Structure-activity relationship of C5-curcuminoids and synthesis of their molecular probes thereof

Article abstract of DOI:10.1016/j.bmc.2009.12.045

A series of novel analogues of 1,5-bis(4-hydroxy-3-methoxyphenyl)-penta-(1E,4E)-1,4-dien-3-one (C₅-curcumin), which is a natural analogue of curcumin isolated from the rhizomes of Curcuma domestica Val. (Zingiberacea), were synthesized and evaluated for their cytotoxicities against human colon cancer cell line HCT-116 to conclude the SAR of C₅-curcuminoids for further development of their use in cancer chemotherapy: (1) Bis(arylmethylidene)acetone serves as a promising skeleton for eliciting cytotoxicity. (2) The 3-oxo-1,4-pentadiene structure is essential for eliciting cytotoxicity. (3) As for the extent of the aromatic substituents, hexasubstituted compounds exhibit strong activities, in which 3,4,5-hexasubstitution results in the highest potency. (5) The symmetry between two aryl rings is not an essential requirement for bis(arylmethylidene)acetones to elicit cytotoxicity. (6) para-Positions allows the installation of additional functional groups for use as molecular probes. By taking advantage of the SAR diagram, we have elaborated several advanced derivatives having GI₅₀ of single-digit micromolar potencies that will function as molecular probes to target and/or report key biomolecules interacting with curcumin and C₅-curcumin.

Full text of DOI:10.1016/j.bmc.2009.12.045

Bioorganic & Medicinal Chemistry 18 (2010) 1083–1092
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Structure–activity relationship of C5-curcuminoids and synthesis of their
molecular probes thereof
Hiroyuki Yamakoshi a, Hisatsugu Ohori b, Chieko Kudo b, Atsuko Sato b, Naoki Kanoh a, Chikashi Ishioka b,
Hiroyuki Shibata c, Yoshiharu Iwabuchi a,
*
a Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aobayama, Sendai, Japan
b Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
c Department of Clinical Oncology, Akita University Hospital, Akita, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel analogues of 1,5-bis(4-hydroxy-3-methoxyphenyl)-penta-(1E,4E)-1,4-dien-3-one (C5-
curcumin), which is a natural analogue of curcumin isolated from the rhizomes of Curcuma domestica
Val. (Zingiberacea), were synthesized and evaluated for their cytotoxicities against human colon cancer
cell line HCT-116 to conclude the SAR of C5-curcuminoids for further development of their use in cancer
chemotherapy: (1) Bis(arylmethylidene)acetone serves as a promising skeleton for eliciting cytotoxicity.
(2) The 3-oxo-1,4-pentadiene structure is essential for eliciting cytotoxicity. (3) As for the extent of the
aromatic substituents, hexasubstituted compounds exhibit strong activities, in which 3,4,5-hexasubstitu-
tion results in the highest potency. (5) The symmetry between two aryl rings is not an essential require-
ment for bis(arylmethylidene)acetones to elicit cytotoxicity. (6) para-Positions allows the installation of
additional functional groups for use as molecular probes. By taking advantage of the SAR diagram, we
have elaborated several advanced derivatives having GI50 of single-digit micromolar potencies that will
function as molecular probes to target and/or report key biomolecules interacting with curcumin and C5-
curcumin.
Received 1 October 2009
Revised 16 December 2009
Accepted 17 December 2009
Available online 23 December 2009
Keywords:
Curcumin
C5-curcumin
Bis(arylmethylidene)acetones
Cytotoxicity
Cancer chemotherapy
Molecular probe
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
gets of curcumin acquire enhanced sensitivity by oncological
transformation.2 However, clinical trials on the oral administration
Turmeric, a yellow powder derived from the rhizome of the
herb Curcuma longa L., has long been used as an essential spice
and a traditional medicine in China and India. Over a long period
of study, its major active constituent curcumin has been found to
exhibit various biological and pharmacological activities including
anti-inflammatory, antioxidant, antimicrobial, antiviral, chemo-
preventive, antiangiogenic, and anticancer activities,1 through
interactions with various biomolecules and biochemical pathways2
of curcumin have revealed the low bioavailability of curcumin ow-
ing to its poor absorption.12,13 Hence, much effort has been de-
voted to developing useful derivatives to not only circumvent its
low bioavailability while maintaining its low toxicity, but also en-
hance its selectivity and potency for addressing the pathological
diversity of human cancer.14–18
Previously, we conducted a screening of an in-house library of
synthetic compounds to obtain clues to enhancing the potential
of dietary phytochemicals, and found two interesting compounds,
namely, GO-035 and GO-949, from a curcumin panel (Fig. 1): GO-
035 exhibits a high cytotoxicity against the human colon cancer
including transcriptional factors (e.g., NF-j
B),3 cell proliferation
pathways (e.g., cyclin D1, and c-myc),4,5 cell survival pathways
(e.g., Bcl-2, Bcl-xL, and cFLIP),6 caspase activation pathways (e.g.,
caspase-8, caspase-3, and caspase-9),7 tumor suppressor pathways
(e.g., p53 and p21),8 death receptor pathways (e.g., DR4 and DR5),9
mitochondrial pathways, and protein kinase pathways (e.g., JNK,
Akt, and AMPK).10,11
The multitargeting feature of curcumin has been considered to
be of special merit for cancer chemoprevention and pharmacother-
apy in light of the evidence that curcumin acts on numerous
biochemical cascades leading to apoptosis, where the cellular tar-
line DLD-1 with a GI50 of 2.0
tent than curcumin (GI50, 8 M), whereas GO-949 shows an atten-
uated GI50 >50
M, which is less than 1/5 that of curcumin.19
lM, which was four times more po-
l
l
We were particularly interested in the fact that a small differ-
ence of just one C1 unit at both the peripherals of 1,5-diaryl-3-
oxo-1,4-pentadiene [bis(arylmethylidene)acetone] brings about
such a significant (>20-fold) difference between their potencies.
Another important fact to emphasize is that GO-035 (1,5-
bis(3,4-dimethoxyphenyl)-(1E,4E)-1,4-pentadien-3-one) is a close
derivative of a natural five-carbon analogue of curcumin, namely
1,5-bis(4-hydroxy-3-methoxyphenyl)-(1E,4E)-1,4-pentadien-3-one
* Corresponding author.
E-mail address: iwabuchi@mail.pharm.tohoku.ac.jp (Y. Iwabuchi).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.12.045

1084
H. Yamakoshi et al. / Bioorg. Med. Chem. 18 (2010) 1083–1092
O
OH
O
MeO
HO
OMe
OH
MeO
HO
OMe
OH
curcumin
*GI50 = 8.0 µM
C5-curcumin
O
C5-curcuminoids
Ar
MeO
OMe
O
MeO
OMe
Ar'
GO-035
1,5-diaryl-3-oxo-1,4-pentadiene motif
O
*GI50 = 2.0 µM
O
O
O
O
O
Ar
Ar'
bis(arylmethylidene)acetones
GO-949
*GI50 > 50 µM
*Cell growth inhibition against DLD-1
Figure 1.
(Fig. 1), of which the isolation from the rhizome of Curcuma domes-
tica Val. and the antioxidative and anti-inflammatory activities
were reported in 1993 by Masuda et al.;20 however, little is known
about its anticancer activity. (In relation to diarylheptanoid curcu-
min, we refer to this natural diarylpentanoid, 1,5-bis(4-hydroxy-3-
methoxyphenyl)-(1E,4E)-1,4-pentadien-3-one,20,21 as ‘C5-curcumin’
hereafter.) Encouraged by this information, we synthesized and
tested the growth-suppressive ability of >50 synthetic analogues
of C5-curcumin to obtain potentially useful analogues, namely,
GO-Y030 and GO-Y031 (Fig. 2):19 both compounds inhibit the
Wnt/b-catenin pathway, whereby they induce the downregulation
ify the comprehensive SAR of C5-curcuminoids for further
development. We also envisioned the development of molecular
probes based on GO-Y030/GO-Y031 to search for possible specific
cellular targets.
In this work, we describe the comprehensive SAR of bis(aryl-
methylidene)acetones and the synthesis of molecular probes for
future chemical biology studies.
2. Results and discussion
2.1. Chemistry
of b-catenin, Ki-Ras, Cyclin D1, c-Myc, and ErbB-2 at 2.5 lM, which
correspond to at least 1/8 the curcumin concentration.19,22 Impor-
tantly, the oral administration of GO-Y030 has been confirmed to
induce a significantly improved chemopreventive ability in the
FAP (familial adenomatous polyposis) mouse with no apparent
toxicity in vivo.23
r
-Symmetric 1,5-diaryl-3-oxo-1,4-pentadienes were synthe-
sized on the basis of the aldol condensation of modified benzalde-
hydes with acetone using established procedures (Scheme 1). The
aldol condensation of a bicycloketone with arylaldehyde was at-
tained by the phase transfer catalysis of hexadecyltrimethylammo-
nium bromide. Asymmetric bis(arylmethylidene)acetones were
synthesized in a two-step aldolization sequence via an aryl methyl
ketone, of which the synthesis relied on Gupta’s golden ratio
employing 1:4 of aryl aldehyde/acetone.24 The optimal monoaldo-
lization of trimethoxybenzaldehydes with acetone was attained
under Strauss’s conditions using dimethylammonium dimethyl
carbamate in CH2Cl2.25 The monoenone GO-Y087 was synthesized
by Saegusa oxidation26 of GO-Y041.
