Design, synthesis, in vitro cytotoxicity evaluation and structure-activity relationship of Goniothalamin analogs

Article abstract of DOI:10.1007/s12272-013-0099-1

A series of six/five member (E/Z)-Goniothalamin analogs were synthesized from commercially available (3,4-dihydro-2H-pyran-2-yl)methanol/5- (hydroxymethyl)dihydrofuran-2(3H)-one in three steps with good to moderate overall yields and their cytotoxicity against lymphoblastic leukemic T cell line (Jurkat E6.1) have been evaluated. Among the synthesized analogs, (Z)-Goniothalamin appeared to be the most active in cytotoxicity (IC ₅₀ = 12 μM). Structure-activity relationship study indicates that introducing substituent in phenyl ring or replacing phenyl ring by pyridine/naphthalene, or decreasing the ring size of lactones (from six to five member) do not increase the cytotoxicity.

Full text of DOI:10.1007/s12272-013-0099-1

Arch. Pharm. Res. (2013) 36:812–831
DOI 10.1007/s12272-013-0099-1
RESEARCH ARTICLE
Design, synthesis, in vitro cytotoxicity evaluation
and structure–activity relationship of Goniothalamin analogs
•
Mazlin Mohideen Suraya Zulkepli Nik-Salmah Nik-Salleh
•
•
•
´ ´
Mohd Zulkefeli Jean-Frederic Faizal Abdullah Weber
•
A. F. M. Motiur Rahman
Received: 21 February 2013 / Accepted: 13 March 2013 / Published online: 31 March 2013
Ó The Pharmaceutical Society of Korea 2013
Abstract A series of six/five member (E/Z)-Goniothal-
amin analogs were synthesized from commercially available
(3,4-dihydro-2H-pyran-2-yl)methanol/5-(hydroxymethyl)
dihydrofuran-2(3H)-one in three steps with good to mod-
erate overall yields and their cytotoxicity against lym-
phoblastic leukemic T cell line (Jurkat E6.1) have been
evaluated. Among the synthesized analogs, (Z)-Gonio-
thalamin appeared to be the most active in cytotoxicity
(IC50 = 12 lM). Structure–activity relationship study
indicates that introducing substituent in phenyl ring or
replacing phenyl ring by pyridine/naphthalene, or
decreasing the ring size of lactones (from six to five
member) do not increase the cytotoxicity.
and Robertson 1967). Since then, it has been isolated from
various sources like Goniothalamus amuyon (Lan et al.
2003). G. andersonni (Jewers et al. 1972), G. borneensis (Cao
et al. 1998), G. dolichocarpus (Goh et al. 1995), G. giganteus
(El-Zayat et al. 1985), G. malayanus (Jewers et al. 1972), G.
macrophyllus (Jewers et al. 1972; Sam et al. 1987), G. uv-
aroides (Ahmad et al. 1991), G. sesquipedalis (Hasan et al.
1995), G. velutinus (Annonaceae) (Jewers et al. 1972),
Cryptocarya latifolia (Drewes et al. 1995), C. moschata
C. (Cavalheiro and Yoshida 2000), wyliei (Lauraceae)
(Drewes et al. 1995), and Bryonopsis laciniosa (Cucurbi-
ataceae) (Mosaddik et al. 2000; Kabir et al. 2003).
Goniothalamin had been showing to induce endocrine
activities, including anti-inflammatory (Tanaka et al.
2001), anti-estrogenic (Zauyah et al. 1997), anti-progesto-
genic (Kabir et al. 2003) and anti-fertility (Azimahtol
Hawariah et al. 1994) activities. Moreover, it had also
demonstrated toxicity against many living organisms, it
was shown to be antibacterial (El-Sharkawy et al. 1996;
Mosaddik and Haque 2003), antifungal (Jewers et al. 1972;
El-Sharkawy et al. 1996), insecticidal (Kabir et al. 2003)
and mosquito larvicide (Jewers et al. 1972; El-Sharkawy
et al. 1996; Mosaddik and Haque 2003), as well as cyto-
toxic on various mammal cell lines (Ali et al. 1997; Azimahtol
Hawariah and Stanslas 1998; Inayat-Hussain et al. 1999; Teoh
and Azimahtol Hawariah 1999; Meenakshii et al. 2000;
Mereyala and Joe 2001; Chien and Azimahtol Hawariah 2003;
Keywords E-Goniothalamin ꢀ Z-Goniothalamin ꢀ
Cytotoxicity ꢀ Jurkat E6.1
Introduction
Goniothalamin (1) is natural styryllactone was first isolated
in 1967 by Hlubucek from Cryptocarya caloneura (Hlubucek
Electronic supplementary material The online version of this
article (doi:10.1007/s12272-013-0099-1) contains supplementary
material, which is available to authorized users.
´
de Fatima and Pilli 2003b; Inayat-Hussain et al. 2003; de
´
Fatima et al. 2005, 2006a; Zhou et al. 2005; ). More specifi-
M. Mohideen ꢀ S. Zulkepli ꢀ N.-S. Nik-Salleh ꢀ M. Zulkefeli ꢀ
J.-F. F. A. Weber ꢀ A. F. M. M. Rahman
cally, Goniothalamin showed to be as potent as tamoxifen, on
both MCF-7 and T47-D cell lines (Zauyah et al. 1997). It
displayed anti-proliferative activity against the following
murine cancer cell lines: P-388 (leukemia), WEHI164 (fibro
sarcoma), and human cancer cell lines: NCI-ADR (breast
expressing a multidrug resistance phenotype), NCI-460
Faculty of Pharmacy, Universiti Teknologi MARA (UiTM),
42300 Puncak Alam, Selangor, Malaysia
A. F. M. M. Rahman (&)
Department of Pharmaceutical Chemistry, College of Pharmacy,
King Saud University, Riyadh 11451, Saudi Arabia
e-mail: afmrahman@ksu.edu.sa
123

Structure–activity relationship of Goniothalamin analogs
813
(lung, non-small cells), UACC62 (melanoma), 786-0 (kidney),
OVCAR03 (ovarian), PCO 3 (prostate), and HT-29 (colon),
U937 (leukemia), Hep3B (hepatoma), HepG2 (hepatocellular
carcinoma), and MDA-MB-231 (estrogen receptor nega-
closing metathesis (Ramachandran et al. 2000; Ram Reddy
´
´
et al. 2001; de Fatima and Pilli 2003a, b; de Fatima et al.
2006a), using expensive Grubbs’ catalyst (Grubbs 2004);
(ii) asymmetric hetero Diels–Alder reactions (Quitschalle
et al. 2001), where benzyl alcohol was used as starting
material with 21 % overall yield; (iii) diastereoselective
[2?2]-cycloaddition reaction (Fournier et al. 2004); (iv)
´
tive breast cancer) (Mu et al. 2003; de Fatima et al. 2006b)
with ICs50 ranging between 1.6 and 9 lM. In contrast,
Azimahtol and coworkers demonstrated that Goniothal-
amin has no significant cytotoxicity toward non-malignant
cells (Azimahtol Hawariah and Stanslas 1998), implying
that it acts mainly on malignant cells (HL-60 and CEM-SS
cells) (Rajab et al. 2005).
´ˇ
´
sulfoxide-modified Julia olefination (Pospısil and Marko
2006); (v) Cosford cross-coupling protocol (Sabitha et al.
2006); and (vi) olefin ring-closing metathesis reaction
(Harsh and O’Doherty 2009). Lipase (Sundby et al. 2004)
and PS-C Amano II (Gruttadauria et al. 2004) have also
been used as catalysts for the synthesis of Goniothalamin.
Finally, solid phase enantioselective oxa Diels–Alder
reaction was introduced by Torben Leßmann in 2004
(Leßmann et al. 2007). Nevertheless, up to this point the
development of procedures for the synthesis of Gonio-
thalamin relied on the use of expensive reagents and/or
many steps, which led continuing interests to develop an
efficient procedure and/or catalyst to future development of
the cytotoxic agents. In this article, we therefore developed
a simple and efficient procedure for the synthesis of Go-
niothalamin and its analogs in three steps with good to
moderate overall yields from (3,4-dihydro-2H-pyran-2-
yl)methanol/5-(hydroxymethyl)dihydrofuran-2(3H)-one
followed by evaluating their cytotoxicity against lympho-
blastic leukemic T cell line (Jurkat E6.1) for continuously
searching for new cytotoxic agents with Structure–activity
relationship (SAR) study.
The mechanism of action of Goniothalamin had been
studied by a number of groups, it was reported that Go-
niothalamin can cause DNA damage in vascular smooth
muscle cells leading to growth inhibition and apoptosis
(Chan et al. 2006), naturally-occurring (R)-Goniothalamin
causes cell death primarily by apoptosis as opposed to
synthetic (S)-Goniothalamin, which induces autophagy (de
´
Fatima et al. 2008), (R)-Goniothalamin provokes apoptosis
in Jurkat T cell and MCF-7 cells by activating caspases 3
and 7 with consequent release of cytochrome c (Inayat-
Hussain et al. 1999; Lee et al. 2003; Inayat-Hussain et al.
2010). This results from a mitochondrial pathway leading
to the activation of the apical caspase-9 with loss of
mitochondrial membrane potential (Dwm) in HL-60 leu-
kemia cells (Inayat-Hussain et al. 2003), over-expression of
full-length receptor for activated protein C-kinase 1
(RACK-1) and pc3n3, which up regulates the endogenous
RACK-1 and protects against Goniothalamin-induced cell
death leading to increase cell survival (Inayat-Hussain
et al. 2009). Goniothalamin also induces the generation of
reactive oxygen species and DNA damage in Jurkat T cells
leading to the activation of an intrinsic apoptotic pathway
that is independent of caspase-2 and Bcl-2 regulation (In-
ayat-Hussain et al. 2010). (R)-Goniothalamin has shown to
cause rapid decrease in the intracellular thiol levels in
human breast cancer cells (MDA-MB-231) in a concen-
tration- and time-dependent manner (Chen et al. 2005).
Treatment of human breast cancer cells (MDA-MB-231)
with (R)-Goniothalamin caused down regulation of tyro-
sine phosphatase (cdc25) inducing G2/M phase arrest
(Chen et al. 2005).
Results and discussions
Synthesis of 6-styryl-5,6-dihydro-2H-pyran-2-one
(E/Z)-Goniothalamin
The starting 3,4-dihydro-2H-pyran-2-carbaldehyde (2)
(Jagtap et al. 2009) (aldehyde 2 is unstable, presence of
aldehyde group was confirmed by proton nuclear magnetic
spectroscopy, which was showing d at 9.64 ppm for alde-
hyde functionality) was prepared via previously reported
Swern oxidation method using commercially available
inexpensive 3,4-dihydro-2H-pyran-2-methanol (3). On the
other hand, benzyltriphenylphosphonium bromide (4a) was
prepared using microwave irradiation for 30 min at 60 °C
in tetrahydrofuran (THF) from triphenylphosphine and
benzyl bromide. Subsequently, Wittig reaction of aldehyde
2 with phosphonium salt 4a was performed in presence of
NaH at low temperature (-15 °C) in THF solution, yielded
2-styryl-3,4-dihydro-2H-pyran (5a) (Schmidt 2004) as a
mixture of E and Z isomer (1:4) with 55 % yield
(Scheme 1). Isomers of 5a (E-5a and Z-5a) were separated
by flash column chromatography and characterized by
Because of its apparent simple structure and the broad
spectrum of activities, Goniothalamin has attracted the
attention of several synthetic groups in recent years. In
1986, Just and Connor reported the first enantioselective
synthesis of (?)-Goniothalamin from diacetone-D-glucose
in 15 steps (O’Connor and Just 1986; Mondon and Gesson
2006). Simultaneously, Riehl and coworkers (1988)
described a similar synthesis of (?)-Goniothalamin from
the same intermediate in 11 steps. Very recently, Gonio-
thalamin was synthesized through various methods:
(i) enantioselective Maruoka allylation followed by ring-
123

814
M. Mohideen et al.
Scheme 1 Synthesis of
2-styryl-3,4-dihydro-2H-pyran
(5a)
(COCl)2
DMSO
Et3N
PPh3Br
O
O
O
4a
OH
O
-78 oC
CH2Cl2
NaH
-15 oC
THF
5a
3
2
(E and Z mixture)
proton nuclear magnetic resonance spectra [E/Z-isomers
were purified by column chromatography using n-hexane.
The first fraction (approximately, Rf = 0.75 n-hexane)
gave Z-isomers and later fraction (approximately,
Rf = 0.40 n-hexane) obtained E-isomers]. In E-5a, olefinic
proton shows a coupling constant of 15.5–16.0 Hz, while
in Z-5a it was 11.5–12.0 Hz. In addition to confirm the
structures of two isomers, resonances of all protons of E-5a
and Z-5a were assigned by double-quantum filtered COSY
experiments and were in agreement with reported data
(Schmidt 2004).
O
O
PDC
t-BuOOH
O
-40 oC
CH2Cl2
E -5a
E-1a
Scheme 2 Oxidation of (E)-2-styryl-3,4-dihydro-2H-pyran (E-5a)
´ˇ ´
(Chidambaram et al. 1989; Pospısil and Marko 2006;
Sabitha et al. 2006).
After successfully obtaining (E)-and (Z)-Goniothalamin,
we used various Wittig reagents (4b–k) to synthesize Go-
niothalamin analogs (1b–k) via the precursors 5b–k
(Scheme 4) using the same condition adopted for (E)-and
(Z)-Goniothalamin.
After successful separation of the two isomers, E-isomer
(E-5a) was oxidized by PDC/t-BuOOH (Chidambaram
et al. 1989) in CH2Cl2 at 0 °C and only trace amount of
(E)-Goniothalamin (E-1a) was obtained. Therefore, we
optimized the conditions of the previously reported method
(Chidambaram et al. 1989) by decreasing the reaction
temperature until -78 °C to obtain the higher yields. To
our delight, when the temperature was -20 °C we obtained
25 % of E-1a; at -40 °C, the yield increased to 78 %
(Scheme 2), however, we could not obtain higher than
78 % yield with lower/higher temperature and we obtained
only 10 % product at -60 °C and 0 % at -78 °C. The
It should be noted that, reaction of 2 with 4c, 4g–k gives
only Z isomers (5c and 5g–k). In addition, one of the
pyridine analogs E-5f gives two by-products in the similar
pattern as Z-5a–k. Isolated yields for all the E/Z isomers of
pyrans (5a–k), lactones (1a–k), peroxides (6a–k) and
pyranones (7a–k) are depicted in Table 2.
Cytotoxicity of 6-styryl-5,6-dihydro-2H-pyran-2-one
(E/Z)-Goniothalamin analogs
1
structures of the compounds were confirmed by H, 13C
and COSY NMR, mass spectrometer and reported melting
´
point (de Fatima et al. 2005).
Cytotoxicity of the prepared compounds (5, 1, 6 and 7) was
screened by the previously reported method (Chan et al.
2006) against lymphoblastic leukemic T cell (Jurkat E6.1)
cancer line. As shown in Table 3, IC50 values of compounds
1a–k were higher than any other by-products (6 or 7) as well
as precursor (5) against Jurkat E6.1 cancer cell line.
On the other hand, Z-5a gave 36 % of (Z)-Goniothal-
´
amin (Z-1a) (de Fatima and Pilli 2003a) with 38 % of (Z)-
6-(tert-butylperoxy)-2-styryl-3,6-dihydro-2H-pyran (Z-6a)
as a by-product at 0 °C. Then we optimized the conditions
adopted for E-isomer (E-5a) and obtained 84 % of Z-1a
with 6 % of unexpected by-product (Z)-Styryl-2,3-dihydro-
4H-pyran-4-one (Z-7a) along with 3 % pyran Z-6a, the by-
product of E-isomers Z-7a is known (Schaus et al. 1998;
Du et al. 2002). The by-product pyran Z-6a was then
treated with triethylamine to obtain Z-1a at 80 °C for 1 h
using a previously reported method (Chidambaram et al.
1989) (Scheme 3).
In our finding, IC50 values of compound Z-1a was
12 lM, and Z-1k was 15 lM against Jurkat E6.1 cell line,
while the natural (E)-(?)-Goniothalamin was having the
IC50 value of 22 lM as positive control. Also for the
compounds Z-1c and Z-1e, the IC50 values were 24 and
32 lM, respectively, which indicate that, these 4 com-
pounds would be a potential anticancer candidates com-
pared with natural (E)-(?)-Goniothalamin. Unfortunately,
synthetic E-isomer of Goniothalamin (E-1a) shows the
IC50 value of 87 lM. On the other hand, precursor of
Goniothalamin (E/Z-isomer of pyran, 5), peroxide (6) and
Pyranone (7) did not show the cytotoxicity.
The experimental data and results for various temper-
atures are summarized in Table 1. The structures of (Z)-
1
Goniothalamin and by-products were confirmed by H,
13C and COSY NMR as well as mass spectroscopy
and were in agreement with those reported values
123

