Synthesis and in-vitro anti-cancer evaluations of multi-methoxylated asymmetrical diarylpentanoids as intrinsic apoptosis inducer against colorectal cancer

Article abstract of DOI:10.1016/j.bmcl.2020.127065

In the present study, a series of nine stable 3,4,5-methoxylphenyl-containing asymmetrical diarylpentanoids, derivatives of curcuminoids, have been synthesized, characterized and evaluated for their in-vitro anti-cancer potential against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, LoVo and SW620, HT29, RKO and NCI-H508, respectively. Structure-activity relationship study on cytotoxicity of tested compounds suggested that the presence of meta-hydroxyl and adjacent dimethoxyl groups are crucial for enhanced cytotoxicity of diarylpentanoids. Among the evaluated analogs, 8 has been identified as the lead compound due to its highest chemotherapeutic index of 9.9 and nano molar scale cytotoxicity against SW620 and RKO. Colonies formation and cell cycle analyses on 8-treated RKO cells showed that 8 exhibits strong anti-proliferative activity by inducing G2/M-phase cell arrest. Subsequent flow cytometry based annexin-V and DCFHDA studies suggested that 8 could induce apoptosis through intracellular ROS-dependent pathway. Further Western blot studies confirmed that 8 has induced intrinsic apoptosis in RKO cells through the up-regulations of Bad and Bax pro-apoptotic proteins and down-regulations of Bcl-2 and Bcl-xL pro-survival proteins. In all, the present results suggest that 8 could be a potent lead which deserves further modification and investigation in the development of small molecule-based anti-colorectal cancer agents.

Full text of DOI:10.1016/j.bmcl.2020.127065

Journal Pre-proofs
Synthesis and in-vitro anti-cancer evaluations of multi-methoxylated asymmet-
rical diarylpentanoids as intrinsic apoptosis inducer against colorectal cancer
Sze Wei Leong, Suet Lin Chia, Faridah Abas, Khatijah Yusoff
PII:
S0960-894X(20)30143-8
DOI:
https://doi.org/10.1016/j.bmcl.2020.127065
BMCL 127065
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Bioorganic & Medicinal Chemistry Letters
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25 February 2020
Please cite this article as: Wei Leong, S., Lin Chia, S., Abas, F., Yusoff, K., Synthesis and in-vitro anti-cancer
evaluations of multi-methoxylated asymmetrical diarylpentanoids as intrinsic apoptosis inducer against colorectal
cancer, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127065
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Synthesis and in-vitro anti-cancer evaluations of multi-methoxylated
asymmetrical diarylpentanoids as intrinsic apoptosis inducer against colorectal
cancer.
Sze Wei Leong a*, Suet Lin Chia a,b*, Faridah Abas b,c, Khatijah Yusoff a,d
aDepartment of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan,
Malaysia
bInstitute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia
cDepartment of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
dMalaysia Genome Institute (MGI), National Institute of Biotechnology Malaysia (NIBM), Jalan Bangi, 43000 Kajang, Selangor Darul Ehsan, Malaysia.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
In the present study, a series of nine stable 3,4,5-methoxylphenyl-containing asymmetrical
diarylpentanoids, derivatives of curcuminoids, have been synthesized, characterized and evaluated
for their in-vitro anti-cancer potential against a panel of BRAF- and KRAS-mutated colorectal
cancer cell lines including T84, LoVo and SW620, HT29, RKO and NCI-H508, respectively.
Structure-activity relationship study on cytotoxicity of tested compounds suggested that the
presence of meta-hydroxyl and adjacent dimethoxyl groups are crucial for enhanced cytotoxicity
of diarylpentanoids. Among the evaluated analogs, 8 has been identified as the lead compound
due to its highest chemotherapeutic index of 9.9 and nano molar scale cytotoxicity against SW620
and RKO. Colonies formation and cell cycle analyses on 8-treated RKO cells showed that 8
exhibits strong anti-proliferative activity by inducing G2/M-phase cell arrest. Subsequent flow
cytometry based annexin-V and DCFHDA studies suggested that 8 could induce apoptosis
through intracellular ROS-dependent pathway. Further Western blot studies confirmed that 8 has
induced intrinsic apoptosis in RKO cells through the up-regulations of Bad and Bax pro-apoptotic
proteins and down-regulations of Bcl-2 and Bcl-xL pro-survival proteins. In all, the present results
suggest that 8 could be a potent lead which deserves further modification and investigation in the
development of small molecule-based anti-colorectal cancer agents.
Keywords:
Diarylpentanoids
Colorectal Cancer
Cytotoxicity
Cell Cycle
Apoptosis
2009 Elsevier Ltd. All rights reserved.
Colorectal cancer (CRC) is the 3rd most common type of cancer
and 2nd leading cause of cancer death worldwide. According to
Globocan 2018, there were 1.8 million people who were diagnosed
with CRC and the death number has exceeded 850,000 cases.
Worrying, these numbers are estimated to be escalated to
approximately 3.1 and 1.3 million, respectively, by 2040.1 On top
of this, CRC has caused a total economic impact of 99 billion USD
globally in 2008 and this number is expected to be increased
exponentially along with the rapid rising of CRC patient number.2
Based upon these, effective treatments with better safety profile
and cheaper cost are urgently needed to reduce the impact of
cancers on global human and economic health.
inhibiting
thymidylate
synthase
that
necessary
for DNA synthesis.3,4 Due to their different in mechanism of
actions, these chemotherapeutic agents are often used as
synergistic combination to treat advanced or metastatic CRC.
Unfortunately, although such combination possesses enhanced
anti-tumor activity, its therapeutic potential was cushioned off by
the associated side effects including nausea, diarrhea, hand-foot
syndrome and neuropathy.5,6 These unpleasant side effects not
only restrict the full anti-cancer potential of the respective
chemotherapy but also reduce the quality of life of the cancer
patients. On this account, safer and more effective drugs are
therefore needed.
To date, available treatments of CRC are solely based on
surgery and chemotherapy. Oxaliplatin and 5-fluorouracil (5-FU)
are the mainstay in CRC treatments. Oxaliplatin is a platinum
metal complex that disrupts DNA replication and transcription by
forming intrastrand platinum-DNA crosslinks while 5-FU is a
pyrimidine antimetabolite that interrupts DNA synthesis by
Among the natural occurring small molecules, curcumin, the
major chemical constituent of turmeric, has been suggested as the
most potent candidate in the search of alternative cancer
therapeutic agents based upon its remarkable anti-cancer
properties. In past few decades, curcumin was showed to inhibit
various cancer cell lines including lung, bladder, colorectal, breast