The observation of quite a huge difference in cytotoxicity
depending on the extent and/or position of the aromatic substitu-
ent encouraged us to pursue further synthetic investigation to clar-
O
MOMO
OMOM
OMOM
OMOM
2.2. Pharmacological evaluation
GO-Y030
*GI50 = 0.3 µM
The anticancer activities of the synthesized compounds were
evaluated from the cell viability of the human colon cancer line
HCT-116 with the quantitation of the uptake and digestion of 2-
(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophe-
nyl)-2H-tetrazolium monosodium salt in accordance with the
manufacturer’s instructions (see Section 4).
O
MeO
OMe
MOMO
OMOM
OMe
OMe
2.3. SAR of C5-curcuminoids
GO-Y031
*GI50 = 0.3 µM
2.3.1. Preliminary SAR of C5-curcumin
Turmeric contains several diarylheptanoids in which curcumin,
demethoxycurcumin, and bisdemethoxycurcumin, featuring a phe-
nolic group and the 1,7-diaryl-3,5-dioxo-1,6-heptadiene skeleton,
*Cell growth inhibition against HCT116
Figure 2.

H. Yamakoshi et al. / Bioorg. Med. Chem. 18 (2010) 1083–1092
1085
2ArCHO
O
10% aq. NaOH
Ar
Ar
O
EtOH or
EtOH/THF
rt, 30 min
O
O
10%aq. NaOH
Ar
Ar
CTABr
2ArCHO
EtOH
rt, 30 min
CTABr : cetyltrimethylammoiumbromide
Ar'CHO
ArCHO
O
10%aq. NaOH
O
10%aq. NaOH
O
Ar
Ar
Ar'
EtOH
EtOH
4
rt, 30 min
rt, 30 min
Ar = 3,4,5-trimethoxyphenyl (12%)
O
DADC
CH2Cl2
rt, 7 days, 89%
MeO
CHO
MeO
MeO
O
4
MeO
OMe
OMe
DADC : dimethylammonium dimethylcarbamate
O
O
1. pyridine, TMSOTf, CH2Cl2
MeO
OMe
OMe
MeO
MeO
OMe
OMe
2. Pd(OAc)2, MeCN
86% for 2 steps
MeO
GO-Y041
GO-Y087
Scheme 1.
Table 1
are the major active constituents responsible for the antioxidative
and anti-inflammatory activities. In 2002, Lee et al. reported that
synthetic 4,40-dimethylcurcumin exhibits a marked cytotoxicity
on human prostate cancer cell lines, indicating that the ethereal
modification of the phenolic groups exerts a significant impact
on the cytotoxic property of curcuminoids.27 In this regard, ques-
tions were raised: (i) how such a significant effect was produced
in the GO-035 by the dimethylation of natural C5-curcumin; and
(ii) what significant effect would dimethyl ether derivatives of C5-
curcumins exert on the anticancer activity in comparison with the
dimethyl ether derivative of C7-curcumin. To address the first
question, a panel of related C5-curcuminoids, namely, C5-curcu-
min (GO-Y022), GO-Y023, GO-Y050, and GO-Y051, was synthe-
sized and their cytotoxicities were compared with that of GO-
035 (Table 1). It was confirmed that GO-035 acquired enhanced
potency compared with natural C5-curcumin (GO-Y022) through
methyl etherification. Interestingly, both the regioisomeric GO-
Y023 and the monomethylated C5-curcumin GO-Y051 showed en-
hanced activities compared with C5-curcumin, indicating the
importance of para-etherification in cytotoxicity enhancement.
Note that Lee et al. reported in 200628 the reversed potencies of
C5-curcumin and dimethylated C5-curcumin (GO-035) determined
on the basis of the anti-prostate cancer activities of these com-
pounds: C5-curcumin was shown to inhibit the growth of PC-3
O
R1
R2
R3
R4
Compound
R1
R2
R3
R4
GI50 (lM)
GO-035
OMe
OMe
OH
OH
OMe
OMe
OH
OMe
OMe
OH
OMe
OMe
OH
OMe
OMe
OMe
OH
OMe
OMe
OMe
1.5
15
0.8
1.5
0.7
GO-Y022
GO-Y023
GO-Y050
GO-Y051
2.3.2. SAR of central tether moiety: C5- versus C7-curcuminoids
The second question regarding the correlation between C7-curc-
uminoids and C5-curcuminoids with respect to cytotoxicity was
addressed using a panel of compounds carrying two 3,4-dime-
thoxybenzene rings at both edges of their alkyl tether, which were
synthesized and evaluated (Table 2). It was found that GO-035 fea-
turing a 3-oxo-1,4-pentadiene tether exhibited the highest activity
among the panel. 4,40-Dimethylcurcumin (GO-Y025) featuring the
3,5-dioxo-2,6-heptadiene tether exhibited a similar GI50 of 2.0
to that of GO-035. GO-Y034 featuring the 1,3-diaryl-3-oxo-2-pro-
pene skeleton showed a decreased GI50 of 7.0 M, showing inter-
lM
and LNCaP cells by 50% at concentrations of 2.4
lM and 1.4
lM,
l
respectively, whereas dimethylated C5-curcumin (GO-035) was
shown to inhibit their growth by 50% at concentrations of
esting contrast to several previously reported examples with
antiangiogenic activities.14 GO-Y032 that has a 3-oxo-1,4-pentadi-
ene moiety merged within a cyclohexanone framework exhibited
no cytotoxicity. The oxime GO-Y010, the monoenone GO-Y087,
3.8
lM and 3.5 lM, indicating the difference in intrinsic activity
between tumor cell lines.

1086
H. Yamakoshi et al. / Bioorg. Med. Chem. 18 (2010) 1083–1092
Table 2
X
MeO
MeO
OMe
OMe
O
N
OH
O
O
O
X
Compound
GI50
GO-Y025
2.0
GO-Y035
1.5
GO-Y034
7.0
(lM)
HO
O
X
Compound
GI50 M)
GO-Y010
>50
GO-Y032
>50
GO-Y037
>50
(
l
n-Pr
O
O
OH
S
O
X
Compound
GI50 M)
GO-Y066
22
GO-Y087
>50
GO-Y041
>50
GO-Y042
>50
(
l
the saturated ketone GO-Y041, and the alcohol GO-Y042 were
completely inactive, clearly indicating that 3-oxo-1,4-pentadiene
plays indispensable roles in cytotoxicity induction. Interestingly,
2.3.4. Advanced SAR of tetra- and hexasubstituted analogues
Having established a fundamental SAR guideline by methoxy
scanning, we next investigated advanced SAR by adding extra
substituents into tetrasubstituted bis(arylmethylidene)acetones
(Table 4) and hexasubstituted bis(arylmethylidene) acetones
(Table 5) with a hope to gain insight into the target biomolecules.
the monosulfide GO-Y066 exhibited a moderate GI50 of 22 lM,
suggesting the reversible nature of the thiol adduct. On the basis
of these data, the bis(arylmethylidene)acetone skeleton of C5-curc-
uminoids was shown to be a reliable platform for the development
of derivatives with an enhanced anticancer activity, and the 3-oxo-
1,4-pentadine structure is essential for C5-curcuminoids to induce
cytotoxicity.
Table 3
O
2.3.3. SAR of aromatic rings: Methoxy scanning
Compound
n
2
4
GI50 (lM)
Ar1
Ar2
To obtain a comprehensive view of the effect of the aromatic
substituent on C5-curcuminoids, we carried out a methoxy scan-
ning of bis(arylmethylidene)acetones, synthesizing and evaluating
Ar1 = Ar2
GO-Y019
GO-Y091
GO-Y013
2-OMe-Ph
3-OMe-Ph
4-OMe-Ph
4.0
9.1
9.0
a
panel of symmetrically/asymmetrically methoxy-substituted
aryl analogues (Table 3). Generally, cytotoxicity increased as the
number of methoxy substituents increased to culminate into
hexamethoxylated bis(arylmethylidene)acetones, but decreased
when the number of methoxy groups reached eight, as in GO-
Y094.
Regarding tetramethoxylated compounds, the
series (cf. GO-035 and GO-Y067) exhibited higher activities than
the asymmetric series (cf. GO-Y049 and GO-Y107). Among the
symmetric series, 2,4-methoxylated GO-Y103, 2,5-methoxylated
GO-Y100, and 2,6-methoxylated GO-Y101 showed attenuated
cytotoxicities, suggesting a disruptive effect of an ortho-methoxyl
group on C5-curcuminoids.
Among hexamethoxylated bis(arylmethylidene)acetones, 3,4,5-
methoxylated GO-Y016 showed the highest potency. The other
compounds exhibited comparable cytotoxicities to GO-035 includ-
GO-Y015
GO-Y103
GO-Y100
GO-Y101
GO-035
2,3-OMe-Ph
2,4-OMe-Ph
2,5-OMe-Ph
2,6-OMe-Ph
3,4-OMe-Ph
3,5-OMe-Ph
1.3
>50
8.1
9.0
1.5
2.0
GO-Y067
r-symmetric
GO-Y020
GO-Y106
GO-Y021
GO-Y104
GO-Y016
6
8
2,3,4-OMe-Ph
2,3,6-OMe-Ph
2,4,5-OMe-Ph
2,4,6-OMe-Ph
3,4,5-OMe-Ph
3.5
2.3
2.0
2.3
0.3
r
-
GO-Y094
2,3,4,6-OMe-Ph
>50
O
Compound
n
GI50
(lM)
Ar1
Ar2
Ar1
Ph
Ar2
ing the
r-symmetric and asymmetric analogues, indicating that
GO-Y110
GO-Y047
3
4
3,4,5-OMe-Ph
3,4-OMe-Ph
4.4
4.0
symmetry is not an essential factor for cytotoxicity.