Structure–activity relationship of Goniothalamin analogs
815
Scheme 3 Synthesis of (Z)-
Goniothalamin (Z-5a)
PDC
t-BuOOH
O
O
O
O
-40 oC
CH2Cl2
O
O
6%
3%
84%
O
O
Z-7a
Z-5a
Z-1a
Z-6a
Et3N
80 oC
toluene
50 %
Synthesis of 5-styryldihydrofuran-2(3H)-one
trifluoromethoxy (–OCF3) group (Z-1k, IC50 = 15 lM)
decrease the activity comparing to Z-Goniothalamin (Z-1a,
IC50 = 12 lM), but still significantly higher or similar com-
paring with natural (E)-(?)-Goniothalamin (IC50 = 22 lM)
in cytotoxicity. Introducing methoxy group in phenyl ring of
Z-1a at12-position;Iodogroupat12-position;Fluorogroupat
11-position, 10/11-positions or 11/12 positions did not
increase the activity of Z-1a.
To extend our interest in continuously searching for the
new cytotoxic agents, we then designed to synthesize new
five-member Goniothalamin analogs using the same
method to see whether these analogs will be a potent
cytotoxic agents or not. In this regard, commercially
available 5-(hydroxymethyl)dihydrofuran-2(3H)-one (8)
was used for the preparation of aldehyde 9 followed by
Wittig reaction with various Wittig reagents (4a–b, 4g–h
and 4l–n) to obtain Goniothalamin analogs (10a–g)
(Scheme 5) in presence of NaH in THF solution at -15 °C.
Isolated yields for all the five-member Goniothalamin
analogs (10a–g) are depicted in Table 4.
Replacing phenyl ring of Z-1a with naphthalene ring
(Z-1b) or pyridine ring (Z-1f) almost did not show activity,
where replacing 6-member lactone ring by 5-member lac-
tone ring (10a–g) of (E/Z)-Goniothalamin shows moderate
activities compare to E-1a but still very less than Z-1a.
Effects of Z-Goniothalamin (Z-1a) on the viability
of Jurkat E6.1 cell line
Cytotoxicity of five-member Goniothalamin analogs
(10a–g)
Z-Goniothalamin (Z-1a) induced
a
dose-dependent
IC50 values of five-member Goniothalamin analogs (10a–
g) were evaluated and found ranging from 62 to 100 lM
for 10a–f, and no cytotoxicity was shown for 10g
(IC50 C 100 lM) against Jurkat E6.1 cell line (Table 5).
decrease in cell viability following a 24-h treatment are
shown in Fig. 1. The IC50 value of Z-Goniothalamin (Z-1a)
was 12 lM which indicate that this compound is efficient
as a cytotoxic agent and in inducing cell death in Jurkat
E6.1 cancer cell line.
SAR study of Goniothalamin analogs
The results of the cytotoxicity of analogs 1 and 10
(Chart 1) against Jurkat E6.1 cell line screening lead to the
following assumptions about the structural activity rela-
tionship (SAR).
Experimental section
General
Synthetic E-Goniothalamin (E-1a) shows the value of
IC50 is 87 lM. Introducing substituents (E-1e, methoxy
groups in 11 and 13 positions) in the phenyl ring of E-1a or
replacing a carbon of E-1a by nitrogen (E-1f) decreased
the cytotoxicity. Interestingly, while phenyl ring was
replaced by naphthalene ring (E-1b), the cytotoxicity was
improved in relation to that of E-1a.
(3,4-dihydro-2H-pyran-2-yl) methanol and all the chemicals
were purchased from Aldrich Chemicals. Organic solvents
Table 1 Oxidation of Z-5a by PDC in the presence of t-BuOOH in
CH2Cl2
Temperature (°C)
Yields (%) of the oxidation products
Z-1a
Z-6a
Z-7a
Z-Goniothalamin (Z-1a) is much more potent (IC50
=
0
36
50
84
29
0
38
2
0
12 lM) than synthetic E-Goniothalamin (E-1a) as well as the
natural (E)-(?)-Goniothalamin (IC50 = 22 lM). Introducing
substituent in phenylringofZ-1a at 11-position withmethoxy
group (Z-1c, IC50 = 24 lM); or 11, 13 positions with meth-
oxy groups (Z-1e, IC50 = 32 lM); or 12-position with
-20
-40
-60
-78
6
3
6
0
Trace
0
0
123

816
M. Mohideen et al.
O
O
O
PDC /
t-BuOOH
O
O
O
O
-40 oC
R
R
R
R
O
CH2Cl2
E-5b-k
E-1b-k
E-6b-k
E-7b-k
R
PPh3Br
4b-k
2
NaH
-15oC
THF
O
O
O
O
PDC /
t-BuOOH
R
O
R
O
R
O
R
-40 oC
O
CH2Cl2
Z-5b-k
Z-1b-k
Z-6b-k
Z-7b-k
O
O
F
R =
N
O
e
b
f
O
d
c
h
F
F
F
F
F
F
F
I
O
g
j
k
i
Scheme 4 Synthesis of Goniothalamin derivatives/analogs
were dried and purified by distillation (wherever appropri-
ate) prior to their use. THF and diethyl ether were freshly
distilled over sodium/benzophenone under nitrogen gas.
Dichloromethane was freshly distilled over calcium hydride
under nitrogen gas. All reactions were carried out under an
atmosphere of nitrogen gas inside the fume hood by using a
flame-dried apparatus with magnetic stirrer, unless otherwise
indicated. TLC analysis was carried out on glass-backed
TLC silica plates (silica gel 60 F254, 0.25 mm) impregnated
with fluorescence indicator (Merck art. 1.05554). The
detection of UV-active substances was visualized using
Ultra-Violet light (kmax = 254 nm) and for non UV active
substances KMnO4/PMA/p-anisaldehyde stains were used.
For all chromatographic purification steps, silica gel (Kie-
selgel 60, particle size range 0.040–0.063 mm) from Merck
(ddd), triplets (t) and multiplets (m), doublets of triplets (dt),
triplets of doublets (td). Occasionally, two-dimensional
NMR experiments such as COSY-45, HMBC, and HSQC
have been taken. MS-TOF spectra were recorded on an
Agilent Technologies 6224 TOF LC/MS. Results are
reported by presenting the mass of the fragments (m/z) as a
proportion of intensity compared to the base peak (100 %)
in percentage. Only signals presenting a high intensity
(C10 %) or characteristics signals (generally [M?H]? are
reported. Melting points were determined in open capillary
tubes with a Bu¨chi Melting Point B-545 apparatus and are
uncorrected. Microwave-heated reactions were performed in
a monomode reactor MicroSYNTH Plus.
General procedure for the preparation of Wittig
reagents
1
was used. H- and 13C-NMR spectrum was recorded on a
Bruker 500 AVANCE III spectrometer. Chemical shift for
1H- and 13C-NMR (d) are reported in ppm. The working
A mixture of (substituted)-benzyl halide (bromide/chloride,
4, 1.0 mmol) with triphenylphosphine (1.0 mmol) in THF
(30 mL) was homogenized by stirring and shaking. The
reaction mixture was exposed to microwave irradiation
(MW) for the appropriate times (30 min) and temperatures
(60 °C). Once the heating cycle is completed, the reaction
mixture was then cooled to ambient temperature, the pre-
cipitated salt was filtered off, washed with cold THF and
1
frequency for H- and 13C- were 500 MHz and 125 MHz,
respectively. CDCl3, CD3OD and Acetone-d6 were used as
internal standard in 1H- as 7.24, 3.31 and 2.05 ppm, while in
13C- as 77, 49, 29.84 and 206.26 ppm respectively. The
coupling constants J are reported in Hertz (Hz). Peaks were
described as broad signals (br), singlet (s), doublets (d),
doublets of doublets (dd), doublets of doublets of doublets
123

Structure–activity relationship of Goniothalamin analogs
817
Table 2 Synthesis of (E)- and (Z)-Goniothalamin (E-1a and Z-1b) and their analogs
Entry
Substrate (R)
Yields (%) of E/Z pyran (5)
Yields (%) of E and Z-isomer of products
Lactones (1)
Peroxide (6)
Pyranone (7)
a
E
Z
(14)
(56)
78
84
0
0
6
10
b
E
Z
(40)
(40)
26
45
0
5
0
0
ca
Z
(37)
51
0
0
d
e
E
Z
(1)
0
0
0
8
(32)
31
10
E
Z
(19)
(19)
13
37
0
7
0
3
f
E
Z
(26)
(26)
18
56
3
2
4
1
ga
Z
(52)
62
6
3
ha
Z
(46)
68
12
5
ia
Z
(70)
58
14
0
ja
Z
Z
(68)
(46)
53
46
8
8
6
5
ka
a
No E-isomers were obtained
dried at 50 °C for overnight and obtained pure (substi-
tuted)-triphenylphosphonium halide (bromide/chloride)
with excellent yields. The compounds were characterized
by NMR and mass spectroscopic data as well as physical
properties such as melting point.
7.85 (m, 6H), 7.77 (m, 6H), 7.32 (m, 1H), 7.23 (t,
J = 7.7 Hz, 2H), 7.17 (m, 2H), 5.37 (d, JHP = 15.1 Hz,
2H, –CH2) ppm.
Naphthalene-2-yl-methyltriphenylphosphonium bromide
(4b)
Benzyltriphenylphosphonium bromide (4a)
White powder, mp. 253.8 °C. 1H-NMR (500 MHz,
CDCl3): d 7.73–7.67 (m, 9H), 7.64 (d, J = 8.0 Hz, 1H),
7.58–7.53 (m, 6H), 7.49 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H),
1
White crystal, mp. 296.4 °C (CAS: 1449-46-3). H-NMR
(500 MHz, Acetone-d6): d 7.94 (td, J = 7.5, 2.0 Hz, 3H),
123

818
M. Mohideen et al.
3,5-Dimethoxybenzyltriphenylphosphonium bromide (4e)
White powder, mp. 267.3 °C (264–265.3 °C, Sun et al.
Table 3 In vitro cytotoxicity of compounds 5, 1, 6 and 7 on Jurkat
E6.1 cell line
Entrya IC50 (lM)
1
2010), H-NMR (500 MHz, CDCl3): d 7.75–7.67 (m, 9H),
5
1
6
7
7.61–7.56 (m, 6H), 6.28 (t, J = 2.4 Hz, 2H), 6.24 (q,
J = 2.3 Hz, 1H), 5.22 (d, JHP = 14.4 Hz, 2H, –CH2), 3.47
(s, 6H, 2 9 –OCH3) ppm.
E
Z
E
Z
E
Z
E
Z
c
c
a
b
c
d
e
f
N/Db N/Db 87
12
90
24
92
32
–
–
–
–
–
[100
–
–
–
–
–
[100
c
c
c
c
c
c
c
c
c
c
[100 [100 52
–
–
Pyridine-2-yl-methyltriphenylphosphonium bromide (4f)
c
c
c
c
–
[100
–
–
–
–
c
[100 [100
[100
[100
[100
[100
1
Light yellow powder, mp. 116.2 °C. H-NMR (500 MHz,
[100 [100 90
CDCl3): d 8.65 (d, J = 5.8 Hz, 1H), 8.34 (d, J = 6.2 Hz,
2H), 8.32 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 7.4 Hz, 1H),
8.09 (t, J = 7.4 Hz, 1H), 7.90–7.75 (m, 6H), 7.71 (d,
J = 8.1 Hz, 1H), 7.64 (td, J = 7.8, 3.6 Hz, 6H), 6.13 (d,
JHP = 15.0 Hz, 2H, –CH2) ppm.
[100 [100 [100 [100 [100 [100 [100 [100
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
g
h
i
–
–
–
–
–
[100
[100
[100
[100
[100
–
–
–
–
–
42
68
44
48
15
–
–
–
–
–
[100
[100
[100
[100
[100
–
–
–
–
–
[100
[100
[100
[100
[100
j
k
a
4-Iodobenzyltriphenylphosphonium bromide (4g)
Natural (E)-(?)-Goniothalamin used as positive control having
IC50 = 22 lM
´
White powder, mp. 269.7 °C (255–256 °C, Rodrıguez
b
et al. 2003), 1H NMR (500 MHz, CDCl3) d ppm: 7.78–7.71
(m, 9H), 7.62–7.57 (m, 6H), 7.39 (dd, J = 9.0, 1.0 Hz,
2H), 6.95 (dd, J = 8.5, 2.5 Hz, 2H), 5.67 (d, JHP = 15 Hz,
2H).
Not detected
c
No compound were evaluated
7.40–7.31 (m, 2H), 7.11 (dt, J = 8.0, 1.5 Hz, 1H), 5.49 (d,
JHP = 14.5 Hz, 2H, –CH2) ppm.
3-Fluorobenzyltriphenylphosphonium bromide (4h)
3-Methoxybenzyltriphenylphosphonium bromide (4c)
White powder, mp. 315 °C (290–292 °C, Wyatt et al.
2006; 290–292 °C, Zhou and Keana 1999), 1H NMR
(500 MHz, CDCl3) d ppm: 7.78–7.73 (m, 9H), 7.64–7.59
(m, 6H), 7.08 (q, J = 8.0 Hz, 1H), 7.04 (d, J = 1.0 Hz,
1H), 6.88 (t, J = 8.5 Hz, 1H), 6.72 (dd, J = 9.5, 1.5 Hz,
1H), 5.56 (d, JHP = 14.5 Hz, 2H).
White powder, mp. 261.7 °C. 1H-NMR (500 MHz,
CDCl3): d 7.67 (m, 9H), 7.56 (td, J = 7.8, 3.5 Hz, 6H),
6.94 (t, J = 8.1 Hz, 1H), 6.69 (m, 2H), 6.57 (m, 1H), 5.22
(d, JHP = 14.4 Hz, 2H, –CH2), 3.45 (s, 3H, –OCH3) ppm.
4-Methoxybenzyltriphenylphosphonium bromide (4d)
2,3-Difluorobenzyltriphenylphosphonium bromide (4i)
White powder, mp. 248.3 °C (234–235 °C, Zhang and Go
2007). H-NMR (500 MHz, CDCl3): d 7.76–7.66 (m, 9H),
7.60 (td, J = 7.8, 3.5 Hz, 6H), 6.98 (dd, J = 8.7, 2.5 Hz,
2H), 6.62 (d, J = 8.7 Hz, 2H), 5.25 (d, JHP = 14.0 Hz, 2H,
–CH2), 3.69 (s, 3H, –OCH3) ppm.
1
White powder, mp. 292.7 °C. 1H NMR (500 MHz, CDCl3)
d ppm: 7.78–7.71 (m, 9H), 7.64–7.58 (m, 6H), 7.29 (t,
J = 6.0, 2.0 Hz, 1H), 7.05–6.97 (m, 1H), 6.92–6.86 (m,
1H), 5.52 (d, JHP = 14.5 Hz, 2H).
Scheme 5 Synthesis of
styryldihydrofuran-2(3H)-one
(10a–g)
(COCl)2
DMSO
Et3N
R
PPh3Br
O
O
O
O
O
4a-b, g-h, l-n
O
-78 oC
CH2Cl2
NaH
-15 oC
THF
OH
O
R
8
9
10a-g
(E and Z)
F
I
R =
S
NC
I
4g
10c
4a
10a
4b
10b
4h
10d
4l
10e
4m
10f
4n
10g
123

