Synthesis and anti-proliferative activity of novel oxepin-annulated coumarins

Article abstract of DOI:10.24820/ark.5550190.p010.547

A series of fused dihydrooxepino[h]- and dihydrooxepino[g]coumarins (7 and 8) were synthesized through allylation, Claisen rearrangement, allylation and ring-closing metathesis (RCM), respectively. All the synthesized compounds were characterized by appropriate spectral analysis. The anti-proliferative activities of compound 5a-c, 6a, 6c, 7a-c and 8a-c were evaluated against human colon cancer (Caco-2), liver cancer (HepG2) and breast cancer (SKBR-3) cell lines using tamoxifen (TAM) as the positive control. Compound 7b showed significant anti-proliferative activity against resistant Caco-2 and SKBR-3 cell lines on comparison with all other coumarin derivatives. Interestingly, compound 8b was more potent than TAM against sensitive HepG2 cell line.

Full text of DOI:10.24820/ark.5550190.p010.547

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Organic Chemistry
Arkivoc 2018, part vii, 0-0
Synthesis and anti-proliferative activity of novel oxepin-annulated coumarins
Saisuree Prateeptongkum,*a Wiratchanee Mahavorasirikul,b and Nongnaphat Duangdeeb
aDepartment of Chemistry, Faculty of Science and Technology, Thammasat University, Pathumthani 12121,
Thailand
bDrug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University,
Pathumthani 12121, Thailand
Email: saisuree@tu.ac.th, saisuree@gmail.com
Received 02-26-2018
Accepted 08-10-2018
Published on line 09-02-2018
Abstract
A series of fused dihydrooxepino[h]- and dihydrooxepino[g]coumarins (7 and 8) were synthesized through
allylation, Claisen rearrangement, allylation and ring-closing metathesis (RCM), respectively. All the
synthesized compounds were characterized by appropriate spectral analysis. The anti-proliferative activities of
compound 5a-c, 6a, 6c, 7a-c and 8a-c were evaluated against human colon cancer (Caco-2), liver cancer
(HepG2) and breast cancer (SKBR-3) cell lines using tamoxifen (TAM) as the positive control. Compound 7b
showed significant anti-proliferative activity against resistant Caco-2 and SKBR-3 cell lines on comparison with
all other coumarin derivatives. Interestingly, compound 8b was more potent than TAM against sensitive
HepG2 cell line.
Keywords: Claisen rearrangement, ring-closing metathesis, coumarin, oxepine, anti-proliferative activity
DOI: https://doi.org/10.24820/ark.5550190.p010.547
Page 1
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
Introduction
Coumarins fused with 5- and 6-membered oxygen heterocycle, known as furocoumarins and
pyranocoumarins, respectively, (Figure 1) are important structural units in many natural products and
biologically active compounds. They exhibit a wide spectrum of pharmaceutical and biological properties,
including anti-inflammatory,1,2 anti-HIV,3 anticancer,4,5 antioxidative,6 antifungal,7 antimicrobial,8
antibacterial,9 anticoagulant,10 anticonvulsant,11 vasorelaxant12 activities.
Figure 1. Examples of bioactive furocoumarins and pyranocoumarins.
Various natural products and bioactive compounds containing oxepane ring, 7–membered oxygen
heterocycle,13-17 have been also reported with a broad range of interesting biological activities such as
antidepressant,18 analgesic,19 antipsychotic,20 antioxidant,21 antimycobacterial17,22 and anticancer23,24 (Figure
2).
Figure 2. Examples of natural products and bioactive compounds containing 7–membered oxygen heterocycle.
Coumarins fused with heterocycles have gained much attention due to their potential biological activities.
However, synthetic study and the evaluation for biological activities of medium ring oxacycle fused coumarins,
especially oxepinocoumarins are scarce.25,26
Page 2
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
Among several methods for the construction of cyclic structures,27-32 ring-closing metathesis (RCM) has
proven to be a powerful method for the synthesis of carbocycles and heterocycles with various ring sizes.33-38
In continuation to our previous work on the synthesis of coumarin derivatives,39 we wish to report here
the synthesis of fused-dihydrooxepino[g]- and [h]coumarins through the combination of allylation, Claisen
rearrangement, allylation and RCM, respectively. Moreover, the evaluation of anticancer activity of
compounds 5a-c, 6a, 6c, 7a-c and 8a-c against Caco-2, HepG2 and SKBR-3 cell lines was performed.
Result and Discussion
The synthesis of the target compounds 7 and 8 was carried out as described in Scheme 1. Coumarins (1a-c)
were efficiently converted to the corresponding allyloxy coumarins (2a-c) in high yields (89-92%) by treatment
with allyl bromide and K2CO3 under reflux in acetone for 16 h. The Claisen rearrangement of 2a-c was carried
out in ethylene glycol at 190oC in sand bath for 24 h leading to mixtures of respective regioisomers 3a-c and
4a-c in 45-96% combined yields.
1
The ratios of two regioisomers 3 and 4 were determined by H NMR spectra of pure mixtures by
1
comparing the integration areas of H5 on the benzene rings of compounds 3 and 4. H NMR chemical shifts
and splitting patterns of two protons on phenyl rings of 3 and 4 are listed on table 1. Because these two
regioisomers were difficult to separate by standard chromatographic purification, we decided to use them as
regioisomeric mixtures for the next allylation reaction.
1
Table 1. H NMR (400 MHz, DMSO-d6) of selected protons on benzene ring of compounds 3 and 4 and the
calculated ratio of 3 and 4
δ of 3 (ppm)
δ of 4 (ppm)
Ratio of 3:4
H5
H6
H5
H8
a
b
c
7.50 (d, J 8.8 Hz)
7.52 (d, J 8.8 Hz)
7.13 (d, J 8.8 Hz)
6.89 (d, J 8.8 Hz)
6.86 (d, J 8.8 Hz)
6.82 (d, J 8.8 Hz)
7.43 (s)
7.44 (s)
7.08 (s)
6.75 (s)
6.73 (s)
6.82 (s)
13.3:1
4.8:1
4.5:1
After completion of the allylation reaction and purification, compounds 5a-c and 6a-c were obtained as
pure regioisomers in 64-70% and 9-15% yields, respectively. The RCM reactions of olefins 5a-c and 6a-c with
Grubbs’ first-generation catalyst in dichloromethane at room temperature for 24 h gave the expected
metathesis products 7a-c and 8a-c in good yields (64-82%).