Scheme 1. General synthetic steps for compounds 1-9x
and prostate cancer cells through multiple pathways while having
excellent safety profile with extremely mild toxicity in-vivo.5–9
Unfortunately, several studies revealed that curcuminoids are
chemically unstable as their unsaturated β-diketone fragment tends
to be cleaved by aldo-keto reductase of liver cells, which thereby
reduce its therapeutic potential.10–12 Based upon this,
monocarbonyl diarylpentanoids,
a
bioactive family of
xReagents and conditions: (a) morpholine, p-toluene-sulfonic acid, toluene,
reflux (2 h); (b) 3,4,5-trimethoxy benzaldehyde, 80˚C (8 h); (c) H2O, reflux
(0.5 h); (d) benzaldehyde, EtOH, 6M NaOH, RT (overnight).
curcuminoid derivatives without the reactive β-diketone moiety
has been the focus of curcuminoid-based studies.
Scheme 1 represents the synthetic pathway of 3,4,5-
trimetoxyphenyl-containing diarylpentanoids. As depicted in
scheme 1, compounds 1-9 were prepared in 2-steps manner which
involved Stork enamine alkylation and aldol condensation.26 Stork
enamine alkylation was first performed by reacting cyclohexanone
with morpholine under reflux condition to achieve intermediate I.
The crude product of intermediate I was then reacted with 3,4,5-
trimethoxybenzaldehyde to afford intermediate II. Upon
purification, intermediate II was further reacted with appropriate
benzaldehydes to achieve target compounds 1-9. Since the final
compounds are asymmetrical diarylpentanoids, the detection of
two singlets at chemical shift of 7.5-8.0 ppm in the proton NMR
spectra is therefore the evidence to confirm the presence of desired
compounds as these two peaks represent the vinylic protons of two
differently substituted bezylidene All synthesized compounds
were purified by column chromatography and characterized by 1H-
NMR, 13C-NMR, and high-resolution electron impact-mass
spectrometry (HRMS). The purity of synthesized compounds was
confirmed to be greater than 95% based on their respective HPLC
profiles. The synthesized compounds were listed in Table 1.
Monocarbonyl diarylpentanoids is a 5-carbon spacer bioactive
family which derived from curcumin by replacing the unstable
diketone moiety with mono ketone fragment. Several studies have
proven that the replacement of such moiety has improved their
stability chemically and metabolically.13,14 Monocarbonyl
diarylpentanoids were found to exhibit excellent anti-cancer
properties based on their anti-proliferative and anti-angiogenetic
effects on various cancer cell lines including breast, lung, colon,
pancreatic and prostate cancer cells.15–19 Meanwhile, several
mechanistic studies showed that monocarbonyl diarylpentanoids
could induce cancer cells’ death through Bcl-2 proteins inhibition
and caspases activation.20–23 Based upon these, monocarbonyl
diarylpentanoid derivatives are therefore a potent family to replace
curcumin in the search of alternative cancer therapeutic agents.
Although diarylpentanoids can be isolated from natural products,
its respective experimental procedures are less cost effective yet
time consuming.24 Therefore, structural modification through
chemical synthesis is currently being pursue. In our previous
study, we have demonstrated that 3,4,5-trimethoxyphenyl moiety
is superior for the anti-cancer activity of monocarbonyl
diarylpentanoid derivatives.25 Thus, in continuing our efforts in
optimizing the monocarbonyl diarylpentanoids, the aim of the
present study is to develop a series of 3,4,5-trimethoxyphenyl-
containing diarylpentanoids and evaluate for their oncolytic
potential.
Table 1. Chemical structures of compounds 1-9
Cmpd
Structure
Cmpd
Structure
Cmpd
7
Structure
1
4
2
5
6
8
9
3
Cmpd = Compound
The in-vitro cytotoxic activity of the synthesized
diarylpentanoids on KRAS (T84, LoVo and SW620) and BRAF
(HT29, RKO and NCI-H508) mutated human colorectal cancer
cell lines were determined by MTT assay as previously
described.25 The preliminary screening results obtained are
summarized Figure 1.