Structure–activity relationship of Goniothalamin analogs
819
Table 4 Synthesis of five-member Goniothalamin analogs (10a–g)
from aldehyde (9)
Table 5 In vitro cytotoxicity of compounds 10a–g on Jurkat E6.1
cell line
Entry
Substrate (R)
Yields (%) of lactones (10)
Entrya
IC50 (lM)
E-10
E-10
Z-10
Z-10
a
b
c
35
16
a
b
c
d
e
f
66
70
60
100
70
75
30
21
15
22
68
77
72
70
65
60
g
[100
[100
a
Natural (E)-(?)-Goniothalamin used as positive control having
IC50 = 22 lM
d
e
18
18
16
20
J = 8.0 Hz, 2H), 7.16 (dd, J = 8.5, 2.5 Hz, 2H), 5.67 (d,
JHP = 15 Hz, 2H).
f
28
15
15
30
4-Methylthiobenzyltriphenylphosphonium bromide (4n)
White powder, mp. 232.9 °C. 1H NMR (500 MHz, CDCl3)
d ppm: 7.74–7.68 (m, 9H), 7.61–7.56 (m, 6H), 7.02–6.99
(dd, 2H), 6.92 (d, 2H), 5.34 (d, J = 14.5 Hz, 2H –CH2),
2.36 (s, 3H).
g
General procedure for the preparation of pyran 5
3,4-Difluorobenzyltriphenylphosphonium bromide (4j)
(Substituted)-benzyl triphenylphosphonium halide (bromide/
chloride 4, 0.3 mmol) was added slowly to a stirrer sus-
pension of NaH (60 % in mineral oil, 0.3 mmol) in dry THF
(5 mL) at -15 °C. The solution was stirred for 30 min,
freshly prepared 3,4-dihydro-2H-pyran-2-carbaldehyde (2,
0.45 mmol) in dry THF (1 mL) was added slowly, stirring
was continued for 3–4 h at the same temperature and 1 h at
room temperature. The reaction mixture was then diluted
with ether, the ether layer were collected, washed with brine,
dried and purified by column chromatography using n-hex-
ane. The earlier fraction gave Z-isomer and the later fraction
obtained E-isomer. The compounds were characterized by
NMR and mass spectroscopic data as well as physical
properties such as melting point.
White powder, mp. 315.5 °C. 1H NMR (500 MHz, CDCl3)
d ppm: 7.80–7.69 (m, 9H), 7.60–7.54 (m, 6H), 7.05–6.01
(m, 1H), 6.98–6.92 (q, J = 9.5 Hz, 1H), 6.82–6.75 (q,
J = 9.5 Hz, 1H), 5.67 (d, JHP = 15.0 Hz, 2H).
4-Trifluoromethoxybenzyltriphenylphosphonium bromide
(4k)
White powder, mp. 314.4 °C. 1H NMR (500 MHz, CDCl3)
d ppm: 7.81–7.73 (m, 9H), 7.63–7.58 (m, 6H) 7.26 (dd,
J = 8.5, 3.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 5.67 (d,
JHP = 14.5 Hz, 2H).
3-Iodobenzyltriphenylphosphonium bromide (4l)
(E)-2-Styryl-3,4-dihydro-2H-pyran (E-5a)
White powder, mp. 291.3 °C. 1H NMR (500 MHz, CDCl3)
d ppm: 7.89–7.72 (m, 9H), 7.65–7.58 (m, 6H), 7.48 (d,
1H), 7.37 (d, 1H), 7.04 (s, 1H), 6.86–6.83 (t, J = 8 Hz,
1H), 5.46 (d, J = 15 Hz, 2H –CH2).
Yellow oil (Rf = 0.68, n-hexane). 1H-NMR (500 MHz,
CDCl3): d 7.38 (dd, J = 8.1, 0.9 Hz, 2H, H11/H13), 7.29
(m, 2H, H10/H14), 7.21 (m, 1H, H12), 6.62 (m, 1H, H8),
6.42 (m, 1H, H2), 6.25 (dd, J = 16.0, 6.2 Hz, 1H, H7),
4.70 (m, 1H, H6), 4.48 (m, 1H, H3), 2.05 (m, 3H, H4/H5),
1.78 (m, 1H, H4) ppm. 13C-NMR (125 MHz, CDCl3): d
143.55, 130.88, 129.06, 128.78, 128.54, 127.36, 126.51,
100.58, 75.29, 29.70, 19.40 ppm.
4-Cyanobenzyltriphenylphosphonium bromide (4m)
White powder, mp. 328.0 °C. 1H NMR (500 MHz, CDCl3)
d ppm: 7.76–7.71 (m, 3H), 7.64–7.53 (m, 12H) 7.35 (d,
123

820
M. Mohideen et al.
12
11
10
O
O
13
14
O
2
2
3
4
O
O
3
4
O
O
1
9
1
14
11
8
13
12
8
6
9
6
O
7
5
5
7
10
Z-1a (12 µM),
Z-1c (11-OCH3), (24 µM),
Z-1d (12-OCH3), (92 µM),
Z-1e (11,13-di-OCH3), (32 µM),
Z-1g (12-I), (42 µM),
E-1b (52 µM)
Z-1b (90 µM)
E-1a (87 µM),
E-1e (11,13-di-OCH3), (90 µM),
O
O
Z-1h (11-F), (68 µM),
O
O
Z-1i (10,11-di-F), (44 µM),
N
Z-1j (11,12-di-F), (48 µM),
Z-1k (12-OCF3), (15 µM),
O
2
N
11
Z-1f (>100 µM)
10
9
12
13
O
E-1f (>100 µM)
1
7
O
13
10
3
12
11
2
5
O
8
9
4
8
7
1
6
3
O
5
4
6
O
O
O
E-10a (66 µM),
Z-10a, (60 µM),
E-10c (11-I), (75 µM),
E-10d (10-F), (68 µM),
E-10e (10-I), (72 µM),
E-10f (11-CN), (65 µM),
E-10g (11-SCH3), (>100 µM),
Z-10c (11-I), (70 µM),
Z-10d (10-F), (77 µM),
Z-10e (10-I), (70 µM),
Z-10f (11-CN), (60 µM),
Z-10g (11-SCH3), (>100 µM),
Z-10b (>100 µM)
E-10b (70 µM)
Chart 1 Structures of Goniothlamin analogs
(Z)-2-Styryl-3,4-dihydro-2H-pyran (Z-5a)
7.47–7.44 (m, 2H, H10), 7.42 (dd, J = 8.5, 1.7 Hz, 1H,
H14/H15), 6.77 (d, J = 11.7 Hz, 1H, H8), 6.44 (dt,
J = 6.4, 1.0 Hz, 1H, H2), 5.83 (dd, J = 11.6, 9.1 Hz, 1H,
H7), 4.79 (td, J = 9.5, 2.5 Hz, 1H, H6), 4.72–4.69 (m, 1H,
H3), 2.14–1.93 (m, 3H, H4/H5), 1.89–1.81 (m, 1H, H4)
ppm. 13C-NMR (125 MHz, CDCl3): d 143.64, 134.05,
132.56, 132.30, 131.53, 128.13, 127.83, 127.60, 126.87,
126.14, 100.52, 71.47, 28.27, 19.37 ppm.
1
Low melting white solid. H-NMR (500 MHz, CDCl3): d
7.29 (m, 5H, –Ph), 6.62 (d, J = 11.5 Hz, 1H, H8), 6.41 (d,
J = 6.2 Hz, 1H, H2), 5.75 (dd, J = 11.5, 9. Hz, 1H, H7),
4.70 (m, 2H, H3, H6), 2.15–2.05 (m, 1H, H4/H5),
2.04–1.96 (m, 1H, H4/H5), 1.94–1.88 (m, 1H, H4/H5),
1.82–1.72 (m, 1H, H4) ppm.
(E)-2-(2-(Naphthalen-2-yl)vinyl)-3,4-dihydro-2H-pyran
(Z)-2-(3-Methoxystyryl)-3,4-dihydro-2H-pyran (Z-5c)
(E-5b)
1
Light yellow oil. H-NMR (500 MHz, CDCl3): d 7.24 (t,
1
Light yellow oil. H-NMR (500 MHz, CDCl3): d 7.78 (d,
J = 8.0 Hz, 1H, H13), 6.87 (dd, J = 8.0, 1.5 Hz, 2H, H10/
H14), 6.81 (m, 1H, H12), 6.59 (d, J = 11.5 Hz, 1H, H8),
6.49 (dt, J = 6.5 Hz, 1H, H2), 5.74 (dd, J = 11.5, 9.0 Hz,
J = 6 Hz, 2H, H11), 7.76 (d, J = 8 Hz, 1H, H13/H16),
7.73 (s, 1H, H18), 7.59 (dd, J = 9.5, 1 Hz, 1H, H10), 7.43
(m, 2H, H14/H15), 6.79 (d, J = 16.0 Hz, 1H, H8), 6.45 (dt,
J = 6.5, 1.0 Hz, 1H, H2), 6.38 (dd, J = 16.0, 6.5 Hz, 1H,
H7), 4.73 (m, 1H, H6), 4.54 (m, 1H, H3), 2.18–2.10 (m,
1H, H4/H5), 2.08–1.98 (m, 2H, H4/H5), 1.87–1.77 (m, 1H,
H4/H5) ppm. 13C-NMR (125 MHz, CDCl3): d 143.51,
130.99, 128.18, 127.98, 127.65, 126.53, 126.24, 125.88,
123.61, 100.60, 75.37, 28.36, 19.42 ppm.
(Z)-2-(2-(Naphthalen-2-yl)vinyl)-3,4-dihydro-2H-pyran
(Z-5b)
1
Light yellow oil. H-NMR (500 MHz, CDCl3): d 7.81 (d,
J = 9.0 Hz, 1H, H11), 7.80 (d, J = 8.5 Hz, overlap, 1H),
Fig. 1 Effects of Z-Goniothalamin (Z-1a) on the viability of Jurkat
E6.1 cell as measured by MTT assay (data were given as mean SD
of three independent experiments)
7.78 (d, J = 8.5 Hz, 1H, H13/H16), 7.74 (s, 1H, H18),
123

Structure–activity relationship of Goniothalamin analogs
821
1H, H7), 4.70 (m, 2H, H6/H3), 3.84 (s, 3H, –OCH3),
2.15–2.05 (m, 1H, H4/H5), 2.03–1.96 (m, 1H, H4/H5),
1.93–1.88 (m, 1H, H4/H5), 1.85–1.75 (m, 1H, H4/H5)
ppm. 13C-NMR (125 MHz, CDCl3): d 143.60, 137.86,
132.24, 131.32, 129.30, 121.26, 114.14, 113.20, 100.52,
71.40, 55.18, 28.21, 19.38 ppm.
CDCl3): d 160.65, 143.59, 138.38, 132.43, 131.46, 106.79,
100.58, 99.82, 71.46, 55.31, 28.22, 19.43 ppm.
(E)-2-(2-(3,4-Dihydro-2H-pyran-2-yl)vinyl)pyridine (E-5f)
1
Light yellow oil. H-NMR (500 MHz, CDCl3): d 8.54 (dt,
J = 4.5, 1.0 Hz 1H, H11), 7.61 (td, J = 8.0, 2.0 Hz, 1H,
H13), 7.26 (d, J = 7.9 Hz, 1H, H14), 7.11 (ddd, J = 7.5,
5.0, 0.5 Hz, 1H, H12), 6.77 (dd, J = 15.8, 5.0 Hz, 1H, H7),
6.70 (d, J = 15.5 Hz, 1H, H8), 6.43 (d, J = 6.5 Hz, 1H,
H2), 4.74–4.70 (m, 1H, H6), 4.58–4.53 (m, 1H, H3),
2.17–2.07 (m, 1H, H4/H5), 2.05–1.97 (m, 2H, H4/H5),
1.82–1.75 (m, 1H, H4/H5) ppm. 13C-NMR (125 MHz,
CDCl3): 155.20, 149.54, 143.35, 136.49, 133.56, 129.97,
122.18, 121.91, 100.65, 74.63, 28.05, 19.29 ppm.
(E)-2-(4-Methoxystyryl)-3,4-dihydro-2H-pyran (E-5d)
1
Light yellow oil. H-NMR (500 MHz, CDCl3): d 7.35 (d,
J = 9.0 Hz, 2H, H10/H14), 6.87 (d, J = 8.5 Hz, 2H, H10/
H14), 6.61 (d, J = 15.9 Hz, 1H, H8), 6.46 (dd, J = 6.5,
2.6 Hz, 1H, H2), 6.15 (dd, J = 16.0, 6.5 Hz, 1H, H7), 4.74
(m, 1H, H6), 4.48 (m, 1H, H3), 3.83 (s, 3H, –OCH3),
2.20–2.10 (m, 1H, H4/H5), 2.09–1.96 (m, 2H, H4/H5),
1.75–1.65 (m, 1H, H4/H5) ppm. 13C-NMR (125 MHz,
CDCl3): d 143.54, 130.54, 127.70, 126.88, 113.99, 100.50,
75.53, 55.29, 37.10, 31.92, 30.03, 29.67, 28.42, 19.46 ppm.
(Z)-2-(2-(3,4-Dihydro-2H-pyran-2-yl)vinyl)pyridine (Z-5f)
1
Light yellow oil. H-NMR (500 MHz, CDCl3): d 8.57 (dt,
(Z)-2-(4-Methoxystyryl)-3,4-dihydro-2H-pyran (Z-5d)
J = 4.5, 1.0 Hz 1H, H11), 7.61 (td, J = 7.5, 1.5 Hz, 1H,
H13), 7.22 (d, J = 8.0 Hz, 1H, H14), 7.09 (ddd, J = 7.5,
5.0, 0.5 Hz, 1H, H12), 6.48 (dd, J = 12.0, 1.1 Hz, 1H, H8)
6.40 (dt, J = 6.5, 2.0 Hz, 1H, H2), 5.95 (dd, J = 12.0,
8.5 Hz, 1H, H7), 5.45 (tdd, J = 9.0, 2.0, 1.0 Hz, 1H, H6),
4.72–4.69 (m, 1H, H3), 2.20–2.12 (m, 1H, H4/H5),
2.11–2.05 (m, 1H, H4/H5), 2.03–1.96 (m, 1H, H4/H5),
1.82–1.78 (m, 1H, H4/H5) ppm. 13C-NMR (125 MHz,
CDCl3): d 155.68, 149.33, 143.42, 136.11, 129.14, 124.18,
121.56, 100.67, 72.31, 27.34, 19.40 ppm.
1
Light yellow oil. H-NMR (500 MHz, CDCl3): d 7.27 (d,
J = 9.5 Hz, 2H, H10/14), 6.91 (d, J = 8.5 Hz, 2H, H11/
H13), 6.59 (d, J = 11.6 Hz, 1H, H8), 6.46 (d, J = 6.2 Hz,
1H, H2), 5.69 (dd, J = 11.6, 9.1 Hz, 1H, H7), 4.74 (m, 2H,
H6/H3), 3.84 (s, 3H, –OCH3), 2.20–2.10 (m, 1H, H4/H5),
2.09–2.00 (m, 1H, H4/H5), 1.98–1.92 (m, 1H, H4/H5),
1.90–1.80 (m, 1H, H4/H5) ppm. 13C-NMR (125 MHz,
CDCl3): d 158.97, 143.68, 131.89, 130.11, 129.53, 129.15,
113.78, 100.44, 71.42, 55.26, 29.69, 28.25, 19.41 ppm.
(Z)-2-(4-Iodostyryl)-3,4-dihydro-2H-pyran (Z-5g)
(E)-2-(3,5-Dimethoxystyryl)-3,4-dihydro-2H-pyran (E-5e)
1
Light yellow liquid. H NMR (500 MHz, CDCl3) d ppm:
1
Light yellow oil. H-NMR (500 MHz, CDCl3): d 6.57 (d,
7.65 (dt, J = 8.5, 1.5 Hz, 2H), 7.02 (dt, J = 8.5, 1.5 Hz,
2H), 6.52 (d, J = 11.5 Hz, 1H), 6.39 (dt, J = 6.0, 1.0 Hz,
1H), 5.76 (dd, J = 11.5, 9.0 Hz, 1H), 4.71–4.67 (m, 1H),
4.60 (td, J = 8.5, 2.0 Hz, 1H), 2.12–2.04 (m, 1H, H4/H5),
2.031–1.955 (m, 1H, H4/H5), 1.97–1.85 (m, 1H, H4/H5),
1.83–1.75 (m, 1H, H4/H5) ppm.
J = 15.5 Hz, 1H, H8), 6.55 (s, 2H, H2), 6.44 (dt, J = 9.0,
1.8 Hz, 1H, H10/H14), 6.37 (d, J = 2.2 Hz, 1H, H12),
6.24 (dd, J = 16.0, 6.1 Hz, 1H, H7), 4.73 (m, 1H, H6),
4.48 (m, 1H, H3), 3.79 (s, 6H, 2 9 –OCH3), 2.17–2.10 (m,
1H, H4/H5), 2.07–1.97 (m, 2H, H4/H5), 1.82–1.75 (m, 1H,
H4/H5) ppm. 13C-NMR (125 MHz, CDCl3): d 160.94,
143.46, 138.81, 130.80, 129.64, 104.65, 100.58, 100.09,
75.15, 55.28, 29.69, 28.30, 19.39 ppm.
(Z)-2-(3-Fluorostyryl)-3,4-dihydro-2H-pyran (Z-5h)
1
Light yellow liquid. H NMR (500 MHz, CDCl3) d ppm:
(Z)-2-(3,5-Dimethoxystyryl)-3,4-dihydro-2H-pyran (Z-5e)
7.31–7.26 (m, 1H), 7.05 (d, J = 7.5 Hz, 1H), 7.02–6.92
(m, 2H), 6.57 (d, J = 11.5 Hz, 1H), 6.41 (d, J = 6.0 Hz,
1H), 5.78 (dd, J = 11.5, 9.0 Hz, 1H), 4.72–4.68 (m, 1H),
4.68–4.62 (m, 1H), 2.15–1.76 (m, 4H).
1
Light yellow oil. H-NMR (500 MHz, CDCl3): d 6.56 (d,
J = 11.5 Hz, 1H, H8), 6.46 (d, J = 2.2 Hz, 1H, H2), 6.41
(d, J = 6.2 Hz, 1H, H14/H10), 6.38 (t, J = 2.2 Hz, 1H,
H12), 5.73 (dd, J = 11.6, 9.1 Hz, 1H, H7), 4.70 (m, 1H,
H6/H3), 3.77 (s, 6H, 2 9 –OCH3), 2.13–2.03 (m, 1H, H4/
H5), 2.02–1.95 (m, 1H, H4/H5), 1.93–1.88 (m, 1H, H4/
H5), 1.85–1.75 (m, 1H, H4/H5) ppm. 13C-NMR (125 MHz,
(Z)-2-(2,3-Difluorostyryl)-3,4-dihydro-2H-pyran (Z-5i)
1
Light yellow liquid. H NMR (500 MHz, CDCl3) d ppm:
7.15–7.02 (m, 3H), 6.65 (d, J = 11.5 Hz, 1H), 6.42 (d,
123