The synthesized compounds 5-8, except for 6b, were evaluated for their in vitro antiproliferative activity
against three cancer cell lines including colorectal adenocarcinoma (Caco-2), hepatocellular carcinoma
(HepG2) and breast carcinoma (SKBR-3) cell lines using MTT assay. The concentration-response studies were
performed in order to determine their half-medium inhibitory concentration (IC50) values (Table 2) by
incubation of cell lines with 11 compounds at concentrations of 0-100 µg/mL for 48 h at 5% CO2 and 37C.
Tamoxifen was also evaluated as references.
Page 3
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
Scheme 1. Synthesis of fused dihydrooxepino[h]- and dihydrooxepino[g]coumarins (7 and 8).
From the analysis of Table 2, it can be concluded that compound 7b was the most cytotoxic to Caco-2 and
SKBR-3 cell lines with IC50 of 30.05 ± 0.71 and 11.18 ± 1.93 μg/mL, respectively. It also showed potent activity
on HepG2 cell with IC50 values of 15.32 ± 0.30 μg/mL. Interestingly, compound 8b has demonstrated the most
promising activity against HepG2 cell line with IC50 values of 8.78 ± 1.21 μg/mL, which is lower than that of
tamoxifen, 5a and 5b (IC50 values of 9.41 ± 1.81, 10.48 ± 3.44 and 10.42 ± 2.16 μg/mL, respectively).
Comparison of the substitution at the C-4 position of the coumarin ring suggested that the propyl group
contributed to the anti-proliferative activity enhancement. Compounds 5b, 7b and 8b were more active than
compounds 5a,c, 7a,c and 8a,c, respectively against almost all tested cell lines. In addition, the nature of the
angularly or linearly fused ring (7 or 8) did not significantly affect the activity. Among the tested cell lines,
HepG2 has proven to be the most sensitive cell line. Approximately half of the tested coumarin derivatives
presented high cytotoxicity (IC50 ≤ 20 μg/mL). On the other hand, Caco-2 has proven to be the most resistant
cell line, since almost all compounds exhibited moderate cytotoxicity (IC50 ranged between 21 and 200 μg/mL).
Page 4
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
Table 2. IC50 values of coumarin derivatives 5-8 and tamoxifen against Caco-2, HepG2 and SKBR-3 cancer cell
lines using MTT assaya
IC50 (µg/mL)
Compound
Caco-2
HepG2
SKBR-3
5a
5b
5c
6a
6c
7a
7b
7c
8a
8b
8c
> 500
10.48 ± 3.44
10.42 ± 2.16
41.61 ± 3.49
59.04 ± 4.30
21.05 ± 3.36
18.64 ± 1.94
15.32 ± 0.30
37.77 ± 8.52
24.3 ± 0.51
8.78 ± 1.21
16.37 ± 2.27
9.41 ± 1.81
38.80 ± 3.19
165.61 ± 9.57
59.70 ± 14.35
101.21 ± 20.23
30.80 ± 1.42
42.77 ± 2.43
11.18 ± 1.93
196.34 ± 2.03
63.76 ± 17.67
30.79 ± 8.50
28.33 ± 12.68
10.96 ± 1.85
105.22 ± 0.72
49.10 ± 7.05
> 500
51.02 ± 24.11
55.54 ± 21.18
30.05 ± 0.71
35.29 ± 1.24
96.72 ± 9.15
73.04 ± 7.82
> 500
Tam
17.77 ± 2.79
a Values represent mean  standard deviation of three parallel measurements. The criteria used to categorize
the cytotoxicity of coumarin derivatives against cancer cell lines, based on U.S. National Cancer Institute (NCI)
and Geran protocol40 were as follows: IC50 ≤ 20 μg/mL = highly cytotoxic, IC50 ranged between 21 and 200
μg/mL = moderately cytotoxic, IC50 ranged between 201 and 500 μg/mL = weakly cytotoxic and IC50 > 501
μg/mL = no cytotoxicity.
Conclusions
We have demonstrated a simple synthetic strategy for synthesis of fused-dihydrooxepino[g]- and
[h]coumarins 7 and 8 via the allylation, Claisen rearrangement, allylation and RCM, respectively. The anti-
proliferative activity of compound 5a-c, 6a, 6c, 7a-c and 8a-c was screened against Caco-2, HepG2 and SKBR-3
cell lines using tamoxifen (TAM) as the positive control. Compound 7b exhibited similar anti-proliferative
activity against resistant SKBR-3 cell to TAM and demonstrated the most potent activity against Caco-2 among
the tested coumarin derivatives. Compound 8b displayed the most potent anti-proliferative activity against
HepG2 cell line. Our results could be used as a starting point for development of powerful coumarin
anticancer therapies.
Page 5
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
Experimental Section
General. Melting points (oC) were measured with the Gallenkamp melting point apparatus and are
1
13
uncorrected. H and C NMR spectra were recorded on a Bruker AV400 spectrometer. Chemical shifts (δ) are
given in ppm and refer to TMS or the residual undeuterated solvent as the internal standard. The following
abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, m =
multiplet, dd = double doublet, br.s = broad singlet. ESI mass spectra were recorded on a Thermo Finnigan LCQ
Advantage Mass Spectrometer. High Resolution Mass Spectrometry was performed with a MicroTOFLC,
Bruker Daltonics. FTIR spectra were obtained with a Perkin Elmer FT-IR Spectrum GX. Column chromatography
was performed on silica gel (Kieselgel 60, 70-230 mesh, Merck) in common glass columns. Preparative TLC was
carried out on silica gel plate (Merck silica gel 60 PF254). All chemicals were obtained from commercial
suppliers, and were used without further purification. The required coumarin precursors 1a-c were prepared
via Pechmann reaction.39
General procedure for allylation of 1a-c. To a solution of phenol derivative (1, 10 mmol) anhydrous K2CO3
(4.15 g, 30 mmol) in acetone (30 mL) was added allyl bromide (1.81 g, 15 mmol). The mixture was heated
under reflux and stirring for 16-18 h. After cooling to room temperature, the precipitated solid was filtered
and washed with acetone. The filtrate was concentrated under reduced pressure and purified by column
chromatography on silica gel using EtOAc/hexane as eluent to afford the corresponding allylic ether 2.25,26
o
7-(Allyloxy)-4-methyl-2H-chromen-2-one (2a). Yield 89%; white solid; mp 100-102 C (from EtOAc-Hexanes)
o
(lit41 mp 100-101 C); Rf 0.68 (20% EtOAc/hexanes); IR (KBr): vmax 3076, 3020, 2953, 1725, 1611, 1392, 1349,
1285, 1263, 1208, 1141, 1069, 994, 936, 857, 838, 810 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.49 (d, J 8.8 Hz, 1H),
6.88 (dd, J 8.8, 2.4 Hz, 1H), 6.83 (d, J 2.4 Hz, 1H), 6.14 (s, 1H), 6.11-5.94 (m, 1H), 5.44 (dd, J 17.2, 1.0 Hz, 1H),
5.34 (dd, J 10.6, 0.6 Hz, 1H), 4.60 (d, J 5.2 Hz, 2H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.63 (C), 161.26
(C), 157.26 (C), 152.50 (C), 132.25 (CH), 125.54 (CH), 118.48 (CH2), 113.74 (C), 112.81 (CH), 112.06 (CH), 101.82
(CH), 69.26 (CH2), 18.63 (CH3); MS (ESI+) m/z (%) 217.0 (M+H+, 100).