4-OMe-Ph
Overall, the methoxy scanning indicated the following: (1) The
3,4,5-methoxylated form is the most potent substitution pattern.
(2) The number of methoxyl groups for potentiating the cytotoxicity
is within 4–6, except in the cases of ortho-substituted analogues. (3)
Symmetrybetween two aryl rings is not an essential requirement for
bis(arylmethylidene)acetones to elicit cytotoxicity.
GO-Y049
GO-Y107
4-OMe-Ph
3-OMe-Ph
3,4,5-OMe-Ph
3,4,5-OMe-Ph
3.0
6.9
GO-Y046
5
6
3,4-OMe-Ph
3,4,5-OMe-Ph
0.4
GO-Y092
GO-Y093
2,3,4-OMe-Ph
2,4,5-OMe-Ph
3,4,5-OMe-Ph
3,4,5-OMe-Ph
1.9
3.3

H. Yamakoshi et al. / Bioorg. Med. Chem. 18 (2010) 1083–1092
1087
Table 4
O
R1
R2
R4
R5
R3
R6
Compound
R1
R2
R3
R4
R5
R6
GI50 (lM)
Symmetric (3,4-substituted)
GO-035
OMe
OMe
OMOM
OH
H
H
H
H
OMe
OMOM
OMe
OH
OMe
OMOM
OH
H
H
H
H
1.5
0.8
15
GO-Y040
GO-Y022
GO-Y023
OMOM
OMe
OH
OMe
OMe
0.8
Symmetric (3,5-substituted)
GO-Y038
GO-Y067
GO-Y030
OH
OMe
OMOM
H
H
H
OH
OMe
OMOM
OH
OMe
OMOM
H
H
H
OH
OMe
OMOM
1.5
2.0
0.3
Asymmetric (3,4,5,30-substituted)
GO-Y098
GO-Y107
GO-Y108
GO-Y097
GO-Y111
GO-Y109
GO-Y112
GO-Y099
GO-Y102
GO-Y105
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OH
OMe
OMOM
OCH(Me)OEt
Cl
OTf
CCPh
OTr
OC(O)Ad
OC14H29
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.9
6.9
4.0
1.4
17
2.4
8.1
8.5
7.6
>50
Table 5
O
R1
R2
R4
R5
R3
R6
Compound
R1
R2
R3
R4
R5
R6
GI50
(l
M)
Symmetric (3,4,5-substituted)
GO-Y026
GO-Y031
GO-Y039
GO-Y044
OMe
OH
OMe
OMe
OMe
OMe
OMe
OH
OMOM
OMEM
OCH2CH2OH
OMe
OMe
OMe
OMe
0.8
0.3
0.4
0.5
OMe
OMe
OMe
OMOM
OMEM
OCH2CH2OH
OMe
OMe
OMe
Asymmetric (3,4,5-substituted)
GO-Y078
GO-Y073
GO-Y082
GO-Y081
GO-Y079
GO-Y016
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OH
OMe
OMe
OMe
OMe
OMe
OMe
0.8
1.7
38
7.0
1.5
0.3
OCH2CH2OH
OCH2CO2H
OCH2CO2Me
OCH(Me)OEt
OMe
Since the fundamental SAR indicated that an ortho-substituent
considerably reduced cytotoxicity, we focused on the meta- and
para-substituted analogues.
Table 5 highlights the advanced SAR of hexasubstituted ana-
logues, indicating the introduction of various functional groups at
the para-position, except for a carboxyl group (cf. GO-Y082), where
As shown in Table 4, all the
r
-symmetric, 3,4-substituted- and
the r-symmetric and asymmetric compounds retained their po-
3,5-substituted analogues showed significant cytotoxicities. Note
that methoxymethylated analogues, namely, GO-Y040 and GO-
Y030, exhibited enhanced cytotoxicities compared with the proto-
typic methoxylated counterpart, namely, GO-Y035 and GO-Y067,
respectively, indicating there being a bit loose space around the
binding sites for the aromatic peripherals. The attitude of tolerance
towards the steric size of substituents was surveyed using a panel
of 3,4,5-trimethoxy-30-substituted derivatives, in which a variety
of substituents were accepted, including adamantanecarboxyl
(GO-Y102) and triphenylmethyl (GO-Y112) derivatives to retain
moderate cytotoxicities, except long alkyloxy derivative (GO-
Y105).
tent cytotoxicities. These results also encouraged us to synthesize
molecular probes employing the hexasubstituted C5-curcuminoid
platform.
2.3.5. Outline of SAR of C5-curcuminoids
The following conclusions about SAR were drawn: (1) Bis(aryl-
methylidene)acetone serves as the most promising skeleton for
eliciting cytotoxicity. (2) The 3-oxo-1,4-pentadiene structure is
essential for eliciting cytotoxicity. (3) Hexasubstituted compounds
exhibit strong activities. (4) 3,4,5-Hexasubstitution results in the
highest potency. (5) The symmetry between two aryl rings is
important for tetrasubstituted analogues but not a requirement

1088
H. Yamakoshi et al. / Bioorg. Med. Chem. 18 (2010) 1083–1092
1) The bis(arylmethylidene)acetone skeleton offers a cytotoxicity.
3) Hexasubstituted compounds
O
2) The 3-oxo-1,4-pentadiene
structure is essential for
cytotoxicity.
exhibited strong activities.
Rm
Rp
Rm
probe
4) A 3,4,5-substituted
compound shows the highest
cytotoxicity.
Rm
Rm
6) Probe position has potential use
for introduction of a probe moiety.
5) Symmetry is important for tetrasubstituted analogues
but not for hexasubstituted analogues.
Figure 3.
for hexasubstituted analogues. (6) para-Positions are allowed to
introduce of additional functional groups for use as molecular
probes. These results are summarized inFigure 3. It would be inter-
esting to point out that installation of methoxymethy groups in-
stead of methoxy groups conferred bis(arylmethylidene)acetones
improved water solubilities.
pounds. Results are shown in Table 6. As expected, almost all the
compounds exhibited strong cell growth inhibition, involving a
large substituent (GO-Y061), azides (e.g., GO-Y085 and GO-Y065),
alkynes (e.g., GO-Y060 and GO-048) and polar triazole (e.g., GO-
Y074 and GO-Y083). Because azides and alkynes have versatile
functions for the preparation of molecular probes,30 several mole-
cules retaining cytotoxicity will find good use in chemical biologi-
cal studies of C5-curcuminoids. We also obtained cytotoxic C5-
curcumin derivatives linked to a fluorescent dye31 that provide
useful insight into the molecular targets of C5-curcuminoids for
further development of anticancer medicines.
2.4. Development of molecular probes of C5-curcuminoid
To date, many lines of evidence have been accumulated con-
firming that a,b-unsaturated ketones are excellent thiol alkylators
via the Michael reaction. Dimmock and co-workers successfully
demonstrated that bis(arylmethylidene)acetones have the highest
efficiency as ‘Michael alkylators’ for thiols.29 Considering the
highly potent cytotoxicity of these compounds reaching GI50 val-
ues down to the submicromolar level, it would be reasonable to ex-
pect that GO-Y016, GO-Y030, and GO-Y031 interact with key
biomolecules, playing crucial roles in cells via specific S-alkylation.
The identification and characterization of such biomolecules which
C5-curcumin targets should provide useful information for cancer
chemotherapy development. With this concept in mind, we envi-
sioned the development of molecular probes based on C5-curcumi-
noids, where we define the criterion for the probe as having a GI50
of single-digit micromolar potency.
3. Conclusion
We determined the SAR of C5-curcuminoids to gain useful in-
sight into the molecular basis of their biological activities and fab-
ricated molecular probes. From the SAR diagram, we have obtained
several potential molecular probes that will target key biomole-
cules of C5-curcuminoids. The SAR diagram will not only provide
useful insight into the chemical biology of C5-curcuminoids, but
also encourage medicinal chemists to design useful derivatives
for cancer chemotherapy. From these findings, we have obtained
useful molecular probes that can form covalent bonds with their
target proteins. The result of our study of such molecular probes
will be reported elsewhere.