822
M. Mohideen et al.
(E)-6-(2-(Naphthalen-2-yl)vinyl)-5,6-dihydro-2H-pyran-2-
J = 6.0 Hz, 1H), 5.76 (dd, J = 11.5, 9.5 Hz, 1H),
one (E-1b)
4.75–4.71 (m, 1H), 4.61–4.55 (m, 1H), 2.15–1.78 (m, 4H).
1
Light yellow oil (26 %). H NMR (500 MHz, CDCl3): d
(Z)-2-(3,4-Difluorostyryl)-3,4-dihydro-2H-pyran (Z-5j)
7.78 (m, 3H, H13, H16, H18), 7.73 (d, J = 5.5 Hz 1H,
H11), 7.57 (ddd J = 4.8, 2.7, 1.6 Hz, 1H, H10), 7.45 (m,
2H, H14/H15), 6.87 (d, J = 16.0 Hz, 1H), 6.41 (dd,
J = 15.9, 6.4 Hz, 1H, H7), 6.34 (dd, J = 15.9, 6.0 Hz, 1H,
H7), 6.10 (m, 1H, H3), 5.10 (m, 1H, H6), 2.61 (m, 2H, H5)
ppm. MS-TOF: m/z [M?Na]?; Calculated for C17H14O2:
273.0894; measured: 273.91.
1
Light yellow liquid. H NMR (500 MHz, CDCl3) d ppm:
7.15–7.07 (m, 2H), 7.03–6.98 (m, 1H), 6.51 (d,
J = 11.5 Hz, 1H), 6.41 (d, J = 6.5 Hz, 1H), 5.76 (dd,
J = 11.5, 9.0 Hz, 1H), 4.73–4.68 (m, 1H), 4.62–4.56 (m,
1H), 2.14–1.76 (m, 4H).
(Z)-2-(4-(Trifluoromethoxy)styryl)-3,4-dihydro-2H-pyran
(E)-6-(3,5-Dimethoxystyryl)-5,6-dihydro-2H-pyran-2-one
(Z-5k)
(E-1e)
1
Light yellow liquid. H NMR (500 MHz, CDCl3) d ppm:
1
Light yellow oil (13 %). H NMR (500 MHz, CDCl3): d
7.31 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.59
(d, J = 12.0 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 5.78 (dd,
J = 11.75, 9.5, 9.0 Hz, 1H), 4.73–4.68 (m, 1H), 4.65–4.59
(m, 1H), 2.15–1.76 (m, 4H).
6.95 (dq, J = 9.5, 6, 3 Hz, 1H, H4), 6.68 (d, J = 15.0 Hz,
1H, H8), 6.57 (d, J = 2.2 Hz, 2H, H10/H14), 6.43 (dd,
J = 2.9, 1.6 Hz, 1H, H12), 6.28 (ddd, J = 15.8, 6.0,
1.4 Hz, 1H, H7), 6.12 (d, J = 9.0 Hz, 1H, H3), 5.13 (m,
1H, H6), 3.83 (s, 6H, 2 9 –OCH3), 2.56 (m, 2H, H5) ppm.
MS-TOF: m/z [M?Na]?; Calculated for C15H16O4:
283.0946; measured: 283.0950.
General procedure for the preparation of Goniothalamin
Analogs 1a–k
t-Butyl hydroperoxide (55 %) (50 lL, 0.3 mmol) was
added to a stirring mixture of pyridinium dichromate
(PDC) (75 mg, 0.2 mmol) in CH2Cl2 (2 mL) at 0 °C and
the stirring was continued for 15 min. The resulting solu-
tion was quickly filtered over a cotton plug and the filtrate
was placed at -40 °C. To this solution, E-5 or Z-5
(0.11 mmol) in CH2Cl2 (1 mL) was added drop wise and
the reaction mixture was stirred at the same temperature for
2 h. A precipitate was formed, CH2Cl2 was evaporated
under reduced pressure and the solid residue was washed
with ether (5 mL). The crude products were purified by
flash chromatography on silica gel (EtOAc:n-hexane, 1:4)
to obtain compounds E-1a–k or Z-1a–k. The compounds
were characterized by NMR and mass spectroscopic data
as well as physical properties such as melting point.
(E)-6-(2-(Pyridin-2-yl)vinyl)-5,6-dihydro-2H-pyran-2-one
(E-1f)
Light yellow oil (18 %), Rf = 0.33, EtOAc:n-hexane (1:4).
1H NMR (500 MHz, CDCl3): d 8.56 (dt, J = 4.5, 1.0 Hz,
1H, H11), 7.61 (td, J = 7.7, 1.8 Hz, 1H, H13), 7.29 (d,
J = 7.9 Hz, 1H, H14), 7.12 (dq, J = 7.5, 4.8, 1.0 Hz, 1H,
H12), 6.82 (q, J = 15.8, 3H, H4/H7/H8), 6.41 (dt, J = 6.3,
1.8 Hz, 1H, H3), 4.82 (m, 1H, H6), 2.14 (m, 2H, H5) ppm.
13C NMR (125 MHz, CDCl3): 154.97, 149.59, 141.24,
136.43, 132.75, 131.57, 122.37, 122.31, 101.07, 100.92,
80.31, 29.68 ppm. MS-TOF: m/z [M?H]?; Calculated for
C12H11NO2: 202.0790; measured: 202.09.
(E)-2-(2-(6-(Tert-butylperoxy)-3,6-dihydro-2H-pyran-2-
yl)vinyl)pyridine (E-6f)
(E)-6-Styryl-5,6-dihydro-2H-pyran-2-one
(E-Goniothalamin, E-1a)
White crystals (3 %), Rf = 0.55, EtOAc:n-hexane (1:4). 1H
NMR (500 MHz, CDCl3): d 8.54 (dt, J = 4.5, 1.0 Hz, 1H,
H11), 7.61 (td, J = 8.0, 1.1 Hz, 1H, H13), 7.30 (d,
J = 8.0 Hz, 1H, H14), 7.11 (ddd, J = 8.0, 4.5, 1.5 Hz, 1H,
H12), 6.78 (d (overlaped), J = 3.7 Hz, 2H, H7/H8), 6.17
(m, 1H, H4), 5.72 (dm, 1H, H3), 5.54 (brs, 1H, H2), 4.68
(dt, J = 10, 4.0, 1H, H6), 2.19 (m, 2H, H5), 1.25 (s, 9H)
ppm. 13C NMR (125 MHz, CDCl3): 155.63, 149.25,
136.03, 135.79, 132.37, 129.71, 128.25, 124.28, 121.55,
121.07, 99.41, 97.58, 80.57, 68.97, 84.85, 60.36, 53.38,
29.69, 26.0 ppm. MS-TOF: m/z [M?H]?; Calculated for
C16H21NO3: 276.1521; measured: 276.15.
Yellow solid (78 %), mp. = 81 °C (80–82 °C, Schaus et al.
1998), Rf = 0.33, EtOAc:n-hexane (1:4). 1H NMR
(500 MHz, CDCl3): d 7.38 (d, J = 8 Hz, 2H, H10/H14)
7.32 (t, J = 7.5 Hz, 2H, H11/H13), 7.26 (t, J = 6.5 Hz, 1H,
H12), 6.91 (ddd, J = 9.8, 6.3, 2.4 Hz, 1H, H4), 6.71 (d,
J = 16.1 Hz, 1H, H8), 6.26 (dd, J = 16.0, 6.3 Hz, 1H, H7),
6.08 (dt, J = 10, 1.5 Hz, 1H, H3), 5.09 (m, 1H, H6), 2.53
(m, 2H, H5) ppm. 13C NMR (125 MHz, CDCl3): d 163.77,
144.43, 135.81, 133.16, 128.69, 128.36, 126.71, 125.69,
121.77, 77.90, 29.91 ppm. MS-TOF: m/z [M?Na]?; Cal-
culated for C13H12O2: 223.0761; measured: 223.10.
123