7-(Allyloxy)-4-propyl-2H-chromen-2-one (2b).42 Yield 92%; light yellow oil; Rf 0.57 (20% EtOAc/hexanes); IR
(nujol): vmax 3082, 2963, 2934, 2875, 2402, 1732, 1614, 1557, 1510, 1456, 1392, 1277, 1201, 1146, 1100, 1012,
843, 580 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J 8.8 Hz, 1H), 6.86 (dd, J 8.6, 2.4 Hz, 1H), 6.81 (d, J 2.4 Hz,
1H), 6.10 (s, 1H), 6.10-5.95 (m, 1H), 5.43 (d, J 17.2 Hz, 1H), 5.32 (d, J 10.4 Hz, 1H), 4.59 (d, J 5.2 Hz, 2H), 2.69 (t,
J 7.6 Hz, 2H), 1.71 (sext, J 7.6 Hz, 2H), 1.04 (t, J 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.45 (C), 161.35 (C),
156.14 (C), 155.50 (C), 132.27 (CH), 125.27 (CH), 118.33 (CH2), 113.05 (C), 112.71 (CH), 110.92 (CH), 102.00
(CH), 69.21 (CH2), 33.74 (CH2), 21.46 (CH2), 13.84 (CH3); MS (ESI+) m/z (%) 245.5 (M+H+, 100).
7-(Allyloxy)-4-phenyl-2H-chromen-2-one (2c). Yield 91%; white solid; mp 85-88 oC (from EtOAc-Hexanes) (lit43
o
mp 85-87 C); Rf 0.80 (40% EtOAc/hexanes); IR (neat): vmax 3080, 1727, 1615, 1550, 1375, 1309, 1284, 1153,
1125, 1023, 938, 857, 777, 713 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.56-7.39 (m, 5H), 7.38 (d, J 9.2 Hz, 1H), 6.90
(d, J 2.4 Hz, 1H), 6.81 (dd, J 8.6, 2.4 Hz, 1H), 6.22 (s, 1H), 6.20-5.85 (m, 1H), 5.42 (dd, J 17.3, 1.4 Hz, 1H), 5.34
13
(dd, J 10.5, 1.3 Hz, 1H), 4.59 (d, J 5.3 Hz, 2H); C NMR (100 MHz, CDCl3): δ 161.74 (C), 161.18 (C), 155.94 (C),
155.79 (C), 135.58 (C), 132.16 (CH), 129.59 (CH), 128.83 (2CH), 128.38 (2CH), 127.99 (CH), 118.55 (CH2), 112.81
(CH), 112.65 (C), 111.94 (CH), 102.02 (CH), 69.28 (CH2); MS (ESI+) m/z (%) 279.2 (M+H+, 100).
General procedure for Claisen rearrangement of 2a-c. A solution of allylic ether (2) (9 mmol) in ethylene
glycol (45 mL) was heated under stirring at 190 ⁰C in sand bath for 24 h. After cooling to room temperature,
the mixture was quenched with water (50 mL) and the aqueous phase was extracted with EtOAc (3 x 45 mL).
The organic phases were combined, dried over anhydrous Na2SO4 and concentrated in vacuo and the residue
Page 6
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
was purified by column chromatography on silica gel using EtOAc/hexane as eluent to give a mixture of
1
regioisomers of 3 as a major product and 4 as a minor product. H NMR and 13C NMR were characterized only
the major products.26
8-Allyl-7-hydroxy-4-methyl-2H-chromen-2-one (3a) and 6-allyl-7-hydroxy-4-methyl-2H-chromen-2-one (4a).
Yield 96% (3a:4a 93:7); pale yellow solid; mp 189-190 oC (from EtOAc-Hexanes); Rf (3a) 0.33, Rf (4a) 0.43 (33%
EtOAc/hexanes); IR (KBr): vmax 3220, 1688, 1606, 1566, 1387, 1318, 1049 cm-1; 1H NMR (400 MHz, DMSO-d6): δ
10.46 (s, 1H), 7.50 (d, J 8.8 Hz, 1H), 6.89 (d, J 8.8 Hz, 1H), 6.13 (s, 1H), 6.09-5.80 (m, 1H), 5.05-4.96 (m, 2H),
3.45 (d, J 6.0 Hz, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 160.75 (C), 160.70 (C), 159.23 (C), 154.13
(C), 153.16 (C), 135.93 (CH), 124.33 (CH), 115.45 (CH2), 113.33 (C), 112.53 (CH), 110.47 (CH), 26.97 (CH2), 18.48
(CH3); MS (ESI+) m/z (%) 217.5 (M+H+, 100).
8-Allyl-7-hydroxy-4-propyl-2H-chromen-2-one (3b) and 6-allyl-7-hydroxy-4-propyl-2H-chromen-2-one (4b).
o
Yield 45% (3b:4b 83:17); light yellow solid; mp 191-203 C (from EtOAc-Hexanes); Rf (3b) 0.30, Rf (4b) 0.23
(20% EtOAc/hexanes); IR (KBr): vmax 3226, 2968, 1661, 1599, 1567, 1393, 1326, 1279, 1114, 915, 842, 805 cm-1;
1H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 7.52 (d, J 8.8 Hz, 1H), 6.86 (d, J 8.8 Hz, 1H), 6.05 (s, 1H), 6.12-
5.83 (m, 1H), 5.07-4.89 (m, 2H), 3.43 (d, J 1.2 Hz, 2H), 2.68 (t, J 7.2 Hz, 2H), 1.61 (sext, J 7.6 Hz, 2H), 0.95 (t, J
7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 160.88 (C), 159.10 (C), 157.63 (C), 153.38 (C), 135.90 (CH), 124.13
(CH), 116.14 (C), 115.52 (CH2), 113.42 (CH), 112.55 (CH), 111.77 (CH), 109.53 (C), 33.43 (CH2), 27.04 (CH2),
21.93 (CH2), 14.14 (CH3); MS (ESI+) m/z (%) 245.2 (M+H+, 100).