From our SAR of C5-curcuminoids, the direction of modification
was set to the para-position of 3,30,4,40,5,50-substituted com-
Table 6
O
MeO
OMe
R1
R2
OMe
OMe
Compound
R1
R2
GI50
(lM)
Compound
R1
R2
GI50 (lM)
GO-Y060
GO-Y085
GO-Y063
GO-Y048
GO-Y065
OMe
OMe
OMOM
OCH2CCH
OCH2CH2N3
OCH2CCH
OCH2CH2N3
OCH2CCH
OCH2CCH
OCH2CH2N3
1.8
9.7
2.4
0.3
7.6
GO-Y074
GO-Y083
GO-Y061
GO-Y076
GO-Y080
OMe
OMe
OMe
OMe
OMe
ORa
ORb
ORc
ORd
ORe
0.8
0.8
0.3
15
2.6
OH
9
NHBoc
Rb =
Rc =
Ra =
OTHP
O
N
N
N
S
9
N
N
N
N
N
N
O
O
O
Rd =
Re =
N
N
9
N
N
9
N
N
B
O
N
O
N
N
F
N
F

H. Yamakoshi et al. / Bioorg. Med. Chem. 18 (2010) 1083–1092
1089
4.1.3. (1E,4E)-1-(3,5-Dimethoxy-4-(methoxymethoxy)phenyl)-
4. Experimental
5-(3,5-dimethoxy-4-(prop-2-ynyloxy)phenyl)penta-1,4-dien-3-
one (GO-Y063)
4.1. Chemical synthesis
Yellow plate (AcOEt/hexane = 2:1): mp 122–124 °C. IR (CHCl3):
3268, 2938, 1649, 1618, 1583, 1500, 1455, 1419, 1277, 1154,
Melting point was determined using a Yazawa BY-2 melting
point apparatus and reported uncorrected. Infrared spectra were
obtained on a JASCO FT/IR-410 Fourier Transform Infrared Spectro-
photometer at a 4.0 cmꢀ1 resolution and reported in wave num-
bers. Proton nuclear magnetic resonance (1H NMR) spectra were
recorded using JEOL JMN-AL400 (400 MHz), and JEOL JNM-ECP-
500 (500 MHz) spectrometers. Chemical shift (d) is reported in
parts per million (ppm) downfield, relative to tetramethylsilane
(TMS). Coupling constant (J) is reported in hertz. Multiplicities
are reported using the following abbreviations: s, singlet; d, dou-
blet; t, triplet; q, quartet; br, broad. Carbon-13 nuclear magnetic
resonance (13C NMR) spectra were recorded using JEOL JMN-
AL400 (100 MHz) and JEOL JNM-ECP-500 (125 MHz) spectrome-
ters. Chemical shift is reported in ppm relative to the center of
CDCl3 or CD3OD. Low- and high-resolution mass spectra were re-
corded on a JEOL JMS-DX303 or JMS-700 using electron impact
(EI). FAB mass spectra were recorded on a JEOL-JMS700 spectrom-
eter using 3-nitrobenzyl alcohol as a matrix. Elemental analysis
was performed using a Yanaco CHN CORDER MT-6. The synthesis
and spectral properties of compounds GO-Y011-Y051 were re-
ported in our previous paper.19 The synthesis schemes for GO-
Y010-Y112 and characterization data other than GO-Y compounds
are provided in Supplementary data. All reactions were carried out
in an atmosphere of argon unless otherwise specified. Anhydrous
solvents were transferred via a syringe to flame-dried glassware,
which had been cooled under a stream of dry nitrogen. Ethereal
solvents and dichloromethane (anhydrous; Kanto Chemical Co.,
Inc.) were used as received. All other solvents were dried and dis-
tilled by standard procedures. Yields refer to chromatographically
and spectroscopically (1H NMR) homogeneous materials unless
otherwise stated. Reagents of the highest commercial quality were
purchased and used without further purification.
1126 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.66 (1H, d, J = 15.9 Hz),
.
7.66 (1H, d, J = 15.9 Hz), 6.98 (1H, d, J = 15.9 Hz), 6.97 (1H, d,
J = 15.9 Hz), 6.85 (4H, s), 5.18 (2H, s), 4.78 (2H, d, J = 2.4 Hz), 3.92
(6H, s), 3.91 (6H, s), 3.61 (3H, s), 2.45 (1H, t, J = 2.4 Hz). 13C NMR
(100 MHz, CDCl3) d 188.4, 153.8, 153.6, 143.4, 143.2, 137.8,
137.0, 131.0, 130.7, 125.0, 124.9, 105.6, 98.2, 79.1, 75.1, 60.0,
57.2, 56.3, 56.2. MS (EI) m/z: 468 (M+). HRMS (EI) Calcd for
C26H28O8: 468.1784. Found: 468.1786. Anal. Calcd for C26H28O8:
C, 66.66; H, 6.02. Found: C, 66.43; H, 6.16.
4.1.4. (1E,4E)-1,5-Bis(4-(2-azidoethoxy)-3,5-
dimethoxyphenyl)penta-1,4-dien-3-one (GO-Y065)
Yellow styloid (CHCl3/hexane = 1:2): mp 107–109 °C. IR
(CHCl3): 2938, 2105, 1650, 1617, 1583, 1502, 1454, 1419, 1278,
1244, 1128 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.67 (2H, d,
.
J = 15.8 Hz), 6.98 (2H, d, J = 15.8 Hz), 6.85 (4H, s), 4.20 (4H, t,
J = 5.3 Hz), 3.92 (12H, s), 3.57 (4H, t, J = 5.3 Hz). 13C NMR
(100 MHz, CDCl3) d 188.4, 153.5, 143.3, 138.8, 130.7, 124.9,
105.5, 71.7, 56.2, 51.1. MS (FAB) m/z: 524 (M+). HRMS (FAB) Calcd
for C25H29N6O7: 525.2106. Found: 525.2106. Anal. Calcd for
C25H28N6O7: C, 57.25; H, 5.38; N, 16.02. Found: C, 57.02; H, 5.68;
N, 16.03.
4.1.5. (E)-1,5-Bis(3,4-dimethoxyphenyl)-5-(propylthio)pent-1-
en-3-one (GO-Y066)
Yellow oil. IR (CHCl3): 2959, 1655, 1593, 1513, 1463, 1420,
1262, 1139, 1024 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.46 (1H, d,
.
J = 16.0 Hz), 7.09 (1H, dd, J = 8.5, 1.9 Hz), 7.02 (1H, d, J = 1.9 Hz),
6.98 (1H, d, J = 2.2 Hz), 6.92 (1H, dd, J = 8.5, 2.2 Hz), 6.86 (1H, d,
J = 8.2 Hz), 6.78 (1H, d, J = 8.2 Hz), 6.55 (1H, d, J = 16.0 Hz), 4.42
(1H, t, J = 7.1 Hz), 3.91 (3H, s), 3.91 (3H, s), 3.90 (3H, s), 3.85 (3H,
s), 3.17 (2H, d, J = 7.1 Hz), 2.24–2.38 (2H, m), 1.54 (2H, m), 0.91
(3H, t, J = 7.5 Hz). 13C NMR (100 MHz, CDCl3) d 196.9, 151.4,
149.2, 148.9, 148.1, 143.1, 127.2, 124.2, 123.1, 120.0, 111.0,
110.8, 110.7, 109.7, 55.9, 55.9, 55.8, 55.8, 47.6, 44.5, 33.5, 22.5,
13.4. MS (EI) m/z: 430 (M+). HRMS (EI) Calcd for C24H30O5S:
430.1814. Found: 430.1824.
4.1.1. (1E,4E)-1-(3,5-Dimethoxy-4-(prop-2-ynyloxy)phenyl)-5-
(3,4,5-trimethoxy-phenyl)-penta-1,4-dien-3-one (GO-Y060)
Yellow needle (AcOEt/hexane = 1:1): mp 118–120 °C. IR
(CHCl3): 3258, 2360, 1649, 1618, 1583, 1501, 1455, 1419, 1317,
1278, 1244, 1127 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.66 (2H, d,
.
J = 15.7 Hz), 6.98 (1H, d, J = 15.7 Hz), 6.97 (1H, d, J = 15.7 Hz), 6.85
(4H, s), 4.79 (2H, d, J = 2.4 Hz), 3.92 (12H, s), 3.90 (3H, s), 2.45
(1H, t, J = 2.4 Hz). 13C NMR (100 MHz, CDCl3) d 188.4, 153.8,
153.5, 143.4, 143.2, 140.5, 137.8, 131.0, 130.2, 125.0, 124.8,
105.7, 105.6, 79.1, 75.1, 61.0, 60.1, 56.3, 56.2. MS (EI) m/z: 438
(M+). HRMS (EI) Calcd for C25H26O7: 438.1679. Found: 438.1670.
Anal. Calcd for C25H26O7: C, 68.48; H, 5.98. Found: C, 68.29;
H, 6.04.
4.1.6. (1E,4E)-1-(4-(2-Hydroxyethoxy)-3,5-dimethoxyphenyl)-5-
(3,4,5-trimethoxy-phenyl)penta-1,4-dien-3-one (GO-Y073)
Yellow oil. IR (CHCl3): 3511, 2940, 1650, 1617, 1582, 1503,
1454, 1419, 1318, 1278, 1244, 1127 cmꢀ1 1H NMR (400 MHz,
.
CDCl3) d 7.66 (2H, d, J = 15.7 Hz), 6.99 (1H, d, J = 15.7 Hz), 6.98
(1H, d, J = 15.7 Hz), 6.86 (2H, s), 6.85 (2H, s), 4.18 (2H, t,
J = 4.4 Hz), 3.92 (6H, s), 3.92 (6H, s), 3.90 (3H, s), 3.75 (2H, m),
3.35 (1H, t, J = 6.3 Hz). 13C NMR (100 MHz, CDCl3) d 188.3, 153.5,
153.4, 143.4, 143.0, 140.4, 138.6, 130.7, 130.2, 125.0, 124.7,
105.6, 105.4, 75.5, 61.4, 60.9, 56.2. MS (EI) m/z: 444 (M+). HRMS
(EI) Calcd for C24H28O8: 444.1784. Found: 444.1787.