Structure–activity relationship of Goniothalamin analogs
823
(E)-2-(2-(Pyridin-2-yl)vinyl)-2H-pyran-4(3H)-one (E-7f)
(Z)-6-(2-(Naphthalen-2-yl)vinyl)-5,6-dihydro-2H-pyran-2-
one (Z-1b)
Light yellow solid (4 %), Rf = 0.40, EtOAc:n-hexane
(1:4). 1H NMR (500 MHz, CDCl3): d 8.56 (d, J = 4.8 Hz,
1H, H11), 7.66 (td, J = 7.5, 2 Hz, 1H, H13), 7.46 (dd,
J = 7.9, 0.9 Hz, 1H, H14), 7.30–7.22 (m, 1H, H7/H8),
7.15 (dq, J = 7.4, 4.9, 1.1 Hz, 1H, H12), 6.39 (m, 1H, H4),
5.99 (d, J = 9.1 Hz, 1H, H2), 4.88 (m, 1H, H3) 4.65 (dd,
J = 9.1, 0.7 Hz, 1H, H6), 2.43 (m, 2H, H5) ppm. 13C NMR
(125 MHz, CDCl3): 152.97, 141.59, 136.42, 122.33,
121.87, 102.71, 101.92, 80.53, 29.67 ppm. MS-TOF: m/
z [M?H]?; Calculated for C12H11NO2: 202.0790; mea-
sured: 202.0866.
Light yellow solid. (45 %). 1H NMR (500 MHz, CDCl3): d
7.81 (dd, J = 9.3, 4.6 Hz, 3H, H13/H16/H18), 7.74 (s, 1H,
H11), 7.47 (m, 2H, H10), 7.38 (dd, J = 8.5 Hz, 1.7 Hz,
1H, H14/H15), 6.90 (d, J = 11.5 Hz, 1H, H8), 6.85 (ddd,
J = 9.8, 5.6, 2.9 Hz, 1H, H4), 6.04 (ddd, J = 9.8, 2.5,
1.2 Hz, 1H, H3), 5.90 (dd, J = 11.5, 9.3 Hz, 1H, H7), 5.36
(m, 1H, H6), 2.49 (m, 2H, H5) ppm. 13C NMR (125 MHz,
CDCl3): d 163.96, 144.48, 134.90, 133.19, 132.74, 128.24,
128.21, 128.16, 127.74, 127.65, 126.47, 126.40, 121.70,
74.27, 29.82, 29.69 ppm. MS-TOF: m/z [M?H]?; Calcu-
lated for C17H14O2: 251.0994; measured: 251.1070.
(Z)-6-Styryl-5,6-dihydro-2H-pyran-2-one
(Z-Goniothalamin, Z-1a)
(Z)-6-(Tert-butylperoxy)-2-(2-(naphthalen-2-yl)vinyl)-3,6-
dihydro-2H-pyran (Z-6b)
Light yellow solid (84 %), Rf = 0.36, EtOAc:n-hexane (1:4).
83 °C. 1H NMR (500 MHz, CDCl3): d 7.34 (t, J = 8 Hz, 2H,
–Ph) 7.27(m, 3H, –Ph), 6.85 (ddd, J = 9.8, 5.6, 2.9 Hz, 1H,
H4), 6.75 (d, J = 11.5 Hz, 1H, H8), 6.03 (ddd, J = 9.8, 2.4,
1.2 Hz, 1H, H3), 5.81 (dd, J = 11.5, 9.3 Hz, 1H, H7), 5.28 (td,
J = 9.9, 4.6 Hz, 1H, H6), 2.47 (m, 2H, H5) ppm. 13C NMR
(125 MHz, CDCl3): d 163.81, 144.43, 135.69, 134.81, 128.61,
128.55, 121.70, 74.14, 29.79 ppm. MS-TOF: m/z [M?Na]?;
Calculated for C13H12O2: 223.0735; measured: 223.0734.
Low melting white crystal (5 %). 1H NMR (500 MHz,
CDCl3): d d 7.70 (m, 2H, H11/H13/H16/H18), 7.43 (ddd,
J = 14.2, 8.3, 4.9, 2H, H10/H14/H15), 6.75 (m, 1H, 1H, H8),
6.18 (m, 1H, H4), 6.12 (m, 1H, H4), 5.73 (dd, J = 11.5,
9.0 Hz, 1H, H7), 5.70–5.66(m, 1H, H7), 5.54(d,J = 10.2 Hz,
1H, H2), 5.33 (brs, 1H, H2), 5.03 (m, 1H, H3), 4.67 (m, 1H,
H6), 2.16 (m, 1H, H5), 1.73 (m, 1H, H5), 1.23 (d, 9H) ppm.
(Z)-6-(3-Methoxystyryl)-5,6-dihydro-2H-pyran-2-one
(Z)-6-(Tert-butylperoxy)-2-styryl-3,6-dihydro-2H-pyran
(Z-1c)
(Z-6a)
1
Light yellow oil (51 %). H NMR (500 MHz, CDCl3): d
White crystal (10 %), mp. 70 °C. 1H NMR (500 MHz,
CDCl3): d 7.40 (d, J = 7.7 Hz, 2H, H10/H14) 7.31 (t,
J = 7.6 Hz, 2H, H11/H13), 7.3 (m, J = 1H, H12) 6.62 (d,
J = 11.6 Hz, 1H, H8), 6.12 (m, 1H, H4), 5.68 (m,
J = 11.5, 9.0 2H, H7), 5.49 (brs, 1H, H2), 4.94 (td,
J = 10.5, 3.4 Hz, 1H, H3), 2.19 (m, 1H, H6), 2.06 (m, 1H,
H5), 1.20 (s, 9H, CH3) ppm. 13C NMR (125 MHz, CDCl3):
d 136.56, 132.64, 131.69, 131.13, 128.99, 128.18, 127.26,
121.36, 97.65, 80.51, 63.74, 30.63, 29.69, 26.45 ppm. MS-
TOF: m/z [M?Na]?; Calculated for C17H22O3: 297.1467;
measured: 297.1484.
7.25 (t, J = 7.7 Hz, 1H, H13), 6.84 (m, 4H, H10/H12/
H14), 6.72 (d, J = 11.6 Hz, 1H, H8), 6.03 (dd, J = 9.8,
4.0 Hz, 1H, H4), 5.81 (dd, J = 11.5, 9.3 Hz, 1H, H7), 5.29
(m, 1H, H3/H6), 3.79 (s, 3H, –OCH3), 2.45 (m, 2H, H5)
ppm. 13C NMR (125 MHz, CDCl3): d 159.69, 144.46,
137.05, 134.74, 129.56, 128.12, 121.68, 120.97, 114.07,
113.61, 74.17, 55.27, 29.77, 29.68, 14.07 ppm. MS-TOF:
m/z [M?H]?; Calculated for C14H14O3: 231.0943; mea-
sured: 231.1018.
(Z)-6-(4-Methoxystyryl)-5,6-dihydro-2H-pyran-2-one
(Z-1d)
(Z)-Styryl-2,3-dihydro-4H-pyran-4-one (Z-7a)
Light yellow solid (31 %). 1H NMR (500 MHz, CDCl3): d
7.21 (d, J = 9.5 Hz, 2H, H10/H14), 6.86 (d, J = 9.5 Hz,
2H, H11/H13), 6.86 (overlaped, 1H), 6.68 (d, J = 11.3 Hz,
1H, H8), 6.04 (dq, J = 9.8, 4.0, 2.4, Hz, 1H, H4), 5.71 (dd,
J = 11.5, 9.3 Hz, 1H, H7), 5.29 (m, 1H, H3/H6), 3.80 (s,
3H, –OCH3), 2.46 (m, 2H, H5) ppm. 13C NMR (125 MHz,
CDCl3): d 159.53, 144.54, 134.59, 130.03, 126.35, 121.71,
113.99, 74.28, 55.29, 29.85, 29.69 ppm. MS-TOF: m/
z [M?H]?; Calculated for C14H14O3: 231.043; measured:
231.1020.
Rf = 0.43, EtOAc/n-hexane (1:4), (5 mg, 6 %), low melt-
ing solid. 1H NMR (500 MHz, CDCl3): d 7.38 (d,
J = 6 Hz, 1 H H4), 7.36–7.18 (m, 5 H, Ph), 6.78 (d,
J = 11.5 1 H, H20), 5.83 (dd, J = 11.5, 9.5 Hz, 1 H, H10),
5.41 (dd, J = 6.0, 1.0 Hz, 1 H, H3), 5.32–5.24 (m, 1 H,
H6), 2.71 (dd, J = 17.0, 12.5 Hz, 1 H, H5), 2.53 (ddd,
J = 17.0, 4.0, 1.0 Hz, 1 H, H5) ppm. MS-TOF: m/
z [M?Na]?; Calculated for C13H12O2: 223.0837; mea-
sured: 223.0734.
123

824
M. Mohideen et al.
(Z)-6-(Tert-butylperoxy)-2-(4-methoxystyryl)-3,6-dihydro-
(Z)-2-(3,5-Dimethoxystyryl)-2H-pyran-4(3H)-one (Z-7e)
2H-pyran (Z-6d)
1
Light yellow solid (3 %). H NMR (500 MHz, CDCl3): d
White crystals (10 %). 1H NMR (500 MHz, CDCl3): d
7.41 (d, J = 8.7 Hz, 2H, H10/H14), 6.89 (d, J = 8.7 Hz,
2H, H11/H13), 6.59 (d, J = 11.6 Hz, 1H, H8), 6.16 (m,
1H, H4), 5.72 (m, 1H, H3), 5.63 (dd, J = 11.6, 8.9 Hz, 1H,
H7), 5.54 (brs, 1H, H2), 4.97 (m, 1H, H6), 3.83 (s, 3H,
–OCH3), 2.22 (m, 1H, H5), 2.10 (m, 1H, H5), 1.27 (s, 9H)
ppm. 13C NMR (125 MHz, CDCl3): 158.11, 131.81,
130.41, 129.48, 121.31, 113.64, 97.86, 80.55, 55.20, 30.73,
29.68, 29.34, 26.54 ppm. MS-TOF: m/z [M?Na]?; Cal-
culated for C18H24O4: 327.1572; measured: 327.1465.
7.41 (d, J = 6 Hz, 1H, H2), 6.77 (d, J = 12 Hz, 1H, H8),
6.50 (d, J = 2 Hz, 1H, H12), 6.44 (m, 2H, H10/H14), 5.86
(dd, J = 9.5, 1.5 Hz, 1H, H7), 5.63 (m, 1H), 5.45 (m, 1H,
H3), 3.81 (s, 6H, 2 9 –OCH3), 2.74 (dd, J = 16.5,
12.5 Hz, 1H, H5), 2.54 (m, 1H, H5) ppm.
(Z)-6-(2-(Pyridin-2-yl)vinyl)-5,6-dihydro-2H-pyran-2-one
(Z-1f)
Light yellow solid (56 %). 1H NMR (500 MHz, CDCl3): d
8.54 (d, J = 4.8 Hz, 1H, H11), 7.64 (td, J = 7.7, 1.9 Hz,
1H, H13), 7.20 (d, J = 2.6 Hz, 1H, H14), 7.12 (dd,
J = 7.6, 4.9 Hz, 1H, H12), 6.93 (dq, J = 9.8, 5.9, 2.5 Hz,
1H, H4), 6.48 (dd, J = 11.9, 1.4 Hz, 1H, H7/H8), 6.27 (m,
1H, H6), 6.02 (ddd, J = 4.3, 2.7, 1.1 Hz, 2H, H3), 2.90 (m,
1H, H5), 2.41 (m, 1H, H5) ppm. MS-TOF: m/z [M?H]?;
Calculated for C12H11NO2: 202.0790; measured: 202.0864.
(Z)-2-(4-Methoxystyryl)-2H-pyran-4(3H)-one (Z-7d)
1
Light yellow solid (8 %). H NMR (500 MHz, CDCl3): d
7.38 (dd, J = 6.0, 0.5 Hz, 1H, H2), 7.16 (d, J = 8.5 Hz,
2H, H10/H14), 6.87 (d, J = 8.5 Hz, 2H, H11/H13), 6.87
(overlaped, 1H), 6.71 (d, J = 11.6 Hz, 1H, H8), 5.73 (dd,
J = 11.5, 9.2 Hz, 1H, H7), 5.42 (dd, J = 6.1, 1.1 Hz, 1H,
H3), 3.80 (s, 3H, –OCH3), 2.71 (dd, J = 16.9, 13.2 Hz, 1H,
H5), 2.53 (dq, J = 8.8, 4.4, 3.3, 1 Hz, 1H, H5), ppm. 13C
NMR (125 MHz, CDCl3): d 163.10, 134.81, 129.97,
125.68, 114.06, 107.21, 75.88, 55.31, 42.09, 29.69,
14.09 ppm. MS-TOF: m/z [M?H]?; Calculated for
C14H14O3: 231.0943; measured: 231.0977.
(Z)-2-(2-(6-(Tert-butylperoxy)-3,6-dihydro-2H-pyran-2-
yl)vinyl)pyridine (Z-6f)
White crystals (2 %). 1H (NMR (500 MHz, CDCl3): d 8.55
(d, J = 4.8 Hz, 1H, H11), 7.60 (td, J = 8.0, 2.0 Hz, 1H,
H13), 7.38 (d, J = 7.9 Hz, 1H, H14), 7.08 (m, 1H, H12),
6.51 (d, J = 11.9 Hz, 1H, H8), 6.17 (m, 1H, H4), 5.92 (dd,
J = 11.9, 8.1 Hz, 1H, H7), 5.69 (m, 1H, H3), 5.49 (brs,
1H, H2), 5.45 (m, 1H, H6), 2.43 (m, 1H, H5), 2.13 (m, 1H,
H5), 1.23 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3): d
155.63, 149.25, 136.03, 132.37, 129.71, 124.28, 121.55,
121.07, 97.58, 80.57, 29.55, 26.47 ppm. MS-TOF: m/
z [M?H]?; Calculated for C16H21NO3 276.1521; mea-
sured: 276.1601.
(Z)-6-(3,5-Dimethoxystyryl)-5,6-dihydro-2H-pyran-2-one
(Z-1e)
Light yellow solid (37 %). 1H NMR (500 MHz, CDCl3): d
6.89 (ddd, J = 9.8, 5.6, 2.9 Hz, 1H, H4), 6.74 (d,
J = 11.5 Hz, 1H, H12), 6.46 (overlaped, 1H), 6.46 (d,
J = 2.2 Hz, 2H, H10), 6.06 (ddd, J = 9.8, 2.5, 1.2 Hz, 1H,
H8), 5.84 (dd, J = 11.4, 9.2 Hz, 1H, H7), 5.33 (m, 1H, H3/
H6), 3.83 (s, 6H, 2 9 –OCH3), 2.50 (m, 2H, H5) ppm. 13
C
(Z)-2-(2-(Pyridin-2-yl)vinyl)-2H-pyran-4(3H)-one (Z-7f)
NMR (125 MHz, CDCl3): d 160.85, 144.57, 137.61,
134.91, 128.25, 121.64, 106.60, 100.08, 74.20, 55.40,
29.77, 29.69 ppm. MS-TOF: m/z [M?Na]?; Calculated for
C15H16O4: 283.0948; measured: 283.0946.
1
Light yellow solid (1 %). H NMR (500 MHz, CDCl3): d
8.56 (d, J = 4.8 Hz, 1H, H11), 7.63 (td, J = 7.7, 1.8 Hz,
1H, H13), 7.37 (d, J = 6.0 Hz, 1H, H14), 7.18 (d,
J = 7.9 Hz, 1H, H2), 7.12 (dq, J = 7.5, 4.8, 0.9 Hz, 1H,
H12), 6.50 (d, J = 11.9 Hz, 1H, H8), 6.37 (m, 1H, H4),
6.03 (dd, J = 11.9, 7.5 Hz, 1H, H7), 5.44 (m, 1H, H3/H6),
2.91 (dd, J = 16.5, 4 Hz, 1H, H5), 2.61 (dd, J = 16.8,
13.1 Hz, 1H, H5) ppm. 13C NMR (125 MHz, CDCl3):
162.94, 149.52, 136.34, 132.36, 129.81, 124.56, 122.02,
107.34, 60.36, 53.37, 40.59, 29.69, 14.18 ppm. MS-TOF:
m/z [M?H]?; Calculated for C12H11NO2: 202.0790; mea-
sured: 202.0883.
(Z)-6-(Tert-butylperoxy)-2-(3,5-dimethoxystyryl)-3,6-
dihydro-2H-pyran (Z-6e)
1
White crystal (7 %). H NMR (500 MHz, CDCl3): d 6.73
(d, J = 11.5 Hz, 1H, H12), 6.52 (d, J = 2.2 Hz, 1H, H10),
6.43 (s, 1H), 6.38 (d, J = 2.0 Hz, 1H, H12), 6.11 (m, 1H,
H3), 5.68 (dd, J = 11.7, 8.9 Hz, 2H, H7), 5.46 (brs, 1H,
H2), 4.95 (m, 1H, H6), 3.77 (s, 6H, 2 9 –OCH3), 2.10 (m,
2H, H5), 1.23 (s, 9H) ppm.
123