8-Allyl-7-hydroxy-4-phenyl-2H-chromen-2-one (3c) and 6-allyl-7-hydroxy-4-phenyl-2H-chromen-2-one (4c).
Yield 63% (3c:4c 82:18); light yellow solid; mp 188-190 oC (from EtOAc-Hexanes); Rf (3c) 0.33, Rf (4c) 0.20 (20%
EtOAc/hexanes); IR (KBr): vmax 3376, 3120, 2950, 1679, 1610, 1592, 1376, 1315, 1260, 1141, 1060, 995 cm-1; 1H
NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 7.65-7.32 (m, 5H), 7.13 (d, J 8.8 Hz, 1H), 6.83 (d, J 8.8 Hz, 1H), 6.10
(s, 1H), 6.00-5.78 (m, 1H), 5.10-4.80 (m, 2H), 3.46 (d, J 6.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ 160.60 (C),
159.49 (C), 156.34 (C), 153.75 (C), 135.90 (C), 135.78 (CH), 129.92 (CH), 128.87 (2CH), 128.81 (2CH), 126.08
(CH), 115.69 (CH2), 113.78 (C), 112.78 (CH), 111.31 (C), 110.53 (CH), 27.09 (CH2); MS (ESI+) m/z (%) 279.4
(M+H+, 100).
General procedure for allylation of the mixtures of 3a-c and 4a-c. The synthesis was carried out from the
mixture of 3a-c and 4a-c, anhydrous K2CO3 and allyl bromide in acetone using the above general procedure for
the synthesis of compounds 2a-c. The diene products 5a-c and 6a-c were obtained after purification by
column chromatography or preparative TLC using EtOAc/hexane as eluent.
o
8-Allyl-7-(allyloxy)-4-methyl-2H-chromen-2-one (5a). Yield 67%; light yellow solid; mp 85-86 C (from EtOAc-
o
Hexanes) [lit25 mp 92-93 C (from acetone)]; Rf 0.72 (33% EtOAc/hexanes); IR (KBr): vmax 2965, 2924, 2855,
1716, 1605, 1385, 1278, 1123, 1056, 844, 813 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J 8.8 Hz, 1H), 6.86 (d, J
8.8 Hz, 1H), 6.15 (s, 1H), 6.14-5.90 (m, 2H), 5.45 (dd, J 17.2, 1.6 Hz, 1H), 5.33 (dd, J 10.6, 1.4 Hz, 1H), 5.10 (dd, J
17.1, 1.7 Hz, 1H), 5.00 (dd, J 10.1, 1.6 Hz, 1H), 4.67 (d, J 4.8 Hz, 2H), 3.66 (d, J 6.4 Hz, 2H), 2.41 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 161.01 (C), 159.17 (C), 152.63 (C), 152.21 (C), 135.24 (CH), 132.70 (CH), 123.00 (CH),
117.54 (CH2), 116.84 (C), 115.29 (CH2), 114.15 (C), 112.24 (CH), 108.33 (CH), 69.42 (CH2), 27.06 (CH2), 18.46
(CH3); MS (ESI+) m/z (%) 257.5 (M+H+, 100).
o
6 -Allyl-7 -( allyloxy)-4 -methyl-2 H-chromen-2 -one (6a). Yield 9%; white solid; mp 103-104 C (from EtOAc-
Hexanes); Rf 0.63 (33% EtOAc/hexanes); IR (KBr): vmax 3071, 2923, 1730, 1613, 1385, 1367, 1274, 1163, 1065,
991, 901, 880, 845 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.34 (s, 1H), 6.80 (s, 1H), 6.14 (s, 1H), 6.12-5.92 (m, 2H),
5.47 (dd, J 17.2, 1.6 Hz, 1H), 5.35 (dd, J 10.6, 1.4 Hz, 1H), 5.18-5.06 (m, 2H), 4.63 (d, J 5.2 Hz, 2H), 3.46 (d, J 6.6
Hz, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.34 (C), 159.24 (C), 153.96 (C), 152.51 (C), 136.09 (CH),
132.25 (CH), 125.94 (C), 124.96 (CH), 117.92 (CH2), 116.13 (CH2), 113.14 (C), 111.93 (CH), 99.89 (CH), 69.19
Page 7
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
(CH2), 34.00 (CH2), 18.58 (CH3); MS (ESI+) m/z (%) 257.5 (M+H+, 100); HRMS (MALDI-TOF): calcd for C16H16NaO3
[M+Na]+: 279.0997; found: 279.0995.
8 -Allyl-7 -( allyloxy)-4 -propyl-2 H-chromen-2 -one (5b). Yield 70%; white solid; mp 70-72 C (from EtOAc-
o
Hexanes); Rf 0.27 (5 % EtOAc/hexanes); IR (KBr): vmax 3090, 3072, 2964, 2924, 2863, 1716, 1605, 1301, 1279,
1127, 1047, 913, 841 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.48 (d, J 8.8 Hz, 1H), 6.86 (d, J 8.8 Hz, 1H), 6.16 (s, 1H),
6.12-5.91 (m, 2H), 5.46 (dd, J 17.2, 1.2 Hz, 1H), 5.33 (dd, J 10.4, 1.2 Hz, 1H) 5.12 (dd, J 17.0, 1.4 Hz, 1H) 5.01
(dd, J 10.0, 0.8 Hz, 1H), 4.67 (d, J 4.8 Hz, 2H), 3.67 (d, J 6.4 Hz, 2H), 2.72 (t, J 7.6 Hz, 2H), 1.75 (sext, J 7.6 Hz,
2H), 1.07 (t, J 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.29 (C), 159.00 (C), 156.04 (C), 152.86 (C), 135.26
(CH), 132.72 (CH), 122.82 (CH), 117.54 (CH2), 116.97 (C), 115.31 (CH2), 113.48 (C), 111.15 (CH), 108.29 (CH),
69.40 (CH2), 33.78 (CH2), 27.11 (CH2), 21.55 (CH2), 13.82 (CH3); MS (ESI+) m/z (%) 285.1 (M+H+, 100); HRMS
(MALDI-TOF): calcd for C18H20NaO3 [M+Na]+: 307.1310; found: 307.1313.