4.1.2. (1E,4E)-1-(3,5-Dimethoxy-4-((1-(4-(tetrahydro-2H-pyran-
2-yloxy)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-5-
(3,4,5-trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y061)
Yellow oil. IR (CHCl3): 2940, 1649, 1682, 1503, 1455, 1419,
1277, 1241, 1126 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.66 (1H, d,
.
4.1.7. (1E,4E)-1-(4-((1-(10-Hydroxydecyl)-1H-1,2,3-triazol-4-
yl)methoxy)-3,5-di-methoxyphenyl)-5-(3,4,5-
J = 15.9 Hz), 7.63 (1H, d, J = 15.7 Hz), 7.58 (1H, s), 7.18 (2H, d,
J = 8.5 Hz), 7.04 (2H, d, J = 8.5 Hz), 6.98 (1H, d, J = 15.9 Hz), 6.97
(1H, d, J = 15.7 Hz), 6.85 (2H, s), 6.78 (2H, s), 5.43 (2H. s), 5.43
(1H, m), 5.23 (2H, s), 3.91 (6H, s), 3.90 (3H, s), 3.86 (1H, m), 3.79
(6H, s), 3.61 (1H, m), 1.96 (2H, m), 1.85 (2H, m), 1.67 (2H, m).
13C NMR (100 MHz, CDCl3) d 188.4, 157.3, 153.5, 153.4, 143.2,
143.1, 140.4, 138.4, 130.6, 130.2, 129.5, 127.4, 124.8, 124.7,
122.7, 116.9, 105.6, 105.4, 96.2, 66.4, 61.9, 60.9, 60.2, 56.1, 56.0,
53.6, 30.1, 25.0, 20.9, 18.5, 14.1. MS (EI) m/z: 587 ([MꢀTHP+]).
HRMS (EI) Calcd for C32H33N3O8: 587.2268. Found: 587.2261.
trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y074)
Yellow amorphous. IR (CHCl3): 3408, 2930, 1650, 1617, 1583,
1502, 1455, 1419, 1318, 1278, 1245, 1127 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) d 7.71 (1H, s), 7.65 (2H, d, J = 16.0 Hz), 6.99
(1H, d, J = 15.7 Hz), 6.98 (1H, d, J = 16.0 Hz), 6.85 (2H, s), 6.83
(2H, s), 5.25 (2H, s), 4.33 (2H, m), 3.91 (6H, s), 3.90 (6H, s), 3.88
(3H, s), 3.62 (2H, s), 2.20 (1H, s), 1.88 (2H, m), 1.55 (2H, m),
1.27–1.30 (12H, m). 13C NMR (100 MHz, CDCl3) d 188.3, 153.4,
153.2, 144.4, 143.2, 143.0, 140.2, 138.4, 130.5, 124.7, 124.6,

1090
H. Yamakoshi et al. / Bioorg. Med. Chem. 18 (2010) 1083–1092
122.6, 105.5, 105.4, 66.3, 62.5, 60.7, 56.0, 56.0, 50.1, 32.5, 30.0,
29.2, 29.1, 29.0, 28.7, 26.2, 25.5. MS (EI) m/z: 637 (M+). HRMS
(EI) Calcd for C35H47N3O8: 637.3363. Found: 637.3354.
(1H, d, J = 15.7 Hz), 7.64 (1H, d, J = 15.9 Hz), 6.97 (1H, d,
J = 15.7 Hz), 6.97 (1H, d, J = 15.9 Hz), 6.85 (2H, s), 6.84 (2H, s),
4.70 (2H, s), 3.92 (6H, s), 3.90 (9H, s), 3.81 (3H, s). 13C NMR
(100 MHz, CDCl3) d 188.1, 169.3, 153.1, 152.5, 143.0, 142.7,
140.1, 138.0, 130.3, 129.9, 124.7, 124.5, 105.3, 69.1, 60.6, 55.9,
55.8, 51.7. MS (EI) m/z: 472 (M+). HRMS (EI) Calcd for C25H28O9:
472.1713.
4.1.8. GO-Y076
Orange oil. IR (CHCl3): 2931, 1729, 1649, 1605, 1501, 1277, 1247,
1128 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.68 (1H, s), 7.65 (1H, d,
.
J = 15.9 Hz), 7.64 (1H, d, J = 15.9 Hz), 7.07 (1H, s), 6.97 (2H, d,
J = 15.9 Hz), 6.87 (1H, d, J = 4.1 Hz), 6.85 (2H, s), 6.83 (2H, s), 6.26
(1H, d, J = 4.1 Hz), 6.10 (1H, s), 5.25 (2H, s), 4.33 (2H, t, J = 7.4 Hz),
4.08 (2H, t, J = 6.6 Hz), 3.92 (6H, s), 3.90 (3H, s), 3.89 (6H, s), 3.29
(2H, t, J = 7.5 Hz), 2.75 (2H, t, J = 7.5 Hz), 2.56 (3H, s), 2.24 (3H, s),
1.89 (2H, m), 1.61 (2H, m), 1.23–1.31 (12H, m). 13C NMR
(100 MHz, CDCl3) d 188.5, 172.6, 160.4, 157.3, 153.7, 153.5, 144.7,
143.8, 143.4, 143.3, 140.5, 138.7, 133.3, 130.7, 130.3, 128.8, 128.1,
124.9, 124.8, 123.8, 122.7, 120.4, 116.7, 105.7, 105.6, 66.7, 64.7,
61.0, 56.2, 56.2, 50.3, 33.4, 30.3, 29.3, 29.3, 29.1, 29.0, 28.6, 26.5,
25.8, 24.0, 14.9, 11.3. MS (FAB) m/z: 912 ([M+H]+). HRMS (FAB) Calcd
for C49H61BF2N5O9: 912.4530. Found: 912.4502.
4.1.13. 2-(2,6-Dimethoxy-4-((1E,4E)-3-oxo-5-(3,4,5-
trimethoxyphenyl)-penta-1,4-dienyl)phenoxy)ethanoic acid
(GO-Y082)
Yellow powder (CHCl3/Et2O): mp 208–210 °C. IR (CHCl3): 3584,
1767, 1617, 1583, 1503, 1419, 1280, 1126 cmꢀ1 1H NMR (400
.
MHz, CDCl3) d 7.68 (1H, d, J = 16.0 Hz), 7.65 (1H, d, J = 15.9 Hz),
7.00 (1H, d, J = 16.0 Hz), 6.97 (1H, d, J = 15.9 Hz), 6.87 (2H, s), 6.85
(2H, s), 4.65 (2H, s), 3.97 (6H, s), 3.92 (6H, s), 3.91 (3H, s). 13C NMR
(100 MHz, CDCl3) d 188.2, 170.1, 153.5, 152.1, 143.8, 142.5, 140.6,
138.0, 131.9, 130.0, 125.7, 124.6, 105.7, 105.3, 71.1, 61.0, 56.3,
56.2. MS (EI) m/z: 458 (M+). HRMS (EI) Calcd for C24H26O9:
458.1577. Found: 458.1540.
4.1.9. (1E,4E)-1-(4-Hydroxy-3,5-dimethoxyphenyl)-5-(3,4,5-
trimethoxyphenyl)-penta-1,4-dien-3-one (GO-Y78)
4.1.14. tert-Butyl 10-(4-((2,6-dimethoxy-4-((1E,4E)-3-oxo-5-
(3,4,5-trimethoxy-phenyl)penta-1,4-dienyl)phenoxy)methyl)-
1H-1,2,3-triazol-1-yl)decylcarbamate (GO-Y083)
Yellow amorphous. IR (CHCl3): 3389, 2939, 1645, 1583, 1505,
1455, 1421, 1283, 1153, 1125 cmꢀ1. UV (CHCl3) 380 nm. 1H NMR
(400 MHz, CDCl3)
d
7.66 (1H, d, J = 15.7 Hz), 7.65 (1H, d,
Yellow amorphous. IR (CHCl3): 3379, 1698, 1649, 1617, 1582,
J = 15.9 Hz), 6.98 (1H, d, J = 15.7 Hz), 6.94 (1H, d, J = 15.9 Hz), 5.99
(1H, s), 3.93 (6H, s), 3.91 (6H, s), 3.90 (3H, s). 13C NMR (100 MHz,
CDCl3) d 188.4, 153.4, 147.2, 143.7, 142.9, 140.3, 137.5, 130.3,
126.2, 124.8, 123.4, 105.5, 105.4, 60.9, 56.3, 56.1. MS (EI) m/z: 400
(M+). HRMS (EI) Calcd for C22H24O7: 400.1522. Found: 400.1502.
1503, 1455, 1419, 1277, 1245, 1128 cmꢀ1 1H NMR (400 MHz,
.