Structure–activity relationship of Goniothalamin analogs
825
(Z)-6-(4-Iodostyryl)-5,6-dihydro-2H-pyran-2-one (Z-1g)
(Z)-6-(Tert-butylperoxy)-2-(3-fluorostyryl)-3,6-dihydro-
2H-pyran (Z-6h)
1
Light yellow solid (62 %). H NMR (500 MHz, CDCl3) d
ppm: 7.67 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H),
6.87–6.84 (ddd, J = 9.5, 5.5, 2.5 Hz, 1H), 6.65 (d,
J = 11.5 Hz, 1H), 6.03 (ddd, J = 9.5, 1.5, 1.0 Hz, 1H),
5.82 (dd, J = 11.5, 9.5 Hz, 1H), 5.22–5.16 (m, 1H),
2.52–2.36 (m, 2H). 13C NMR (500 MHz, CDCl3) d ppm:
163.60, 144.43, 137.71, 135.07, 133.85, 130.40, 128.63,
121.66, 93.71, 73.86 and 29.68. MS-TOF: m/z [M?H]?;
Calculated for C13H11IO2: 326.9804; measured: 326.9883.
White powder (12 %). 1H NMR (500 MHz, CDCl3) d ppm:
7.35–7.28 (m, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.17 (d,
J = 10.0 Hz, 1H), 6.98 (dt, J = 8.5, 2.5 Hz, 1H), 6.62 (d,
J = 11.5 Hz, 1H), 6.20–6.14 (m, 1H), 5.78 (dd, J = 11.5,
9.0 Hz, 1H), 5.75–5.70 (m, 1H), 5.53 (s, 1H), 4.98–4.91
(m, 1H), 2.27–2.19 (m, 1H), 2.13–2.05 (m, 1H), 1.26 (s,
9H). 13C NMR (500 MHz, CDCl3) d ppm: 163.77, 161.81,
138.62, 132.13, 131.62, 129.65, 124.82, 121.29, 115.70,
114.23, 97.67, 80.73, 63.47, 30.57, 26.37. MS-TOF: m/
z [M?Na]?; Calculated for C17H21FO3: 315.1372; mea-
sured: 315.1377.
(Z)-6-(Tert-butylperoxy)-2-(4-iodostyryl)-3,6-dihydro-2H-
pyran (Z-6g)
1
White powder (6 %). H NMR (500 MHz, CDCl3) d ppm:
(Z)-2-(3-Fluorostyryl)-2H-pyran-4(3H)-one (Z-7h)
7.63 (d, J = 8.5 Hz, 2H), 7.23 (dd, J = 8.0, 1.5 Hz, 1H),
7.18 (dd, J = 8.0, 1.5 Hz, 1H), 6.49 (d, J = 12.0 Hz, 1H),
6.14–6.09 (m, 1H), 5.74–5.65 (m, 2H), 5.49 (s, 1H),
4.88–4.82 (m, 1H), 2.21–2.13 (m, 1H), 2.06–1.98 (m, 1H),
1.23 (s, 9H). 13C NMR (500 MHz, CDCl3) d ppm: 137.35,
135.95, 131.89, 131.56, 130.94, 121.29, 97.85, 93.00,
80.66, 63.51, 30.61, 29.67, 26.47. MS-TOF: m/z [M?Na]?;
Calculated for C17H21IO3: 423.0433; measured: 423.0434.
1
Light yellow liquid (5 %). H NMR (500 MHz, CDCl3) d
ppm: 7.38 (d, J = 6.5 Hz, 1H), 7.34–7.28 (m, 1H),
7.02–6.97 (m, 2H), 6.94 (d, J = 9.5 Hz, 1H), 6.74 (d,
J = 11.5 Hz, 1H), 5.87 (dd, J = 11.5, 9.5 Hz, 1H), 5.43
(dd, J = 6.3, 1.0, 0.5 Hz, 1H), 5.26–5.19 (m, 1H), 2.71
(dd, J = 16.8, 13.5, 13.0 Hz, 1H), 2.54–2.48 (m, 1H). 13C
NMR (500 MHz, CDCl3) d ppm: 191.32, 163.76, 162.86,
161.79, 137.57, 134.00, 130.19, 128.33, 124.26, 115.24,
107.33, 75.42, 41.88. MS-TOF: m/z [M?H]?; Calculated
for C13H11FO2: 219.0743; measured: 219.0843.
(Z)-2-(4-Iodostyryl)-2H-pyran-4(3H)-one (Z-7g)
1
Light yellow liquid (3 %). H NMR (500 MHz, CDCl3) d
ppm: 7.68 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H),
6.96 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 11.5 Hz, 1H), 5.85
(dd, J = 11.5, 9.0 Hz, 1H), 5.42 (dd, J = 6.0, 1.0 Hz, 1H),
5.23–5.16 (m, 1H), 2.70 (dd, J = 16.8, 13.5, 13.0 Hz, 1H),
2.50 (dq, J = 16.9, 1.5, 1.0 Hz, 1H). 13C NMR (500 MHz,
CDCl3) d ppm: 191.29, 162.83, 137.77, 134.90, 134.13,
130.28, 128.02, 107.33, 93.85, 75.44, 41.90, 29.68. MS-
TOF: m/z [M?Na]?; Calculated for C13H11IO2: 348.9701;
measured: 348.9728.
(Z)-6-(2,3-Difluorostyryl)-5,6-dihydro-2H-pyran-2-one
(Z-1i)
1
Light yellow solid (58 %). H NMR (500 MHz, CDCl3) d
ppm: 7.13–7.01 (m, 3H), 6.88–6.83 (d, J = 8.0 Hz, 1H),
6.68 (d, J = 11.5 Hz, 1H), 6.03–5.94 (m, 2H), 5.14–5.07
(m, 1H), 2.53–2.39 (m, 2H). 13C NMR (500 MHz, CDCl3)
d ppm: 163.59, 148.84, 148.82, 144.36, 134.26, 133.59,
130.10, 128.68, 121.71, 121.46, 120.98, 73.78, 29.69. MS-
TOF: m/z [M?H]?; Calculated for C13H20F2O3: 259.0547;
measured: 259.0611.
(Z)-6-(3-Fluorostyryl)-5,6-dihydro-2H-pyran-2-one (Z-1h)
1
Light yellow solid (68 %). H NMR (500 MHz, CDCl3) d
(Z)-6-(Tert-butylperoxy)-2-(2,3-difluorostyryl)-3,6-
ppm: 7.33–7.28 (m, 1H), 7.05 (d, J = 8.0 Hz, 1H),
7.01–6.92 (m, 2H), 6.89–6.84 (m, 1H), 6.70 (d,
J = 11.5 Hz, 1H), 6.03 (ddd, J = 10.0, 1.5, 1.0 Hz, 1H),
5.85 (dd, J = 11.5, 9.5 Hz, 1H), 5.28–5.21 (m, 1H),
2.53–2.39 (m, 2H). 13C NMR (500 MHz, CDCl3) d ppm:
163.68, 161.76, 144.49, 137.73, 133.54, 130.16, 128.95,
124.37, 121.63, 115.43, 114.88, 73.86, 29.64. MS-TOF: m/
z [M?H]?; Calculated for C13H11FO2: 219.0743; mea-
sured: 219.0829.
dihydro-2H-pyran (Z-6i)
White powder (14 %). 1H NMR (500 MHz, CDCl3) d ppm:
7.41–7.36 (m, 1H), 7.10–6.99 (m, 2H), 6.64 (d,
J = 11.5 Hz, 1H), 6.14–6.09 (m, 1H), 5.89–5.83 (dd,
J = 11.75, 9.5, 9.0 Hz,1H), 5.69–5.64 (m, 1H), 5.48 (s,
1H), 4.80–4.74 (m, 1H), 2.23–2.15 (m, 1H), 2.07–2.00 (m,
1H), 1.24 (s, 9H). 13C NMR (500 MHz, CDCl3) d ppm:
151.52, 149.35, 147.16, 133.98, 131.59, 126.46, 125.93,
123

826
M. Mohideen et al.
124.34, 123.64, 121.24, 116.3, 97.61, 80.58, 63.79, 30.35,
26.42. MS-TOF: m/z [M?Na]?; Calculated for
C17H20F2O3: 333.1278; measured: 333.1277.
z [M?H]?; Calculated for C14H11F3O3: 285.0660; mea-
sured: 285.0733.
(Z)-6-(Tert-butylperoxy)-2-(4-(trifluoromethoxy)styryl)-
(Z)-6-(3,4-Difluorostyryl)-5,6-dihydro-2H-pyran-2-one
3,6-dihydro-2H-pyran (Z-6k)
(Z-1j)
1
White powder (8 %). H NMR (500 MHz, CDCl3) d ppm:
1
Light yellow solid (53 %). H NMR (500 MHz, CDCl3) d
7.53 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 6.65
(d, J = 11.5 Hz, 1H), 6.18 (m, 1H), 5.76 (dd, J = 11.5,
9.0 Hz, 1H), 5.73 (m, 1H), 5.55 (s, 1H), 4.91 (m, 1H), 2.25
(m, 1H), 2.09 (m, 1H), 1.28 (s, 9H). 13C NMR (500 MHz,
CDCl3) d ppm: 148.44, 135.09, 131.93, 131.67, 130.59,
121.52, 121.22, 120.68, 97.91, 80.71, 63.36, 30.68, 26.41.
MS-TOF: m/z [M?Na]?; Calculated for C18H21F3O4:
381.1290; measured: 381.1289.
ppm: 7.17–7.05 (m, 2H), 7.04–6.99 (m, 1H), 6.89–6.84 (m,
1H), 6.65 (d, J = 11.5 Hz, 1H), 6.07–6.03 (m, 1H), 5.84
(dd, J = 11.3, 9.5, 9.0 Hz, 1H), 5.22–5.16 (m, 1H),
2.54–2.39 (m, 2H). 13C NMR (500 MHz, CDCl3) d ppm:
163.52, 151.12, 149.13, 144.35, 132.74, 132.48, 128.86,
124.95, 121.72, 117.54, 73.64, 29.67. MS-TOF: m/z
[M?H]?; Calculated for C13H10F2O2: 237.0649; measured:
237.0729.
(Z)-2-(4-(Trifluoromethoxy)styryl)-2H-pyran-4(3H)-one
(Z)-6-(Tert-butylperoxy)-2-(3,4-difluorostyryl)-3,6-
(Z-7k)
dihydro-2H-pyran (Z-6j)
1
Light yellow liquid (5 %). H NMR (500 MHz, CDCl3) d
1
White powder (8 %). H NMR (500 MHz, CDCl3) d ppm:
ppm: 7.42 (d, J = 6.0 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H)
7.24 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 11.5 Hz, 1H), 5.92
(dd, J = 11.5, 9.0 Hz, 1H), 5.48 (dd, J = 6.3, 1.0, 0.5 Hz,
1H), 5.29–5.22 (m, 1H), 2.77 (dd, J = 17.0, 13.0 Hz, 1H),
2.56 (dq, J = 19.5, 6.5, 5.3, 3.8, 3.0, 1.0, 0.5 Hz, 1H). 13C
NMR (500 MHz, CDCl3) d ppm: 191.39, 162.91, 148.89,
134.09, 133.84, 130.03, 128.08, 121.44, 121.06, 107.34,
75.37, 39.28. MS-TOF: m/z [M?H]?; Calculated for
C14H11F3O3: 285.0660; measured: 285.0734.
7.36–7.30 (m, 1H), 7.20–7.15 (m, 1H), 7-12-7.05 (m, 1H),
6.53 (d, J = 11.5 Hz, 1H), 6.15–6.10 (m, 1H), 5.72–5.66
(m, 2H), 5.49 (s, 1H), 4.87–4.81 (m, 1H), 2.23–2.14 (m,
1H), 2.06–1.99 (m, 1H), 1.24 (s, 9H). 13C NMR (500 MHz,
CDCl3) d ppm: 150.95, 148.98, 133.36, 131.59, 125.47,
121.19, 117.90, 116.91, 97.97, 80.93, 63.19, 30.67, 26.36.
MS-TOF: m/z [M?Na]?; Calculated for C17H20F2O3:
333.1278; measured: 333.1318.
(Z)-2-(3,4-Difluorostyryl)-2H-pyran-4(3H)-one (Z-7j)
General procedure for the preparation of 10a–g
1
Light yellow liquid (6 %). H NMR (500 MHz, CDCl3) d
In a stirrer suspension of sodium hydride (NaH) in dry THF
at -40 °C was added Phosphonium salt 4 under nitrogen
atmosphere, stirrer were continue for 30 min, a solution of
aldehyde 9 (aldehyde 9 is unstable, conversion of alcohol
to aldehyde was confirmed by 1HNMR spectroscopy,
which was showing d at 9.58 ppm for aldehyde function-
ality) in dry THF (5 mL) was added drop wise. The reac-
tion mixture was stirred for 6 h at the same temperature
and was continued overnight at room temperature. Brine
was added to the reaction mixture followed by addition of
Et2O. The ether layers were collected and aqueous layer
were washed three time with ether, the combined organic
phases were dried over anhydrous MgSO4, evaporated,
residue was subjected to flash chromatography on silica gel
(EtOAc:n-hexane, 1:4, V/V) to afford E-/Z-isomer of 10.
ppm: 7.38 (d, J = 6.0 Hz, 1H), 7.17–7.10 (m, 1H),
7.09–7.03 (m, 1H), 6.97–6.92 (m, 1H), 6.68 (d,
J = 11.5 Hz, 1H), 5.85 (dd, J = 11.5, 9.0 Hz, 1H), 5.43
(dd, J = 6.0, 1.0 Hz, 1H), 5.21–5.14 (m, 1H), 2.74–2.66
(dd, J = 17.0, 13.0 Hz, 1H), 2.51 (dq, J = 16.8, 4.0,
3.5 Hz, 1H). 13C NMR (500 MHz, CDCl3) d ppm: 191.14,
162.73, 151.18, 149.19, 133.29, 132.38, 128.29, 124.84,
117.55, 107.40, 75.20, 41.86. MS-TOF: m/z [M?Na]?;
Calculated for C13H10F2O2: 259.0547; measured: 259.0612.
(Z)-6-(4-(Trifluoromethoxy)styryl)-5,6-dihydro-2H-pyran-
2-one (Z-1k)
1
Light yellow solid. H NMR (500 MHz, CDCl3) d ppm:
7.30 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H),
6.88–6.83 (m, 1H), 6.72 (d, J = 11.5 Hz, 1H), 6.06–6.02
(m, 1H), 5.85 (dd, J = 11.5, 9.0 Hz, 1H), 5.24–5.18 (m,
1H), 2.54–2.39 (m, 2H). 13C NMR (500 MHz, CDCl3) d
ppm: 163.59, 148.83, 144.36, 134.26, 133.59, 130.10,
128.68, 121.71, 121.46, 120.98, 73.78, 29.28. MS-TOF: m/
(E)-5-Styryldihydrofuran-2(3H)-one (E-10a)
1
Colorless powder (35 %). H NMR (500 MHz, CDCl3): d
7.37 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H),
7.28–2.26 (m, 1H), 6.67 (d, J = 16.0 Hz, 1H), 6.23 (dd,
123