o
6-Allyl-7-(allyloxy)-4-propyl-2H-chromen-2-one (6b). Yield 13%; light yellow solid; mp 60-62 C (from EtOAc-
Hexanes); Rf 0.20 (5% EtOAc/hexanes); IR (KBr): vmax 3059, 2930, 1726, 1618, 1382, 1271, 1163, 1105, 986 cm-
1; 1H NMR (400 MHz, CDCl3): δ 7.37 (s, 1H), 6.81 (s, 1H), 6.14 (s, 1H), 6.12-5.90 (m, 2H), 5.47 (dd, J 17.2, 1.2 Hz,
2H), 5.35 (dd, J 10.8, 1.2 Hz, 2H), 5.13 (s, 1H), 5.12-5.05 (m, 1H), 4.63 (d, J 5.2 Hz, 2H), 3.46 (d, J 6.4 Hz, 2H),
2.72 (t, J 7.6 Hz, 2H), 1.74 (sext, J 7.5 Hz, 2H), 1.07 (t, J 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.60 (C),
159.09 (C), 156.25 (C), 154.20 (C), 136.12 (CH), 132.27 (CH), 125.85 (C), 124.77 (CH), 117.92 (CH2), 116.11
(CH2), 112.50 (C), 110.81 (CH), 100.09 (CH), 69.18 (CH2), 34.00 (CH2), 33.70 (CH2), 21.39 (CH2), 13.86 (CH3); MS
(ESI+) m/z (%) 285.1 (M+H+, 100); HRMS (MALDI-TOF): calcd for C18H20NaO3 [M+Na]+: 307.1310; found:
307.1303.
o
8 -Allyl-7 -( allyloxy)-4 -phenyl-2 H-chromen-2 -one (5c). Yield 64%; white solid; mp 101-103 C (from EtOAc-
Hexanes); Rf 0.30 (10% EtOAc/hexanes); IR (KBr): vmax 3084, 3061, 2926, 1716, 1605, 1558, 1424, 1374, 1277,
1118, 1069, 910, 861, 773, 700 cm-1; 1H-NMR (400 MHz, CDCl3): µ 7.62-7.39 (m, 5H), 7.32 (d, J 8.8 Hz, 1H), 6.80
(d, J 8.8 Hz, 1H), 6.24 (s, 1H), 6.18-5.93 (m, 2H), 5.47 (dd, J 17.3, 1.3 Hz, 1H), 5.43 (dd, J 10.6, 1.0 Hz, 1H) 5.34
(dd, J 17.1, 1.4 Hz, 1H) 5.32 (dd, J 10.0, 1.1 Hz, 1H), 4.66 (d, J 5.0 Hz, 2H), 3.72 (d, J 6.4 Hz, 2H); 13C NMR (100
MHz, CDCl3): µ 160.94 (C), 159.30 (C), 155.85 (C), 153.22 (C), 135.98 (C), 135.16 (CH), 132.64 (CH), 129.32 (CH),
128.67 (2CH), 128.37 (2CH), 125.71 (CH), 117.60 (CH2), 117.04 (C), 115.42 (CH2), 113.22 (C), 112.15 (CH),
108.34 (CH), 69.42 (CH2), 27.14 (CH2); MS (ESI+) m/z (%) 274.7 (23), 319.5 (M+H+, 100); HRMS (MALDI-TOF):
calcd for C21H18NaO3 [M+Na]+: 341.1154; found: 341.1135.
6-Allyl-7-(allyloxy)-4-phenyl-2H-chromen-2-one (6c). Yield 15%; viscous liquid; Rf 0.23 (10% EtOAc/hexanes);
IR (ATR): vmax 3071, 2989, 2850, 1714, 1614, 1548, 1445, 1368, 1273, 1152, 992, 911, 852, 769, 699 cm-1; 1H
NMR (400 MHz, CDCl3): µ 7.60-7.34 (m, 5H), 7.23 (s, 1H), 6.86 (s, 1H), 6.21 (s, 1H), 6.12-5.99 (m, 1H), 5.99-5.81
(m, 1H), 5.46 (dd, J 17.2, 1.2 Hz, 1H), 5.34 (dd, J 10.8, 1.2 Hz, 1H), 5.01 (s, 1H), 5.00-4.90 (m, 1H), 4.64 (d, J 4.8
Hz, 2H), 3.35 (d, J 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): µ 161.11 (C), 159.48 (C), 155.70 (C), 154.75 (C),
136.01 (CH), 135.82 (C), 132.24 (CH), 129.43 (CH), 128.72 (2CH), 128.35 (2CH), 127.36 (CH), 126.09 (C), 117.93
(CH2), 115.80 (CH2), 112.11 (C), 111.99 (CH), 100.22 (CH), 69.29 (CH2), 33.91 (CH2); MS (ESI+) m/z (%) 274.2
(100), 305.3 (25), 318.6 (M+, 32); HRMS (MALDI-TOF): calcd for C21H18NaO3 [M+Na]+: 341.1154; found:
341.1144.
General procedure for ring-closing metathesis of 5a-c and 6a-c. The solution of Grubbs’ first-generation
catalyst (4 mg, 0.9 mol%) in dry dichloromethane (DCM) (10 mL) was added to a solution of 5 or 6 (0.5 mmol)
in dry DCM (40 mL) under N2 atmosphere. The solution was stirred at room temperature for 24 h. After the
evaporation of the solvent, the residue was separated by CC using EtOAc/hexane as eluent to give the
oxepinocoumarins (7 or 8).25,26
Page 8
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
4-Methyl-8,11-dihydro-2H-oxepino[2,3-h]chromen-2-one (7a). Yield 82%; white solid; mp 118-120 oC (from
o
EtOAc-Hexanes) [lit26 mp 109-111 C (from DCM)]; Rf 0.33 (2 0 % EtOAc/hexanes); IR (KBr): vmax 3082, 3025,
2979, 2927, 2837, 1727, 1708, 1598, 1425, 1385, 1270, 1077, 855 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.42 (d, J
8.6 Hz, 1H), 7.01 (d, J 8.6 Hz, 1H), 6.20 (d, J 1.2 Hz, 1H), 6.00-5.82 (m, 1H), 5.62-5.49 (m, 1H), 4.71-4.59 (m, 2H)
3.88-3.73 (m, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.03 (C), 160.69 (C), 152.38 (C), 151.09 (C),
127.30 (CH), 126.33 (CH), 123.32 (C), 123.16 (CH), 117.72 (CH), 116.33 (C), 113.08 (CH), 70.79 (CH2), 22.49
(CH2), 18.65 (CH3); MS (ESI+) m/z (%) 229.1 (M+H+, 100).
