ¼ 15 Hz, CHCOO); ESI-HRMS calculated
for C27H24O4: 412.1675. Found: 413.1616 (Mþ þ H); Anal. cacld.
for C27H24O4: C, 78.62; H, 5.86. Found: C, 78.80; H, 5.55.
13-ylmethyl ester (14n)
Yield: 48%; DSC: 2848C; IR (KBr, cmꢀ1): 2963, 2922, 2852, 1710,
1277, 1184, 1115, 1011, 820, 668; 1H-NMR (300 MHz, CDCl3)
d ¼ 4.92 (s, 2H, CH2OAr), 4.99 (s, 2H, CH2OAr), 5.24 (s, 2H,
ArCH2O), 5.90 (s, 2H, CH¼CH), 6.43 (d, 1H, J ¼ 15 Hz, CH-Ar),
6.63 (m, 1H, Ar-H), 7.25–7.27 (m, 2H, Ar-H), 7.33 (d, 1H, J ¼ 6 Hz,
Ar-H), 7.40–7.44 (m, 2H, Ar-H), 7.48–7.50 (m, 1H, Ar-H), 7.58 (d, 1H,
J ¼ 15 Hz, CHCOO); 13C-NMR (100 MHz, CDCl3) d ¼ 57.14, 57.54,
61.71, 86.59, 86.73, 91.40, 103.74, 111.54, 118.22, 119.62, 122.13,
122.96, 126.60, 130.35, 130.76, 131.86, 132.98, 136.50, 143.11,
155.41, 157.75, 166.52; ESI-HRMS calculated for C24H17BrO4:
448.0310. Found: 449.0373 (Mþ þ H), 451.5791 (Mþ þ 2); Anal.
cacld. for C24H17BrO4: C, 64.16; H, 3.81. Found: C, 64.02; H, 3.99.
3-(4-Ethyl-phenyl)-acrylic acid 2,11-dioxa-bicyclo-
[10.3.1]hexadeca-1(15),6,12(16),13-tetraene-4,8-diyn-
13-ylmethyl ester (14j)
Yield: 40%; IR (KBr, cmꢀ1): 2959, 1707, 1635, 1270, 1164, 1109,
1001, 821, 750; 1H-NMR (300 MHz, CDCl3) d ¼ 1.23 (t, 3H,
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2011, 344, 564–571
Synthesis and Anticancer Activity of 13-Membered
571
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5.00 (s, 2H, CH2OAr), 5.24 (s, 2H, ArCH2O), 5.91 (s, 2H, CH¼CH),
6.40 (d, 1H, J ¼ 15 Hz, CH-Ar), 6.63 (m, 1H, Ar-H), 7.22–7.42
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Screening of NCI-60 human tumor cell lines
Details of the methodology for NCI 60 cell line screening are
described at http://dtp.nci.nih.gov/branches/btb/ivclsp.html.
Briefly, the panel is organized into nine sub panels representing
diverse histologies: Leukemia, melanoma, and cancers of lung,
colon, kidney, ovary, breast, prostate, and central nervous sys-
tem. The cells are grown in supplemented RPM1 1640 medium
for 24 h. The test compounds were dissolved in DMSO and
incubated with cells at 10 mM. The assay is terminated by
addition of cold trichloroacetic acid, and the cells are fixed
and stained with sulforhodamine B. Bound stain is solubilized,
and the absorbance is read on an automated plate reader. The
output from the single dose screen was reported as a mean graph
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DSR thanks Department of Science and Technology (DO No: SR/FTP/CSA-18/
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thankful to CSIR for the award of senior research fellowship. Thanks to
USIC-CIF, University of Delhi, Delhi, India for NMR data. The authors
would like to thank the NCI Developmental Therapeutics Program for 60
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The authors have declared no conflict of interest.
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ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com