Structure–activity relationship of Goniothalamin analogs
827
J = 16.0, 6.5 Hz, 1H), 5.13–5.08 (m, 1H), 2.60–2.56 (m,
2H), 2.50–2.42 (m, 1H), 2.12–2.05 (m, 1H). 13C NMR
(125 MHz, CDCl3): d 176.81, 135.68, 132.89, 128.71,
128.39, 126.72, 126.42, 80.63, 28.97, 28.53 ppm. MS-
TOF: m/z [M?H]?; Calculated for C12H13O2: 189.09;
measured: 189.09.
176.65, 137.83, 135.20, 131.69, 128.40, 127.31, 93.85,
80.26, 28.75, 28.43 ppm. MS-TOF: m/z [M?H]?; Calcu-
lated for C12H12O2 I: 314.9837; measured: 314.9879.
(Z)-5-(4-Iodostyryl)dihydrofuran-2(3H)-one (Z-10c)
White powder (22 %). 1H NMR (500 MHz, CDCl3): d 7.72
(d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.71 (d,
J = 11.5 Hz, 1H), 5.77 (dd, J = 11.5, 9.0 Hz, 1H),
5.25–5.22 (m, 1H), 2.69–2.55 (m, 2H), 2.49–2.42 (m, 1H),
2.13–2.05 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): d
176.70, 137.66, 135.02, 133.90, 130.47, 129.58, 93.71,
76.38, 29.30, 28.88 ppm. MS-TOF: m/z [M?H]?; Calcu-
lated for C12H12O2 I: 314.9837; measured: 314.9880.
(Z)-5-Styryldihydrofuran-2(3H)-one (Z-10a)
1
Colorless powder (16 %). H NMR (500 MHz, CDCl3): d
7.37 (t, J = 7.5 Hz, 2H) ppm, 7. 34 (t, J = 7.5 Hz, 1H),
7.22 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 11.5 Hz, 1H), 5.71
(dd, J = 11.5, 9.0 Hz, 1H), 5.31 (m, 1H), 2.69–2.53 (m,
2H), 2.51–2.44 (m, 1H), 2.25–2.15 (m, 1H) ppm. 13C NMR
(125 MHz, CDCl3): d 176.85, 135.64, 134.81, 128.85,
128.69, 128.48, 127.92, 77.90, 28.75, 28.43 ppm. MS-
TOF: m/z [M?H]?; Calculated for C12H13O2: 189.0916;
measured: 189.0922.
(E)-5-(3-Fluorostyryl)dihydrofuran-2(3H)-one (E-10d)
1
White solid (18 %). H NMR (500 MHz, CDCl3): d 7.28
(tdd, J = 7.8, 6.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.07
(dt, J = 10.0, 2.0 Hz, 1H), 6.96 (td, J = 8.5, 2.5 Hz, 1H),
6.64 (d, J = 15.8 Hz, 1H), 6.19 (dd, J = 15.8, 6.0 Hz,
1H), 5.10 (q, J = 6.0 Hz, 1H), 2.61–2.52 (m, 2H),
2.51–2.44 (m, 1H), 2.14–2.01 (m, 1H) ppm. 13C NMR
(125 MHz, CDCl3): d 176.64, 164.06, 138.04, 131.55,
130.24, 127.84, 122.66, 115.30, 113.24, 80.13, 28.77,
28.41. MS-TOF: m/z [M?H]?; Calculated for C12H12O2F:
207.0777; measured: 207.0831.
(E)-5-(2-(Naphthalen-2-yl)vinyl)dihydrofuran-2(3H)-one
(E-10b)
1
White solid (30 %). H NMR (500 MHz, CDCl3): d 7.78
(d, J = 8.5 Hz, 3H), 7.74 (s, 1H), 7.57 (dd, J = 8.5 Hz,
1H), 7.50–7.42 (m, 2H), 6.83 (d, J = 16.0 Hz, 1H,), 6.31
(dd, J = 16.0, 6.5 Hz, 1H) 5.20–5.14 (m, 1H), 2.64–2.58
(m, 2H), 2.55–2.45 (m, 1H), 2.16–2.09 (m, 1H) ppm. 13C
NMR (125 MHz, CDCl3): d 176.84, 133.48.133.32,
133.11, 133.01, 128.44, 128.11, 127.71, 127.18, 126.72,
126.48, 126.32, 123.36, 80.74, 28.94, 28.58 ppm. MS-
TOF: m/z [M?H]?; Calculated for C16H15O2: 239.0994;
measured: 239.1070.
(Z)-5-(3-Fluorostyryl)dihydrofuran-2(3H)-one (Z-10d)
1
White solid (16 %). H NMR (500 MHz, CDCl3): d 7.32
(tdd, J = 7.8, 6.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.99
(td, J = 10.0, 2.0 Hz, 1H), 6.94 (dt, J = 9.0, 2.0 Hz, 1H),
6.70 (d, J = 11.5 Hz, 1H), 6.75 (dd, J = 11.5, 9.0 Hz,
1H), 5.27–5.21 (m, 1H), 2.63–2.52 (m, 2H), 2.47–2.39 (m,
1H), 2.10–2.00 (m, 1H) ppm. 13C NMR (125 MHz,
CDCl3): d 176.66, 163.06, 137.68, 133.54, 130.09, 130.02,
124.46, 115.59, 114.96, 76.34, 29.27, 28.86. MS-TOF: m/
z [M?H]?; Calculated for C12H12O2F: 207.0777; mea-
sured: 207.0821.
(Z)-5-(2-(Naphthalen-2-yl)vinyl)dihydrofuran-2(3H)-one
(Z-10b)
1
White solid (15 %). H NMR (500 MHz, CDCl3): d 7.82
(d, J = 8.5 Hz, 3H), 7.71 (s, 1H), 7.48 (m, 2H), 7.37 (dd,
J = 8.5, 2.5 Hz, 2H), 6.91 (d, J = 11.5 Hz, 1H,), 5.79 (dt,
J = 11.5, 9.0 Hz, 1H) 5.40–4.31 (m, 1H), d 2.65–2.50 (m,
2H), 2.50–2.40 (m, 1H), 2.12–2.04 (m, 1H) ppm. 13C NMR
(125 MHz, CDCl3): d 176.89, 134.92, 133.16, 133.14,
132.75, 129.20, 128.15, 128.12, 127.81, 127.67, 126.50,
126.43, 76.84, 29.94, 28.98 ppm. MS-TOF: m/z [M?H]?;
Calculated for C16H15O2: 239.0994; measured: 239.1088.
(E)-5-(3-Iodostyryl)dihydrofuran-2(3H)-one (E-10e)
1
Colorless oil (18 %). H NMR (500 MHz, CDCl3): d 7.77
(t, J = 2.0 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.64 (d,
J = 7.5 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.95 (t,
J = 7.5 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.22 (dd,
J = 16.0, 6.5 Hz, 1H), 5.13 (m, 1H),), 2.64–2.58 (m, 2H),
2.54–2.49 (m, 1H), 2.14–2.07 (m, 1H) ppm. 13C NMR
(125 MHz, CDCl3): d 176.63, 137.90, 137.19, 135.53,
131.10, 130.35, 127.91, 126.01, 94.64, 80.11, 28.77,
28.40 ppm. MS-TOF: m/z [M?H]?; Calculated for
C12H12O2 I: 314.9837; measured: 314.9888.
(E)-5-(4-Iodostyryl)dihydrofuran-2(3H)-one (E-10c)
1
White solid (21 %). H NMR (500 MHz, CDCl3): d 7.69
(d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.62 (d,
J = 16.0 Hz, 1H), 6.23 (dd, J = 16.0, 6.5 Hz, 1H),
5.17–5.12 (m, 1H), 2.66–2.61 (m, 2H), 2.55–2.48 (m, 1H),
2.16–2.07 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): d
123

828
M. Mohideen et al.
(Z)-5-(3-Iodostyryl)dihydrofuran-2(3H)-one (Z-10e)
J = 11.5 Hz, 1H), 6.13 (dd, J = 11.5, 9.0 Hz, 1H), 5.08
(m, 1H),), 2.62–2.55 (m, 2H), 2.49–2.42 (m, 1H), 2.46 (s,
–SCH3, 3H) 2.12–2.035 (m, 1H) ppm. 13C NMR
(125 MHz, CDCl3): d 176.79, 139.02, 132.50, 132.35,
127.10, 126.53, 125.72, 80.70, 28.89, 28.56, 15.64 (–S–
CH3) ppm. MS-TOF; m/z [M?H]?; Calculated for
C13H15O2 S: 235.0748; measured: 235.0790.
White powder (20 %). 1H NMR (500 MHz, CDCl3): d 7.67
(d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.27 (dd, J = 8.0, 2.5 Hz,
1H), 7.23 (t, J = 8.0 Hz, 1H), 6.69 (d, J = 11.9 Hz, 1H),
5.78 (dd, J = 11.5, 7.0 Hz, 1H), 5.25 (m, 1H),), 2.68–2.58
(m, 2H), 2.50–2.42 (m, 1H), 2.12–2.05 (m, 1H) ppm. 13C
NMR (125 MHz, CDCl3): d 176.55, 137.74, 137.43, 136.89,
133.07, 130.16, 130.13, 127.82, 94.50, 76.26, 29.24,
28.82 ppm. MS-TOF: m/z [M?H]?; Calculated for
C12H12O2 I: 314.9837; measured: 314.9877.
Cytotoxicity assay
Each compound was tested in vitro against lympho-
blastic leukemic T cell Jurkat E6.1 cell. Cells were
prepared at 2 9 106 cells/mL. A twofold dilution of
compound [100 mM stock in phosphate-buffered saline
(PBS), penicillin/streptomycin] was prepared in a 96-
well plate in a series of concentration from 0 to 200 lM
(100 lL per well). Compounds were dissolved in
dimethyl sulfoxide (DMSO), filter sterilized, diluted at
the appropriate concentrations with the culture medium.
In all wells, 1 % DMSO concentration was fixed.
Dilutions of compounds were freshly prepared before
each experiment. Then, 100 lL of 2 9 106 cells/mL
was added to each well (final volume 200 lL of cells at
1 9 106 cells/mL treated with 0, 6.25, 12.5, 25, 50 and
100 lM compound). Cells were treated with the extracts
for 48 h and cytotoxic effects were determined by 3-
(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium
bromide based colorimetric assay. This method depends
on the cleavage of tetrazolium salt to purple formazan
crystals by mitochondrial enzymes of metabolically
active cells. After treatment incubation, 20 lL, 5 mg/mL
MTT (in PBS) was added to each well in dark. Briefly,
before the end of incubation period, medium of the cells
was removed and wells were washed by pre-warmed PBS
to remove any trace of compounds and to prevent color
interference while optical density determination. MTT
stock solution (5 mg/mL) were diluted to 1:10 ratio into
complete culture media, 150 lL of MTT dilution were
added into each well and incubated for 4 h at 37 °C.
After 3.5 h, plates were centrifuged at 1800 rpm for
15 min at 37 °C to avoid accidental removal of formazan
crystals. Crystals were dissolved with 100 lL DMSO.
The absorbance was determined at 570 nm using
microtiter plate reader. Results were represented as per-
centage of cell viability and calculated by the following
formula.
(E)-5-(4-Cyanostyryl)dihydrofuran-2(3H)-one (E-10f)
1
White solid (28 %). H NMR (500 MHz, CDCl3): d 7.61
(d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 6.69 (d,
J = 16.0 Hz, 1H), 5.31 (dd, J = 16.0, 6.0 Hz, 1H),
5.15–5.10 (m, 1H), 2.62–2.57 (m, 2H), 2.53–2.47 (m, 1H),
2.13–2.04 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): d
176.38, 140.13, 132.54, 130.61, 130.34, 127.19, 118.64,
111.72, 79.61, 28.65, 28.27 ppm. MS-TOF: m/z [M?H]?;
Calculated for C13H12O2 N: 214.0790; measured:
214.0877.
(Z)-5-(4-Cyanostyryl)dihydrofuran-2(3H)-one (Z-10f)
1
White solid (15 %). H NMR (500 MHz, CDCl3): d 7.65
(d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.75 (d,
J = 11.5 Hz, 1H), 5.85 (dd, J = 11.5, 9.5 Hz, 1H),
5.18–5.11 (m, 1H), 2.66–2.52 (m, 2H), 2.47–2.38 (m, 1H),
2.12–2.01 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): d
176.34, 140.11, 133.21, 132.29, 131.52, 129.35, 118.47,
111.76, 75.87, 29.18, 28.70 ppm. MS-TOF: m/z [M?H]?;
Calculated for C13H12O2 N: 214.0790; measured:
214.0827.
(E)-5-(4-Methylthiostyryl)dihydrofuran-2(3H)-one (E-10g)
1
White solid (15 %). H NMR (500 MHz, CDCl3): d 7.32
(d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.65 (d,
J = 15.5 Hz, 1H), 6.18 (dd, J = 15.5, 6.5 Hz, 1H), 5.13
(q, J = 7.0 Hz, 1H),), 2.65–2.59 (m, 2H), 2.52–2.46 (m,
1H), 2.50 (s, –SCH3, 3H), 2.16–2.08 (m, 1H) ppm. 13C
NMR (125 MHz, CDCl3): d 176.78, 139.03, 132.50,
132.35, 127.11, 126.53, 125.71, 80.07, 28.90, 28.56, 15.64
(–S–CH3) ppm. MS-TOF: m/z [M?H]?; Calculated for
C13H15O2 S: 235.0793; measured: 235.0785.
%viability ¼ ½ðODS ꢁ ODB=ODC ꢁ ODBÞ ꢂ 100ꢃ
(Z)-5-(4-(Methylthiostyryl)dihydrofuran-2(3H)-one
ODB indicated the optical density of blank, ODS indicated
the optical density of sample and ODC indicated the optical
density of control. Assays were performed in triplicate on
three independent experiments.
(Z-10g)
1
White solid (30 %). H NMR (500 MHz, CDCl3): d 7.29
(d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.61 (d,
123