4-Propyl-8,11-dihydro-2H-oxepino[2,3-h]chromen-2-one (7b). Yield 69%; light yellow solid; mp 85-87 oC (from
EtOAc-Hexanes); Rf 0.53 (20% EtOAc/hexanes); IR (KBr): vmax 2959, 2924, 2853, 1708, 1622, 1272, 1154, 1132,
1
1058, 1022, 842 cm-1; H-NMR (400 MHz, CDCl3): δ 7.46 (d, J 8.8 Hz, 1H), 7.00 (d, J 8.8 Hz, 1H), 6.19 (s, 1H),
6.01-5.82 (m, 1H), 5.68-5.49 (m, 1H), 4.71-4.59 (m, 2H) 3.88-3.71 (m, 2H), 2.72 (t, J 7.6 Hz, 2H), 1.73 (sext, J 7.6
Hz, 2H), 1.05 (t, J 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.85 (C), 160.97 (C), 156.20 (C), 151.32 (C),
127.30 (CH), 126.33 (CH), 123.49 (C), 122.98 (CH), 117.67 (CH), 115.68 (C), 112.00 (CH), 70.78 (CH2), 33.93
(CH2), 22.53 (CH2), 21.52 (CH2), 13.79 (CH3); MS (ESI+) m/z (%) 257.0 (M+H+, 100); HRMS (MALDI-TOF): calcd for
C16H16NaO3 [M+Na]+: 279.0997; found: 279.0990.
o
4-Phenyl-8,11-dihydro-2H-oxepino[2,3-h]chromen-2-one (7c). Yield 65%; white solid; mp 118-120 C (from
EtOAc-Hexanes); Rf 0.47 (20% EtOAc/hexanes); IR (KBr): vmax 3070, 3028, 2924, 2854, 1723, 1597, 1370, 1260,
1073, 708 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.61-7.39 (m, 5H), 7.32 (d, J 8.6 Hz, 1H), 6.97 (d, J 8.6 Hz, 1H), 6.30
(s, 1H), 6.10-5.89 (m, 1H), 5.70-5.53 (m, 1H), 4.79-4.60 (m, 2H) 3.98-3.80 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
162.16 (C), 160.66 (C), 156.02 (C), 151.70 (C), 135.77 (C), 129.45 (CH), 128.75 (2CH), 128.36 (2CH), 127.34 (CH),
126.41 (CH), 125.86 (CH), 123.38 (C), 117.72 (CH), 115.43 (C), 113.06 (CH), 70.75 (CH2), 22.56 (CH2); MS (ESI+)
m/z (%) 291.1 (M+H+, 100); HRMS (MALDI-TOF): calcd for C19H14NaO3 [M+Na]+: 313.0841; found: 313.0838.
o
4 -Methyl-6 ,9 -dihydro-2 H-oxepino[3 ,2 -g]chromen-2 -one (8a). Yield 78%; white solid; mp 168-169 C (from
EtOAc-Hexanes); Rf 0.27 (20% EtOAc/hexanes); IR (KBr): vmax 3055, 3024, 2928, 2850, 1709, 1611, 1389, 1362,
1151, 1135, 1067 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.32 (s, 1H), 7.05 (s, 1H), 6.22 (s, 1H), 6.00-5.85 (m, 1H),
5.61-5.47 (m, 1H), 4.73-4.60 (m, 2H) 3.57 (d, J 8.2 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.73
(C), 160.82 (C), 152.60 (C), 151.78 (C), 132.27 (C), 127.11 (CH), 126.02 (CH), 124.03 (CH), 116.04 (C), 113.69
(CH), 110.10 (CH), 71.40 (CH2), 31.45 (CH2), 18.49 (CH3); MS (ESI+) m/z (%) 229.1 (M+H+, 100); HRMS (MALDI-
TOF): calcd for C14H12NaO3 [M+Na]+: 251.0684; found: 251.0675.
o
4 -Propyl-6 ,9 -dihydro-2 H-oxepino[3 ,2 -g]chromen-2 -one (8b). Yield 64%; white solid; mp 118-121 C (from
EtOAc-Hexanes); Rf 0.30 (30% EtOAc/hexanes); IR (KBr): vmax 2960, 2926, 2853, 1708, 1621, 1154, 842 cm-1; 1H-
NMR (400 MHz, CDCl3): δ 7.34 (s, 1H), 7.06 (s, 1H), 6.22 (s, 1H), 6.01-5.83 (m, 1H), 5.62-5.45 (m, 1H), 4.75-4.60
(m, 2H) 3.57 (d, J 3.2 Hz, 2H), 2.73 (t, J 7.6 Hz, 2H), 1.75 (sext, J 7.5 Hz, 2H), 1.08 (t, J 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 161.56 (C), 161.08 (C), 155.55 (C), 153.84 (C), 132.21 (C), 127.11 (CH), 126.02 (CH), 123.75 (CH),
115.39 (C), 112.58 (CH), 110.29 (CH), 71.41 (CH2), 33.73 (CH2), 31.52 (CH2), 21.33 (CH2), 13.79 (CH3); MS (ESI+)
m/z (%) 257.2 (M+H+, 100); HRMS (MALDI-TOF): calcd for C16H16NaO3 [M+Na]+: 279.0997; found: 279.0990.
o
4 -Phenyl-6 ,9 -dihydro-2 H-oxepino[3 ,2 -g]chromen-2 -one (8c). Yield 79%; light yellow solid; mp 135-139 C
(from EtOAc-Hexanes); Rf 0.37 (20% EtOAc/hexanes); IR (KBr): vmax 3061, 2927, 2855, 1725, 1615, 1378, 1359,
1275, 1146, 701 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.62-7.33 (m, 5H), 7.17 (s, 1H), 7.10 (s, 1H), 6.28 (s, 1H),
5.94-5.78 (m, 1H), 5.60-5.40 (m, 1H), 4.78-4.59 (m, 2H), 3.44 (d, J 3.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
161.93 (C), 160.76 (C), 155.34 (C), 154.24 (C), 135.63 (C), 132.21 (C), 129.50 (CH), 128.80 (2CH), 128.31 (2CH),
126.99 (CH), 126.42 (CH), 126.17 (CH), 115.04 (C), 113.73 (CH), 110.30 (CH), 71.36 (CH2), 31.33 (CH2); MS (ESI+)
m/z (%) 274.2 (28), 291.2 (M+H+, 100); HRMS (MALDI-TOF): calcd for C19H14NaO3 [M+Na]+: 313.0841; found:
313.0842.