CDCl3) d 7.71 (1H, s), 7.66 (1H, d, J = 15.9 Hz), 7.65 (1H, d,
J = 15.9 Hz), 6.99 (2H, d, J = 15.9 Hz), 6.85 (2H, s), 6.83 (2H, s),
5.24 (2H, s), 4.34 (2H, t, J = 7.2 Hz), 3.91 (6H, s), 3.91 (3H, s), 3.90
(6H, s), 3.09 (2H, m), 1.88 (2H, m), 1.43–1.46 (11H, m), 1.26–1.30
(12H, m). 13C NMR (100 MHz, CDCl3) d 188.2, 155.8, 153.4, 153.2,
144.4, 143.1, 143.0, 140.2, 138.4, 130.5, 130.0, 124.7, 124.6,
122.6, 105.4, 105.3, 66.3, 60.7, 56.0, 55.9, 50.0, 40.3, 30.1, 29.8,
29.1, 29.0, 28.9, 28.7, 28.2, 28.2, 26.5, 26.2. MS (FAB) m/z: 736
(M+). HRMS (FAB) Calcd for C40H56N4O9: 736.4047. Found:
736.4046.
4.1.10. (1E,4E)-1-(4-(1-Ethoxyethoxy)-3,5-dimethoxyphenyl)-5-
(3,4,5-trimethoxy-phenyl)penta-1,4-dien-3-one (GO-Y079)
Yellow oil. IR (CHCl3): 2938, 1650, 1617, 1582, 1501, 1419,
1277, 1244, 1128 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.66 (2H, d,
.
J = 15.7 Hz), 6.98 (2H, d, J = 15.7 Hz), 6.85 (4H, s), 5.33 (1H, q,
J = 5.1 Hz), 3.94 (6H, s), 3.91 (3H, s), 3.90 (6H, s), 3.82 (1H, m),
3.64 (1H, m), 1.51 (3H, d, J = 5.1 Hz), 1.19 (3H, t, J = 7.3 Hz). 13C
NMR (100 MHz, CDCl3) d 188.4, 153.5, 153.4, 143.3, 143.2, 140.4,
137.5, 130.3, 130.2, 124.8, 124.7, 105.6, 105.6, 103.3, 62.9, 60.9,
56.2, 56.0, 20.9, 15.1. MS (EI) m/z: 472 (M+). HRMS (EI) Calcd for
C26H31O8: 471.2008.
4.1.15. (1E,4E)-1-(4-(2-Azidoethoxy)-3,5-dimethoxyphenyl)-5-
(3,4,5-trimethoxy-phenyl)penta-1,4-dien-3-one (GO-Y085)
Yellow oil. IR (CHCl3): 2938, 2105, 1649, 1617, 1582, 1503,
1454, 1418, 1277, 1127 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.66
.
(2H, d, J = 15.9 Hz), 6.98 (1H, d, J = 15.9 Hz), 6.97 (1H, d,
J = 15.9 Hz), 6.85 (4H, s), 4.19 (2H, t, J = 5.2 Hz), 3.92 (12H, s),
3.90 (3H, s), 3.56 (2H, t, J = 5.2 Hz). 13C NMR (100 MHz, CDCl3) d
188.4, 153.5, 153.4, 143.4, 143.2, 140.4, 138.7, 130.7, 130.2,
124.9, 124.7, 105.6, 105.4, 71.6, 61.0, 56.2, 51.1. MS (FAB) m/z:
470 ([M+H]+). HRMS (FAB) Calcd for C24H28O7N3: 470.1927. Found:
470.1940.
4.1.11. 10-(4-((2,6-Dimethoxy-4-((1E,4E)-3-oxo-5-(3,4,5-
trimethoxyphenyl)penta-1,4-dienyl)phenoxy)methyl)-1H-1,2,3-
triazol-1-yl)decyl 2-((3,5,6-trimethyl-1,7-di-oxo-1,7-
dihydropyrazolo[1,2-a]pyrazol-2-yl)methylthio)ethanoate
(GO-Y080)
Yellow oil. IR (CHCl3): 2931, 1742, 1582, 1502, 1418, 1277,
1229, 1126 cmꢀ1
.
1H NMR (400 MHz, CDCl3) d 7.69 (1H, s), 7.66
4.1.16. (E)-1,5-Bis(3,4-dimethoxyphenyl)pent-1-en-3-one (GO-
Y087)
(1H, d, J = 16.1 Hz), 7.65 (1H, d, J = 16.1 Hz), 6.98 (2H, d,
J = 16.1 Hz), 6.86 (2H, s), 6.84 (2H, s), 5.24 (2H, s), 4.35 (2H, t,
J = 7.1 Hz), 4.13 (2H, t, J = 6.8 Hz), 3.92 (6H, s), 3.90 (3H, s), 3.89
(6H, s), 3.83 (2H, s), 3.26 (2H, s), 2.41 (3H, s), 1.89 (3H, s), 1.83
(3H, s), 1.62–1.64 (4H, m), 1.27–1.31 (12H, m). 13C NMR
(100 MHz, CDCl3) d 188.5, 169.6, 160.6, 160.0, 153.7, 153.5,
146.1, 144.8, 144.4, 143.4, 143.3, 140.5, 138.7, 130.8, 130.3,
125.0, 124.8, 122.8, 115.1, 112.8, 105.7, 105.6, 66.7, 66.1, 61.0,
56.3, 56.2, 56.2, 50.3, 32.7, 30.3, 29.3, 29.3, 29.1, 28.9, 28.5, 26.4,
25.8, 25.3, 11.7, 7.1, 6.9. MS (FAB) m/z: 902 ([M+H]+). HRMS
(FAB) Calcd for C47H60N5O11S: 902.4010. Found: 902.4011.
Pale yellow solid. IR (CHCl3): 2935, 1682, 1653, 1594, 1513, 1234,
1139, 1024 cmꢀ1. UV (CHCl3) 337 nm. 1H NMR (400 MHz, CDCl3) d
7.49 (1H, d, J = 16.1 Hz), 7.10 (1H, d, J = 8.3 Hz), 7.04 (1H, s), 6.86
(1H, d, J = 8.3 Hz), 6.80–6.75 (3H, m), 6.61 (1H, d, J = 16.1 Hz), 3.90
(6H, s), 3.87 (3H, s), 3.87 (3H, s), 3.84 (3H, s), 2.96 (4H, s). 13C NMR
(100 MHz, CDCl3) d 199.0, 151.1, 149.0, 148.7, 147.1, 142.5, 133.7,
127.2, 124.1, 122.8, 120.0, 111.7, 111.2, 110.9, 109.5, 55.9, 55.8,
55.8, 55.7, 42.4, 29.9. MS (EI) m/z: 418 (M+). HRMS (EI) Calcd for
C23H30O7: 418.1992. Found: 418.2004.
4.1.17. (1E,4E)-1-(2,3,4-Trimethoxyphenyl)-5-(3,4,5-
trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y092)
Yellow oil. IR (CHCl3): 2930, 1671, 1651, 1620, 1596, 1487,
4.1.12. Methyl 2-(2,6-dimethoxy-4-((1E,4E)-3-oxo-5-(3,4,5-trime-
thoxyphenyl)-penta-1,4-dienyl)phenoxy)ethanoate (GO-Y081)
Yellow amorphous. IR (CHCl3): 2941, 1759, 1649, 1618, 1583,
1290, 1255, 1185, 1102, 1047 cmꢀ1 1H NMR (400 MHz, CDCl3) d
.
1503, 1419, 1278, 1127 cmꢀ1
.
1H NMR (400 MHz, CDCl3) d 7.66
7.70 (2H, d, J = 15.9 Hz), 7.33 (2H, t, J = 8.0 Hz), 7.21 (2H, d,

H. Yamakoshi et al. / Bioorg. Med. Chem. 18 (2010) 1083–1092
1091
J = 8.0 Hz), 7.13 (2H, t, J = 2.5 Hz), 7.06 (2H, d, J = 15.9 Hz), 6.96 (2H,
dd, J = 8.0, 2.5 Hz), 3.86 (6H, s). 13C NMR (100 MHz, CDCl3) d 188.7,
159.8, 143.1, 136.1, 129.8, 125.5, 121.0, 116.2, 113.2, 55.2. MS (EI)
m/z: 294 (M+). HRMS (EI) Calcd for C19H18O3: 294.1256. Found:
294.1241.
(1H, d, J = 1.2 Hz), 6.88 (1H, d, J = 16.0 Hz), 6.83 (1H, d,
J = 16.0 Hz), 6.83 (2H, s), 6.71 (1H, dd, J = 8.0, 1.2 Hz), 3.92, (6H,
s), 3.90 (3H, s). 13C NMR (100 MHz, CDCl3) d 188.5, 156.6, 153.4,
143.7, 143.1, 142.9, 140.3, 135.1, 130.1, 128.8, 128.6, 127.7,
127.2, 125.1, 124.8, 123.0, 121.5, 120.6, 105.5, 90.7, 60.8, 56.0.
MS (EI) m/z: 581 [(MꢀH)+]. HRMS (EI) Calcd for C39H33O5:
581.2328. Found: 581.2332.
4.1.18. (1E,4E)-1-(2,4,5-Trimethoxyphenyl)-5-(3,4,5-
trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y093)
Yellow box (AcOEt/hexane = 1:2): mp 160–162 °C. IR (CHCl3):
4.1.23. (1E,4E)-1-(3-(Adamantane-1-carboxy)phenyl) 5-(3,4,5-
trimethoxyphenyl)-penta-1,4-dien-3-one (GO-Y102)
2928, 1681, 1593, 1462, 1250, 1212, 1101 cmꢀ1
.