Structure–activity relationship of Goniothalamin analogs
829
simple synthesis of a-pyrone, ( )-argentilactone and ( )-gonio-
thalamin. Tetrahedron Letters 30(18): 2429–2432.
Conclusion
Chien, A.L.T., and L.P. Azimahtol Hawariah. 2003. Styrylpyrone
derivative induces apoptosis through the up-regulation of bax in
the human breast cancer cell line MCF-7. Journal of Biochem-
istry and Molecular Biology 36: 269–274.
In conclusion, in contrast with the use of expensive
reagents and/or many steps, we have applied a short and an
efficient procedure for the synthesis of Goniothalamin
analogs. Commercially available inexpensive 3,4-dihydro-
2H-pyran-2-methanol/5-(hydroxymethyl)dihydrofuran-
2(3H)-one were used as starting materials for the prepa-
ration of aldehydes. Easy accessible reagents/catalysts/
solvents were used for the Wittig reaction. E/Z-isomers of
the precursor of Goniothalamin were easily separated by
flash column chromatography. A large number of Gonio-
thalamin analogs have been synthesized and evaluated for
their cytotoxicity against lymphoblastic leukemic T cell
line (Jurkat E6.1), and Z-Goniothalamin and Z-(4-triflu-
oromethoxy)-Goniothalamin were found the most potent in
cytotoxicity, whereas Z-(3-methoxy)-Goniothalamin and Z-
(3,5-dimethoxy)-Goniothalamin showed excellent cyto-
toxicity, compare with natural (E)-(?)-Goniothalamin.
ˆ
´
ˆ
De Fatima, A., L.K. Kohn, M.A. Antonio, J.E. De Carvalho, and R.A.
Pilli. 2005. (R)-Goniothalamin: Total syntheses and cytotoxic
activity against cancer cell lines. Bioorganic & Medicinal
Chemistry 13(8): 2927–2933.
ˆ
´
De Fatima, A., L.K. Kohn, J.E. De Carvalho, and R.A. Pilli. 2006a.
Cytotoxic activity of (S)-goniothalamin and analogues against
human cancer cells. Bioorganic & Medicinal Chemistry 14(3):
622–631.
ˆ
´
De Fatima, A., L.V. Modolo, L.S. Conegero, R.A. Pilli, C.V. Ferreira,
L.K. Kohn, and J.E. De Carvalho. 2006b. Styryl lactones and
their derivatives: Biological activities, mechanisms of action and
potential leads for drug design. Current Medicinal Chemistry
13(28): 3371–3384.
ˆ
´
De Fatima, A., and R.A. Pilli. 2003a. Enantioselective approach to the
asymmetric synthesis of (6R)-hydroxymethyl-5,6-dihydro-2H-
pyran-2-one. A formal synthesis of (R)-argentilactone and total
synthesis of (R)-goniothalamin (RR-820CP). Arkivoc 2003(10):
118–126.
ˆ
´
De Fatima, A., and R.A. Pilli. 2003b. Total syntheses of (R)-
argentilactone and (R)-goniothalamin via catalytic enantioselective
allylation of aldehydes. Tetrahedron Letters 44(48): 8721–8724.
Acknowledgments This work was supported by a Grant from the
Ministry of Science, Technology and Innovation, Malaysia (MOSTI)
(Biotech Grant Number-30600007001). Authors are thankful to Dr.
S. H. Inayat-Hussain and Dr. K. M. Chan for their cordial help on
cytotoxicity experiments.
ˆ
´
De Fatima, A., W.F. Zambuzzi, L.V. Modolo, C.A.B. Tarsitano, F.R.
Gadelha, S. Hyslop, J.E.D. Carvalho, I. Salgado, C.V. Ferreira,
and R.A. Pilli. 2008. Cytotoxicity of goniothalamin enantiomers
in renal cancer cells: Involvement of nitric oxide, apoptosis and
autophagy. Chemico-Biological Interactions 176(2–3): 143–150.
Drewes, S.E., M.M. Horn, and R.S. Shaw. 1995. A-pyrones and their
derivatives from two cryptocarya species. Phytochemistry 40(1):
321–323.
References
Du, H., J. Long, J. Hu, X. Li, and K. Ding. 2002. 3,30-Br2-BINOL-Zn
complex: A highly efficient catalyst for the enantioselective
hetero-Diels–Alder reaction. Organic Letters 4(24): 4349–4352.
El-Sharkawy, S., Z. Yusuf, L.P. Azimahtol Hawariah, and A.M. Ali.
1996. Metabolism of goniothalamin in animal and microbial
system. Bollettino Chimico Farmaceutico 135(1): 35–40.
El-Zayat, A.A.E., N.R. Ferrigni, T.G. Mccloud, A.T. Mckenzie, S.R.
Byrn, J.M. Cassady, C.-J. Chang, and J.L. Mclaughlin. 1985.
Goniothalenol: A novel, bioactive, tetrahydrofurano-2-pyrone
from Goniothalamus giganteus (Annonaceae). Tetrahedron
Letters 26(8): 955–956.
Fournier, L., P. Kocienski, and J.-M. Pons. 2004. The b-lactone route
to a,b-unsaturated d-lactones. Total syntheses of ( )-goniothal-
amin and (-)-massoialactone. Tetrahedron 60(7): 1659–1663.
Gillard, F., D. Heissler, and J.-J. Riehl. 1988. Synthesis of the 5,6-
dihydro-2-pyrone moiety of (?)-anamarin. Journal of the
Chemical Society, Perkin Transactions 10(8): 2291–2295.
Goh, S.H., G.C.L. Ee, C.H. Chuah, and C. Wei. 1995. Styrylpyrone
derivatives from Goniothalamus dolichocarpus. Australian
Journal of Chemistry 48(2): 199–205.
Ahmad, F.B., W.A. Tukol, S. Omar, and A.M. Sharif. 1991. 5-Acetyl
goniothalamin, a styryl dihydropyrone from Goniothalamus
uvaroides. Phytochemistry 30(7): 2430–2431.
Ali, A.M., M.M. Mckeen, M. Hamid, Q.B. Aun, Y. Zauyah, H.L.P.
Azimahtol, and K. Kawazu. 1997. Cytotoxicity and electron
microscopy of cell death induced by goniothalamin. Planta
Medica 63(01): 81–83.
Azimahtol Hawariah, L.P., M. Munawer, and L.B. Din. 1994. Anti-
fertility effect of goniothalamin: A styrylpyrone isolated from
Goniothalamus tapis miq. Asia Pacific journal of pharmacology
9(273–277): 273.
Azimahtol Hawariah, L.P., and J. Stanslas. 1998. Antagonistic effects
of styrylpyrone derivative (spd) on 7, 12, dimethylbenzanthra-
cene-induced rat mammary tumors. In vivo 12(4): 403–410.
Cao, S.-G., X.-H. Wu, K.-Y. Sim, B.K.H. Tan, J.T. Pereira, and S.-H. Goh.
1998. Styryl-lactone derivatives and alkaloids from Goniothalamus
borneensis (Annonaceae). Tetrahedron 54(10): 2143–2148.
Cavalheiro, A.J., and M. Yoshida. 2000. 6-[x-Arylalkenyl]-5,6-
dihydro-a-pyrones from Cryptocarya moschata (Lauraceae).
Phytochemistry 53(7): 811–819.
Chan, K.M., N.F. Rajab, M.H.A. Ishak, A.M. Ali, K. Yusoff, L.B.
Din, and S.H. Inayat-Hussain. 2006. Goniothalamin induces
apoptosis in vascular smooth muscle cells. Chemico-Biological
Interactions 159(2): 129–140.
Chen, W.-Y., C.-C. Wu, Y.-H. Lan, F.-R. Chang, C.-M. Teng, and Y.-
C. Wu. 2005. Goniothalamin induces cell cycle-specific apop-
tosis by modulating the redox status in MDA-MB-231 cells.
European Journal of Pharmacology 522(1–3): 20–29.
Chidambaram, N., K. Satyanarayana, and S. Chandrasekaran. 1989. A
general approach to the synthesis of 5,6-dihydro-2(2H)pyranones;
Grubbs, R.H. 2004. Olefin metathesis. Tetrahedron 60(34): 7117–7140.
Gruttadauria, M., P. Lo Meo, and R. Noto. 2004. Short and efficient
chemoenzymatic synthesis of goniothalamin. Tetrahedron Let-
ters 45(1): 83–85.
Harsh, P., and G.A. O’doherty. 2009. De novo asymmetric syntheses of
(?)-goniothalamin, (?)-goniothalamin oxide, and 7,8-bis-epi-
goniothalamin using asymmetric allylations. Tetrahedron 65(26):
5051–5055.
Hasan, C.M., M.A. Hussain, M.Y. Mia, and M.A. Rashid. 1995.
Goniothalamin from Goniothalamus sesquipedalis. Fitoterapia
4: 378–379.
123

830
M. Mohideen et al.
Hlubucek, J.R., and A.V. Robertson. 1967. (?)-(5S)-d-Lactone of
5-hydroxy-7-phenylhepta-2,6-dienoic acid, a natural product
from Cryptocarya caloneura (Scheff.) Kostermans. Australian
Journal of Chemistry 20(10): 2199–2206.
Inayat-Hussain, S.H., B.O. Annuar, L.B. Din, A.M. Ali, and D. Ross.
2003. Loss of mitochondrial transmembrane potential and
caspase-9 activation during apoptosis induced by the novel
styryl-lactone goniothalamin in HL-60 leukemia cells. Toxicol-
ogy in Vitro 17(4): 433–439.
Inayat-Hussain, S.H., K.M. Chan, N.F. Rajab, L.B. Din, S.C. Chow,
A. Kizilors, F. Farzaneh, and G.T. Williams. 2010. Goniothal-
amin-induced oxidative stress, DNA damage and apoptosis via
caspase-2 independent and Bcl-2 independent pathways in jurkat
T-cells. Toxicology Letters 193(1): 108–114.
O’connor, B., and G. Just. 1986. Syntheses of argentilactone 11 and
goniothalamin 15. Tetrahedron Letters 27(43): 5201–5202.
´ˇ
´
Pospısil, J., and I.E. Marko. 2006. Total synthesis of (R)-(?)-
goniothalamin and (R)-(?)-goniothalamin oxide: First applica-
tion of the sulfoxide-modified Julia olefination in total synthesis.
Tetrahedron Letters 47(33): 5933–5937.
Quitschalle, M., M. Christmann, U. Bhatt, and M. Kalesse. 2001.
Synthesis of unsaturated lactone moieties by asymmetric hetero
Diels–Alder reactions with binaphthol–titanium complexes.
Tetrahedron Letters 42(7): 1263–1265.
Rajab, N.F., Z.A. Hamid, H. Hassan, A.M. Ali, L.B. Din, and S.H.
Inayat-Hussain. 2005. Evaluation of the cytotoxic and genotoxic
effects of goniothalamin in leukemic cell lines. Environmental
Mutagen Research 27(3): 161–164.
Inayat-Hussain, S.H., A.B. Osman, L.B. Din, A.M. Ali, R.T.
Snowden, M. Macfarlane, and K. Cain. 1999. Caspases-3 and -
7 are activated in goniothalamin-induced apoptosis in human
jurkat T-cells. FEBS Letters 456(3): 379–383.
Ram Reddy, M.V., H.C. Brown, and P.V. Ramachandran. 2001.
Asymmetric allylboration for the synthesis of b-hydroxy-d-
lactone unit of statin drug analogs. Journal of Organometallic
Chemistry 624(1–2): 239–243.
Inayat-Hussain, S.H., L.T. Wong, K.M. Chan, N.F. Rajab, L.B. Din,
R. Harun, A. Kizilors, N. Saxena, M. Mourtada-Maarabouni, F.
Farzaneh, and G.T. Williams. 2009. RACK-1 overexpression
protects against goniothalamin-induced cell death. Toxicology
Letters 191(2–3): 118–122.
Ramachandran, P.V., M.V.R. Reddy, and H.C. Brown. 2000.
Asymmetric synthesis of goniothalamin, hexadecanolide, mas-
soia lactone, and parasorbic acid via sequential allylboration–
esterification ring-closing metathesis reactions. Tetrahedron
Letters 41(5): 583–586.
´
´
Jagtap, P.G., Z. Chen, K. Koppetsch, E. Piro, P. Fronce, G.J. Southan, and
K.-N. Klotz. 2009. Synthesis of (R)-3,4-dihydro-2H-pyran-2-car-
boxaldehyde: Application to the synthesis of potent adenosine A2A
and A3 receptor agonist. Tetrahedron Letters 50(22): 2693–2696.
Jewers, K., J.B. Davis, J. Dougan, A.H. Manchanda, G. Blunden, A.
Kyi, and S. Wetchapinan. 1972. Goniothalamin and its distribu-
tion in four goniothalamus species. Phytochemistry 11(6):
2025–2030.
Kabir, K.E., A.R. Khan, and M.A. Mosaddik. 2003. Goniothalamin—
a potent mosquito larvicide from Bryonopsis laciniosa L.
Journal of Applied Entomology 127(2): 112–115.
Lan, Y.-H., F.-R. Chang, J.-H. Yu, Y.-L. Yang, Y.-L. Chang, S.-J. Lee,
and Y.-C. Wu. 2003. Cytotoxic styrylpyrones from Goniothala-
mus amuyon L. Journal of Natural Products 66(4): 487–490.
Lee, A.T., L.P. Azimahtol Hawariah, H.L. Azimahtol, and A.N. Tan.
2003. Styrylpyrone derivative (SPD) induces apoptosis in a
caspase-7-dependent manner in the human breast cancer cell line
MCF-7. Cancer Cell International 3: 1–8.
Leßmann, T., M.G. Leuenberger, S. Menninger, M. Lopez-Canet, O.
Mu¨ller, S. Hu¨mmer, J. Bormann, K. Korn, E. Fava, M. Zerial,
Thomas U. Mayer, and H. Waldmann. 2007. Natural product-
derived modulators of cell cycle progression and viral entry by
enantioselective oxa Diels–Alder reactions on the solid phase.
Chemistry & Biology 14(4): 443–451.
Meenakshii, N., A. Lee, H.L.P. Azimahtol, and S. Hasidah. 2000.
Increased levels of apoptosis correlate with p53 protein
accumulation in response to styrylpyrone derivative (SPD)
treatment of the ‘‘Huggins Tumor’’. Malaysian Applied Biology
29(1 & 2): 121–126.
Mereyala, H.B., and M. Joe. 2001. Cytotoxic activity of styryl
lactones and their derivatives. Current Medicinal Chemistry—
Anti-Cancer Agents 1(3): 293–300.
Mondon, M., and J.-P. Gesson. 2006. Asymmetric synthesis of styryl-
lactones. Current Organic Synthesis 3(1): 41–75.
RodrıGuez, J.G., R. Martın-Villamil, and A. Lafuente. 2003. P-
Extended conjugate phenylacetylenes Synthesis of 4-[(E) and
(Z)-2-(4-ethenylphenyl)ethenyl]pyridine. Dimerization, quater-
nation and formation of charge–transfer complexes. Tetrahedron
59(7): 1021–1032.
Sabitha, G., K. Sudhakar, and J.S. Yadav. 2006. Application of the
cosford cross-coupling protocol for the stereoselective synthesis
of (R)-(?)-goniothalamin, (R)-(?)-kavain and (S)-(?)-7,8-di-
hydrokavain. Tetrahedron Letters 47(48): 8599–8602.
Sam, T.W., C. Sew-Yeu, S. Matsjeh, E.K. Gan, D. Razak, and A.L.
Mohamed. 1987. Goniothalamin oxide: An embryotoxic com-
pound from Goniothalamus macrophyllus (Annonaceae). Tetra-
hedron Letters 28(22): 2541–2544.
˚
Schaus, S.E., J. Branalt, and E.N. Jacobsen. 1998. Asymmetric hetero-
Diels–Alder reactions catalyzed by chiral (salen)chromium(III)
complexes. The Journal of Organic Chemistry 63(2): 403–405.
Schmidt, B. 2004. Ruthenium-catalyzed olefin metathesis double-
bond isomerization sequence. The Journal of Organic Chemistry
69(22): 7672–7687.
Sun, B., J. Hoshino, K. Jermihov, L. Marler, J.M. Pezzuto, A.D.
Mesecar, and M. Cushman. 2010. Design, synthesis, and
biological evaluation of resveratrol analogues as aromatase and
quinone reductase 2 inhibitors for chemoprevention of cancer.
Bioorganic & Medicinal Chemistry 18(14): 5352–5366.
Sundby, E., L. Perk, T. Anthonsen, A. Jørgen Aasen, and T. Vidar
Hansen. 2004. Synthesis of (?)-goniothalamin and its enantio-
mer by combination of lipase catalyzed resolution and alkene
metathesis. Tetrahedron 60(3): 521–524.
Tanaka, S., S. Yoichi, L. Ao, M. Matumoto, K. Morimoto, N.
Akimoto, G. Honda, M. Tabata, T. Oshima, T. Masuda, M. Zaini
Bin Asmawi, Z. Ismail, S.M. Yusof, L.B. Din, and I.M. Said.
2001. Potential immunosuppressive and antiinflammatory activ-
ities of Malaysian medicinal plants characterized by reduced cell
surface expression of cell adhesion molecules. Phytotherapy
Research 15(8): 681–686.
Teoh, P.L., and L.P. Azimahtol Hawariah. 1999. Effects of
styrylpyrne derivative (SPD) on expression of Bcl-2 and box
genes in human ovarian carcinoma cell line, Caov-3. Malaysian
Applied Biology 28(1 & 2): 107–111.
Mosaddik, M.A., M. Ekramul Haque, and M. Abdur Rashid. 2000.
Goniothalamin from Bryonopsis laciniosa linn (cucurbiataceae).
Biochemical Systematics and Ecology 28(10): 1039–1040.
Mosaddik, M.A., and M.E. Haque. 2003. Cytotoxicity and antimi-
crobial activity of goniothalamin isolated from Bryonopsis
laciniosa. Phytotherapy Research 17(10): 1155–1157.
Mu, Q., W.D. Tang, R.Y. Liu, C.M. Li, L.G. Lou, H.D. Sun, and C.Q.
Hu. 2003. Constituents from the stems of Goniothalamus
griffithii. Planta Medica 69(09): 826–830.
Wyatt, P., A. Hudson, J. Charmant, A.G. Orpen, and H. Phetmung.
2006. Synthesis and chemistry of enantiomerically pure 10,11-
dihydrodibenzo[b,f]thiepines. Organic & Biomolecular Chemis-
try 4(11): 2218–2232.
123

Structure–activity relationship of Goniothalamin analogs
831
Zauyah, Y., A.H. Lope Pihie, R.M. Noah, and J. Stanslas. 1997.
Cytotoxicity of goniothalamin on hormone-dependent breast
cancer cells. Malaysian Journal of Biochemistry and Molecular
Biology 2: 29–32.
Zhang, W., and M.L. Go. 2007. Quinone reductase induction activity
of methoxylated analogues of resveratrol. European Journal of
Medicinal Chemistry 42(6): 841–850.
styryl-lactone derivatives. Chemical & Pharmaceutical Bulletin
53(11): 1387–1391.
Zhou, Z.-L., and J.F.W. Keana. 1999. A practical synthesis of 4-(substi-
tuted-benzyl)piperidines and ( )-3-(substituted-benzyl)pyrrolidines
via a wittig reaction. The Journal of Organic Chemistry 64(10):
3763–3766.
Zhou, F.S., W.D. Tang, Q. Mu, G.X. Yang, Y. Wang, G.L. Liang, and
L.G. Lou. 2005. Semisynthesis and antitumor activities of new
123