Page 9
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
Cell line maintenance. The Three cancer cell lines used in this study were obtained from ATCC (MD, USA) and
are as follows: colorectal adenocarcinoma (Caco-2), hepatocellular carcinoma (HepG2) and breast carcinoma
(SKBR-3) cell lines. The Caco-2 and HepG2 cells were cultured in EMEM medium whereas SKBR-3 was cultured
in DMEM medium. All media (Gibco, Langley, VA, USA) were supplemented at 10% with fetal bovine serum
(Gibco) and streptomycin plus penicillin (100 µg/mL and 100 U/mL, respectively; Sigma Co., Madrid, Spain). All
cells were maintained at 37°C, 95% relative humidity with 5% CO2 atmosphere.
Evaluation of cell viability. All the candidates oxepin-annulated coumarins 5-8 were evaluated in vitro for their
anti-proliferative activity against three different cancer cell lines, colorectal adenocarcinoma (Caco-2),
hepatocellular carcinoma (HepG2) and breast carcinoma (SKBR-3) cell lines using the 3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay as previously reported technique.44 In brief, cells were
seeded into 96-well tissue culture plates in appropriated basal medium for each cell line containing 10% FBS to
a final volume of 100 µL. The cells were subjected to different treatments after 24 h of seeding. The cells were
then incubated for 48 h with test compounds, tamoxifen as a positive control, or vehicle (DMSO). MTT
solutions were then added and cells were incubated for 3 h. After that, the supernatants were removed and
the precipitated formazan was dissolved by adding 200 µL of DMSO. Absorbance at 570 nm was determined
using a microplate reader (Varioskan™ Flash Multimode Reader; Thermo Scientific™). Results were calculated
by subtracting blank readings.
Data analysis. The IC50 values were obtained from the curve fitted to the means of the absorbance quotients
with respect to the control.
Acknowledgements
This research was supported by Thammasat University under TU research Scholar, Contract No. 2/14/2558.
We thank Ms. Duangkamon Saekow for her excellent technical support. We sincerely thank Assoc. Prof. Dr.
Kobtham Sathirakul, Mahidol University for providing Caco-2 cell line. We also acknowledge Chulabhorn
Research Institute for the HRMS analysis.
Supporting Information
Supporting Information associated with this article are available: 1H and 13C spectra of compounds 2-8.
References
1. Symeonidis, T.; Fylaktakidou, K.C.; Hadjipavlou-Litina, D.J.; Litinas, K.E. Eur. J. Med. Chem. 2009, 44, 5012.
https://doi.org/10.1016/j.ejmech.2009.09.004
2. Lee, J.; Lee, Y.J.; Kim, J.; Bang, O.S. Molecules 2015, 20, 20967.
https://doi.org/10.3390/molecules201219738
3. Olomola, T.O.; Mosebi, S.; Klein, R.; Traut-Johnstone, T.; Coates, J.; Hewer, R.; Kaye, P.T. Bioorg. Chem.
2014, 57, 1.
https://doi.org/10.3390/molecules201219738
Page 10
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
4. Chauthe, S.K.; Mahajan, S.; Rachamalla, M.; Tikoo, K.; Singh, I.P. Med. Chem. Res. 2015, 24, 2476.
https://doi.org/10.1007/s00044-014-1312-6
5. Luo, K.W.; Sun, J.G.; Chan, J.Y.; Yang, L.; Wu, S.H.; Fung, K.P.; Liu, F.Y. Chemotherapy 2011, 57, 449.
https://doi.org/10.1159/000331641
6. Piao, X.L.; Park, I.H.; Baek, S.H.; Kim, H.Y.; Park, M.K.; Park, J.H. J. Ethnopharmacol. 2004, 93, 243.
https://doi.org/10.1016/j.jep.2004.03.054
7. Song, P.P.; Zhao, J.; Liu, Z.L.; Duan, Y.B.; Hou, Y.P.; Zhao, C.Q.; Wu, M.; Wei, M.; Wang, N.H.; Lv, Y.; Han,
Z.J. Pest Manag. Sci. 2017, 73, 94.
https://doi.org/10.1002/ps.4422
8. Kaneria, A.R.; Giri, R.R.; Bhila, V.G.; Prajapati, H.J.; Brahmbhatt, D.I. Arab. J. Chem. 2017, 10, S1100.
https://doi.org/10.1016/j.arabjc.2013.01.017
9. Zhang, G.; Zhang, Y.; Yan, J.; Chen, R.; Wang, S.; Ma, Y.; Wang, R. J. Org. Chem. 2012, 77, 878.
https://doi.org/10.1021/jo202020m
10. Lipeeva, A.V.; Khvostov, M.V.; Baev, D.S.; Shakirov, M.M.; Tolstikova, T.G.; Shults, E.E. Med. Chem. 2016,
12, 674.
https://doi.org/10.2174/1573406412666160129105115
11. Tosun, F.; Kızılay, Ç.A.; Erol, K.; Kılıҫ, F.S.; Kürkҫüoğlu, M.; Başer, K.H.C. Food Chem. 2008, 107, 990.
https://doi.org/10.1016/j.foodchem.2007.08.085
12. Wang, T.; Wang, C.; Zhou, N.; Pan, X.; He, H. Med. Chem. Res. 2015, 24, 2417.
https://doi.org/10.1007/s00044-014-1303-7
13. Macías, F.A.; Torres, A.; Galindo, J.L.G.; Varela, R.M.; Álvarez, J.A.; Molinillo, J.M.G. Phytochemistry 2002,
61, 687.