1H NMR
(400 MHz, CDCl3)
d
8.07 (1H, d, J = 16.0 Hz), 7.64 (1H, d,
Yellow oil. IR (CHCl3): 2907, 1745, 1651, 1620, 1582, 1504,
J = 16.0 Hz), 7.12 (1H, s), 7.01 (1H, d, J = 16.0 Hz), 6.99 (1H, d,
J = 16.0 Hz), 6.84 (2H, s), 6.52 (1H, s), 3.94 (3H, s), 3.92 (6H, s),
3.91 (3H, s), 3.90 (6H, s). 13C NMR (100 MHz, CDCl3) d 188.9,
154.4, 153.4, 152.6, 143.3, 142.4, 140.2, 138.2, 130.5, 125.0,
123.7, 115.3, 110.9, 105.5, 98.8, 60.9, 56.5, 56.3, 56.2, 56.0. MS
(EI) m/z: 414 (M+). HRMS (EI) Calcd for C23H26O7: 414.1679. Found:
414.1663. Anal. Calcd for C23H26O7: C, 66.65; H, 6.32. Found: C,
66.36; H, 6.36.
1321, 1209, 1182, 1127, 1101, 1052 cmꢀ1 1H NMR (400 MHz,
.
CDCl3) d 7.70 (1H, d, J = 16.0 Hz), 7.66 (1H, d, J = 16.0 Hz), 7.43
(1H, dt, J = 7.8, 1.8 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.34 (1H, t,
J = 1.8 Hz), 7.09 (1H, dt, J = 7.8, 1.8 Hz), 7.08 (1H, d, J = 16.0 Hz),
6.94 (1H, d, J = 16.0 Hz), 6.85 (2H, s), 3.92, (6H, s), 3.90 (3H, s),
2.11–2.08 (9H, m), 1.82–1.75 (6H, m). 13C NMR (100 MHz, CDCl3)
d 188.4, 175.9, 153.4, 151.5, 143.5, 142.0, 140.5, 136.3, 130.1,
129.8, 125.9, 125.9, 124.9, 123.5, 120.8, 105.6, 60.9, 56.1, 41.0,
38.7, 36.4, 27.8. MS (EI) m/z: 502 (M+). HRMS (EI) Calcd for
C31H34O6: 502.2355. Found: 502.2344.
4.1.19. (1E,4E)-1,5-Bis(2,3,4,6-tetramethoxyphenyl)penta-1,4-
dien-3-one (GO-Y094)
Yellow box (AcOEt/hexane = 1:1): mp 171–173 °C. IR (CHCl3):
4.1.24. (1E,4E)-1-(3-(Tetradecyloxy)phenyl)-5-(3,4,5-
trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y105)
Yellow oil. IR (CHCl3): 2923, 1651, 1619, 1581, 1504, 1267,
2938, 1637, 1592, 1565, 1315, 1204, 1105 cmꢀ1
.
1H NMR
(400 MHz, CDCl3)
d 8.02 (2H, d, J = 16.4 Hz), 7.50 (2H, d,
J = 16.4 Hz), 6.30 (2H, s), 3.93 (6H, s), 3.92 (6H, s), 3.91 (6H, s),
3.83 (6H, s). 13C NMR (100 MHz, CDCl3) d 192.1, 156.4, 155.2,
154.5, 136.5, 133.5, 127.6, 111.1, 92.1, 61.1, 61.1, 56.0, 55.9. MS
(EI) m/z: 474 (M+). HRMS (EI) Calcd for C25H30O9: 474.1890. Found:
474.1874. Anal. Calcd for C25H30O9: C, 63.28; H, 6.37. Found: C,
63.07; H, 6.33.
1244, 1128, 1102 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.69 (1H, d,
.
J = 15.8 Hz), 7.65 (1H, d, J = 15.8 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.18
(1H, d, J = 7.9 Hz), 7.13 (1H, t, J = 2.3 Hz), 7.08 (1H, d, J = 15.8 Hz),
6.96 (1H, d, J = 15.8 Hz), 6.94 (1H, dd, J = 7.9, 2.3 Hz), 6.84 (2H, s),
3.98 (2H, t, J = 6.6 Hz), 3.91, (6H, s), 3.90 (3H, s), 1.80 (2H, m),
1.47 (2H, m), 1.35–1.26 (20H, m), 1.88 (3H, t, J = 6.9 Hz). 13C
NMR (100 MHz, CDCl3) d 188.6, 159.5, 153.5, 143.3, 143.2, 140.4,
136.1, 130.2, 129.8, 125.3, 125.0, 120.9, 116.7, 113.9, 105.6, 68.1,
60.9, 56.2, 31.9, 29.6, 29.6, 29.6, 29.6, 29.5, 29.3, 29.2, 26.0, 22.6,
14.0. MS (EI) m/z: 536 (M+). HRMS (EI) Calcd for C34H48O5:
536.3502. Found: 536.3494.
4.1.20. (1E,4E)-1-(3-(1-Ethoxyethoxy)phenyl)-5-(3,4,5-
trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y097)
Yellow oil. IR (CHCl3): 2976, 1650, 1619, 1581, 1504, 1320,
1127, 1102 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.69 (1H, d,
.
J = 15.8 Hz), 7.65 (1H, d, J = 15.8 Hz), 7.32 (1H, m), 7.26 (1H, m),
7.25 (1H, m), 7.08 (1H, d, J = 15.8 Hz), 7.06 (1H, m), 6.96 (1H, d,
J = 15.8 Hz), 6.85 (2H, s), 5.44 (1H, q, J = 5.3 Hz), 3.92, (6H, s), 3.90
(3H, s), 3.79 (1H, m), 3.57 (1H, m), 1.54 (3H, d, J = 5.3 Hz), 1.23
(3H, t, J = 6.9 Hz). 13C NMR (100 MHz, CDCl3) d 188.5, 157.2,
153.4, 143.4, 142.9, 140.3, 136.1, 130.1, 130.0, 125.3, 124.9,
122.0, 119.4, 116.7, 105.5, 99.4, 61.2, 61.0, 56.2, 20.2, 15.3. MS
(EI) m/z: 412 (M+). HRMS (EI) Calcd for C24H28O6: 412.1886. Found:
412.1901.
4.1.25. (1E,4E)-1,5-Bis(2,3,6-trimethoxyphenyl)penta-1,4-dien-
3-one (GO-Y106)
Yellow needle (AcOEt/hexane = 1:1): mp. 116–118 °C. IR
(CHCl3): 2938, 1644, 1578, 1485, 1256, 1107 cmꢀ1 1H NMR
.
(400 MHz, CDCl3)
d 8.05 (2H, d, J = 16.3 Hz), 7.64 (2H, d,
J = 16.3 Hz), 6.90 (2H, d, J = 8.9 Hz), 6.62 (2H, d, J = 8.9 Hz), 3.87
(6H, s), 3.87 (6H, s), 3.85 (6H, s). 13C NMR (100 MHz, CDCl3) d
192.2, 153.8, 150.0, 147.1, 133.8, 130.1, 118.8, 114.4, 105.9, 60.9,
56.5, 56.0. MS (EI) m/z: 414 (M+). HRMS (EI) Calcd for C23H26O7:
414.1679. Found: 414.1673. Anal. Calcd for C23H26O7: C, 66.65; H,
6.32. Found: C, 66.54; H, 6.37.
4.1.21. (1E,4E)-1-(3-Hydroxyphenyl)-5-(3,4,5-
trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y098)
Yellow plate (AcOEt/hexane = 1:1): mp 137–139 °C. IR (CHCl3):
3353, 1644, 1617, 1582, 1504, 1274, 1126 cmꢀ1
.
1H NMR
4.1.26. (1E,4E)-1-(3-Methoxyphenyl)-5-(3,4,5-
(400 MHz, CDCl3)
d
7.71 (1H, d, J = 16.0 Hz), 7.67 (1H, d,
trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y107)
Yellow oil. IR (CHCl3): 2939, 1650, 1619, 1581, 1504, 1319,
J = 16.0 Hz), 7.29 (1H, t, J = 7.8 Hz), 7.20 (1H, d, J = 7.8 Hz), 7.16
(1H, s), 7.09 (1H, d, J = 16.0 Hz), 6.96 (1H, d, J = 16.0 Hz), 6.91
(1H, d, J = 7.8 Hz), 6.84 (2H, s), 5.79 (1H, br s), 3.92, (6H, s), 3.91
(3H, s). 13C NMR (100 MHz, CDCl3) d 189.0, 156.3, 153.5, 143.9,
143.3, 140.5, 136.3, 130.2, 130.2, 125.3, 125.0, 121.0, 117.8,
115.0, 105.7, 61.0, 56.2. MS (EI) m/z: 340 (M+). HRMS (EI) Calcd
for C20H20O5: 340.1311. Found: 340.1295. Anal. Calcd for
C20H20O5: C, 70.57; H, 5.92. Found: C, 70.57; H, 6.07.
1267, 1245, 1126, 1102 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.71
.