https://doi.org/10.1016/S0031-9422(02)00370-9
14. Bruder, M.; Haseler, P.L.; Muscarella, M.; Lewis, W.; Moody, C.J. J. Org. Chem. 2010, 75, 353.
https://doi.org/10.1021/jo902117e
15. Vyvyan, J.R.; Oaksmith, J.M.; Parks, B.W.; Peterson, E.M. Tetrahedron Lett. 2005, 46, 2457.
https://doi.org/10.1016/j.tetlet.2005.02.053
16. Zhang, C.L.; Liu, Y.F.; Wang, Y.; Liang, D.; Jiang, Z.B.; Li, L.; Hao, Z.Y.; Luo, H.; Shi, G.R.; Chen, R.Y.; Cao, Z.Y.;
Yu, D.Q. Org. Lett. 2015, 17, 5686.
https://doi.org/10.1021/acs.orglett.5b02982
17. Li, H.; Jean, A.; Webster, D.; Robichaud, G.A.; Calhoun, L.A.; Johnson, J.A.; Gray, C.A. J. Nat. Prod. 2015, 78,
2837.
https://doi.org/10.1021/acs.jnatprod.5b00627
18. Trabanco, A.A.; Alonso, J.M.; Andrés, J.I.; Cid, J.M.; Fernández, J.; Iturrino, L.; Megens, A. Chem. Pharm.
Bull. 2004, 52, 262.
https://doi.org/10.1248/cpb.52.262
19. Agnew, M.N.; Rizwaniuk, A.; Ong, H.H.; Wichmann, J.K. J. Heterocycl. Chem. 1986, 23, 265.
https://doi.org/10.1002/jhet.5570230155
20. Trabanco, A.A.; Alonso, J.M.; Cid, J.M.; Font, L.M.; Megens, A. Farmaco 2005, 60, 241.
https://doi.org/10.1016/j.farmac.2004.12.008
21. Jinno, S.; Okita, T. Heterocycles 1999, 51, 303.
https://doi.org/10.3987/COM-98-8390
Page 11
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
22. Kittakoop, P.; Nopichai, S.; Thongon, N.; Charoenchai, P.; Thebtaranonth, Y. Helv. Chim. Acta 2004, 87,
175.
https://doi.org/10.1002/hlca.200490006
23. Pettit, G.R.; Numata, A.; Iwamoto, C.; Usami, Y.; Yamada, T.; Ohishi, H.; Cragg, G.M. J. Nat. Prod. 2006, 69,
323.
https://doi.org/10.1021/np058075+
24. Wang, L.; Xie, S.; Ma, L.; Chen, Y.; Lu W. Bioorg. Med. Chem. 2015, 23, 1950.
https://doi.org/10.1016/j.bmc.2015.03.031
25. Chattopadhyay, S.K.; Maity, S.; Panja, S. Tetrahedron Lett. 2002, 43, 7781.
https://doi.org/10.1016/S0040-4039(02)01806-3
26. Litinas, K.E.; Mangos, A.; Nikkou, T.E.; Hadjipavlou-Litina, D.J. J. Enzyme Inhib. Med. Chem. 2011, 26, 805.
https://doi.org/10.3109/14756366.2011.555944
27. Yet, L. Chem. Rev. 2000, 100, 2963.
https://doi.org/10.1021/cr990407q
28. Elliott, M.C. J. Chem. Soc., Perkin Trans. 1, 2000, 1291.
https://doi.org/10.1039/a903885j
29. Nandi, S.; Singha, R.; Ray, J.K. Tetrahedron 2015, 71, 669.
https://doi.org/10.1016/j.tet.2014.12.016
30. Das, S.N.; Chowdhury, A.; Tripathi, N.; Jana, P.K.; Mandal, S.B. J. Org. Chem. 2015, 80, 1136.
https://doi.org/10.1021/jo502672x
31. Yadav, D.B.; Taleli, L.; van der Westhuyzen, A.E.; Fernandes, M.A.; Dragoun, M.; Prokop, A.; Schmalz, H.-
G.; de Koning, C.B.; van Otterlo, W.A.L. Eur. J. Org. Chem. 2015, 5167.
https://doi.org/10.1002/ejoc.201500573
32. Wang, Y.; Chen, Y.; He, Q.; Xie, Y.; Yang, C. Helv. Chim. Acta 2013, 96, 296.
https://doi.org/10.1002/hlca.201200116
33. van Otterlo, W.A.L.; Ngidi, E.L.; Coyanis, E.M.; de Koning, C.B. Tetrahedron Lett. 2003, 44, 311.
https://doi.org/10.1016/S0040-4039(02)02522-4
34. Doveston, R.G.; Steendam, R.; Jones, S.; Taylor, R.J.K. Org. Lett., 2012, 14, 1122.
https://doi.org/10.1021/ol300039x
35. Nicolaou, K.C.; Bulger, P.G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490.
https://doi.org/10.1002/anie.200500369
36. Stenne, B.; Timperio, J.; Savoie, J.; Dudding, T.; Collins, S.K. Org. Lett., 2010, 12, 2032.
https://doi.org/10.1021/ol100511d
37. Calder, E.D.D.; Sharif, S.A.I.; McGonagle, F.I.; Sutherland, A. J. Org. Chem. 2015, 80, 4683.
https://doi.org/10.1021/acs.joc.5b00583
38. Aderibigbe, B.A.; Green, I.R.; Mabank, T.; van Rensburg, M.J.; Morgans, G.L.; Fernandes, M.A.; Michael,
J.P.; van Otterlo, W.A.L. Tetrahedron 2017, 73, 4671.
https://doi.org/10.1016/j.tet.2017.06.039
39. Prateeptongkum, S.; Duangdee, N.; Thongyoo, P. Arkivoc 2015, (v), 248.
http://dx.doi.org/10.3998/ark.5550190.p008.947
40. Geran, R.I.; Greenberg, N.H.; MacDonald, M.M.; Schumaker, A.M.; Abbott, B.J. Cancer Chemother. Rep. 3
1972, 3, 59.
41. Kaufman, K.D. US 3 201 421, 1965.
42. Ahluwalia, V.K.; Tripathi, R.P. J. Indian Chem. Soc. 1984, 61, 1023.
Page 12
©ARKAT USA, Inc

Arkivoc 2018, vii, 0-0
Prateeptongkum, S. et al.
43. Ahuja, M.; Bandopadhyay, M.; Seshadri, T.R. Indian J. Chem. 1974, 12, 292.
44. 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.
Page 13
©ARKAT USA, Inc