(1H, d, J = 15.9 Hz), 7.66 (1H, d, J = 15.9 Hz), 7.33 (1H, t,
J = 8.0 Hz), 7.22 (1H, d, J = 8.0 Hz), 7.15 (1H, t, J = 2.0 Hz), 7.08
(1H, d, J = 15.9 Hz), 6.96 (1H, d, J = 15.9 Hz), 6.96 (1H, dd, J = 8.0,
2.0 Hz), 6.85 (2H, s), 3.92, (6H, s), 3.90 (3H, s), 3.86 (3H, s). 13C
NMR (100 MHz, CDCl3) d 188.7, 160.0, 153.5, 143.5, 143.1, 140.5,
136.2, 130.3, 130.0, 125.5, 125.0, 121.1, 116.3, 113.4, 105.7, 61.0,
56.2, 55.4. MS (EI) m/z: 354 (M+). HRMS (EI) Calcd for C21H22O5:
354.1467. Found: 354.1454.
4.1.22. (1E,4E)-1-(3,4,5-Trimethoxyphenyl)-5-(3-
(trityloxy)phenyl)penta-1,4-dien-3-one (GO-Y099)
Yellow amorphous. IR (CHCl3): 3007, 1650, 1618, 1581, 1504,
4.1.27. (1E,4E)-1-(3-(Methoxymethoxy)phenyl)-5-(3,4,5-
trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y108)
Yellow oil. IR (CHCl3): 2939, 1650, 1619, 1582, 1504, 1321,
1448, 1320, 1241, 1127 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.59
.
(1H, d, J = 16.0 Hz), 7.48 (1H, d, J = 16.0 Hz), 7.46 (6H, m), 7.31–
7.21 (9H, m), 7.05 (1H, d, J = 8.0 Hz), 7.00 (1H, t, J = 8.0 Hz), 6.96
1243, 1151, 1127, 1103, 1007 cmꢀ1 1H NMR (400 MHz, CDCl3) d
.

1092
H. Yamakoshi et al. / Bioorg. Med. Chem. 18 (2010) 1083–1092
7.70 (1H, d, J = 15.9 Hz), 7.66 (1H, d, J = 15.9 Hz), 7.33 (1H, t,
J = 7.6 Hz), 7.31 (1H, m), 7.26 (1H, d, J = 7.6 Hz), 7.09 (1H, m),
7.08 (1H, d, J = 15.9 Hz), 6.97 (1H, d, J = 15.9 Hz), 6.85 (2H, s),
5.22 (2H, s), 3.92, (6H, s), 3.90 (3H, s), 3.51 (3H, s). 13C NMR
(100 MHz, CDCl3) d 188.7, 157.7, 153.5, 143.5, 143.0, 140.5,
136.3, 130.3, 130.0, 125.6, 125.0, 122.3, 118.6, 115.5, 105.6, 94.5,
61.0, 56.2, 56.1. MS (EI) m/z: 384 (M+). HRMS (EI) Calcd for
C22H24O6: 384.1573. Found: 384.1555.
phenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium
monosodium salt in accordance with the manufacturer’s instruc-
tions (Dojindo Laboratories, Kumamoto, Japan) using a 96-well
plate reader, MPR-4Ai (Tosoh Corp., Tokyo, Japan). The percentage
cell growth of the control, which was treated with 1% DMSO alone,
was calculated and plotted, and then mean growth inhibitory con-
centration (GI50) was determined.
Acknowledgements
4.1.28. 3-((1E,4E)-3-Oxo-5-(3,4,5-trimethoxyphenyl)penta-1,4-
dienyl)phenyl trifluoromethanesulfonate (GO-Y109)
This work was partly supported by a Grant-in Aid for the Re-
search Fellowship for Young Scientists (H.Y) and Grant-in-Aid for
the Grobal COE Program for ‘International Center of Research &
Education for Molecular Complex Chemistry’ from Ministry of Edu-
cation, Culture, Sports, Science, and Technology, Japan.
Yellow amorphous. IR (CHCl3): 1651, 1622, 1581, 1504, 1419,
1320, 1212, 1127 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.70 (1H, d,
.
J = 15.7 Hz), 7.68 (1H, d, J = 15.9 Hz), 7.62 (1H, d, J = 7.9 Hz), 7.53
(1H, m), 7.51 (1H, t, J = 7.9 Hz), 7.31 (1H, dd, J = 7.9, 2.2 Hz), 7.12
(1H, d, J = 15.9 Hz), 6.95 (1H, d, J = 15.7 Hz), 6.86 (2H, s), 3.93,
(6H, s), 3.91 (3H, s). 13C NMR (100 MHz, CDCl3) d 187.9, 153.4,
149.8, 144.0, 140.6, 140.2, 137.5, 130.7, 129.9, 128.2, 127.1,
123.4, 122.5, 120.3, 118.6 (1C, q, J = 321.2 Hz), 105.6, 60.8, 56.0.
MS (EI) m/z: 472 (M+). HRMS (EI) Calcd for C21H19F3O7S:
472.4326. Found: 472.0775.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.12.045.
References and notes
4.1.29. (1E,4E)-1-Phenyl-5-(3,4,5-trimethoxyphenyl)penta-1,4-
dien-3-one (GO-Y110)
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.
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2009, 100, 956.
24. Paul, S.; Gupta, M. Synth. Commun. 2005, 35, 213.
25. Kreher, U. P.; Rosamilia, A. E.; Raston, C. L.; Scott, J. L.; Strauss, C. R. Org. Lett.
2003, 5, 3107.
26. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
27. Ohtsu, H.; Xiao, Z.; Ishida, J.; Nagai, M.; Wang, H.-K.; Itokawa, H.; Su, C.-Y.; Shih,
C.; Chiang, T.; Chang, E.; Lee, Y.; Tsai, M.-Y.; Chang, C.; Lee, K.-H. J. Med. Chem.
2002, 45, 5037.
28. Lin, L.; Shi, Q.; Nyarko, A. K.; Bastow, K. F.; Wu, C.-C.; Su, C.-Y.; Shih, C. C.-Y.;
Lee, K.-H. J. Med. Chem. 2006, 49, 3963.
4.1.30. (1E,4E)-1-(3-Chlorophenyl)-5-(3,4,5-
trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y111)
Yellow plate (AcOEt/hexane = 1:4): mp 102–104 °C. IR (CHCl3):
2938, 1651, 1620, 1581, 1504, 1418, 1318, 1126, 1102 cmꢀ1 1H
.
NMR (500 MHz, CDCl3) d 7.66 (2H, d, J = 15.8 Hz), 7.62 (1H, t,
J = 1.7 Hz), 7.48 (1H, dd, J = 8.0, 1.7 Hz), 7.38 (1H, dd, J = 8.0,
1.7 Hz), 7.35 (1H, t, J = 8.0 Hz), 7.11 (1H, d, J = 15.8 Hz), 6.93 (1H,
d, J = 15.8 Hz), 6.85 (2H, s), 3.92, (6H, s), 3.91 (3H, s). 13C NMR
(125 MHz, CDCl3) d 188.3, 153.6, 143.8, 141.5, 140.7, 136.7,
135.0, 130.3, 130.2, 130.1, 127.8, 126.8, 126.2, 125.1, 105.7, 61.0,
56.3. MS (EI) m/z: 358 (M+). HRMS (EI) Calcd for C20H19ClO4:
358.0972. Found: 358.0949. Anal. Calcd for C20H19ClO4: C, 66.95;
H, 5.34. Found: C, 66.93; H, 5.33.
4.1.31. (1E,4E)-1-(3-(Phenylethynyl)phenyl)-5-(3,4,5-
trimethoxyphenyl)penta-1,4-dien-3-one (GO-Y112)
Yellow oil. IR (CHCl3): 2938, 1651, 1619, 1582, 1504, 1418,
1322, 1127, 1101 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.81 (1H,
.
m), 7.72 (1H, d, J = 15.9 Hz), 7.67 (1H, d, J = 15.9 Hz), 7.65–7.54
(4H, m), 7.42–7.36 (4H, m), 7.15 (1H, d, J = 15.9 Hz), 6.96 (1H, d,
J = 15.9 Hz), 6.86 (2H, s), 3.92, (6H, s), 3.91 (3H, s). 13C NMR
(100 MHz, CDCl3) d 188.5, 153.5, 143.6, 142.1, 140.6, 135.1,
133.3, 131.6, 131.0, 130.2, 129.0, 128.5, 128.4, 128.3, 125.7,
125.1, 124.2, 122.9, 105.7, 90.2, 88.5, 61.0, 56.2. MS (EI) m/z: 424
(M+). HRMS (EI) Calcd for C28H24O4: 424.1675. Found: 424.1663.
4.2. Cell growth suppression analysis
HCT116 was obtained from the Cell Resource Center for Bio-
medical Research (Institute of Development, Aging and Cancer, To-
hoku University, Sendai, Japan). The growth suppressive effects of
the compounds were measured for 48 h. Cell viability was assayed
by quantifying the uptake and digestion of 2-(2-methoxy-4-nitro-
29. Das, U.; Sharma, R. K.; Dimmock, J. R. Curr. Med. Chem. 2009, 16, 2001.
30. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
31. Thuaud, F.; Bernard, Y.; Turkeri, G.; Dirr, R.; Aubert, G.; Cresteil, T.; Baguet, A.;
Tomasetto, C.; Svitkin, Y.; Sonenberg, N.; Nebigil, C. G.; Désaubry, L. J. Med.
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