Figure 1. Inhibitory activities of synthesized compounds against KRAS (T84,
LoVo and SW620) and BRAF (HT29, RKO and NCI-H508) mutated human
colorectal cancer cell lines at a testing concentration of 10 µM. The red line
across the graph represents the threshold percentage for further IC50
determination
effect against different cell lines, IC50 determination and SAR
study were performed. Table 2 has summarized the IC50 values of
the synthesized compounds on various cell lines, in which 5-FU
and normal human dermal fibroblasts (NHDF) were served as
controls. Meanwhile, since 7 and 9 have been reported as strong
anti-cancer agents, they therefore were served as reference
compounds to evaluate the successfulness of the present
optimization study in improving the anti-cancer potential of
diarylpentanoid system.25
As expected, all synthesized diarylpentanoid analogs showed
significant cytotoxicity against all tested cancer cell lines at a
testing concentration of 10 µM. This has confirmed the superior
anti-cancer activity of 3,4,5-trimethoxyphenyl fragment. To
further inspect the role of different functional groups on cytotoxic
Table 2. Cytotoxicity of 1-9 on T84, LoVo and SW620, HT29, RKO and NCI-H508 and NHDF cell lines
IC50 (µM)
Chemotherapeutic
Compound
R1
KRAS
BRAF
NHDFb
index
T84a LoVoa SW620a HT29a RKOa NCI-H508a
5-FU
-
>10
4.2
3.5
3.9
2.2
3.6
6.5
2.1
1.8
1.9
2.7
2.8
2.3
2.6
1.9
2.7
4.8
1.1
1.1
1.7
>10
3.3
4.1
4.5
2.1
3.2
>10
2.0
0.8
1.6
>10
2.8
1.7
3.2
1.6
8.5
7.6
1.2
3.4
1.5
2.9
2.5
2.2
3.6
1.5
3.1
6.5
1.2
0.7
1.3
8.8
2.7
4.0
4.8
2.0
7.0
5.6
2.2
4.0
1.7
>50
12.4
11.1
18.8
4.0
9.0
25.3
7.9
-
1
2
3
4
5
6
7
8
9
2-Br
2-F
3.0-5.0
2.7-6.5
3.9-7.2
1.8-2.7
1.1-3.3
3.3-5.3
3.6-7.2
1.8-9.9
3.1-4.5
2-OMe
3.4-F
3,4-OH
3-Cl-4OH
2,3-OMe
3-OH
6.9
5.8
3,4-OMe
a Colorectal cancer cells
b Normal human dermal fibroblast cells
As shown in Table 2, all synthesized compounds except 5 and
6 have displayed excellent cytotoxicity on all tested cancer cell
lines (< 5 µM) in which 8 was found to be the most potent
candidate due to its highest chemotherapeutic index of 9.9 and
lowest IC50 values of 0.8 and 0.7 µM against SW620 and RKO,
respectively. Meanwhile, three other compounds (4,7 and 9) were
found to possess strong cytotoxicity based on their IC50 values of
approximately 2 µM across all tested cancer cell lines. However,
among these three strong cytotoxic agents, 4 was having the least
potential due to its relatively higher toxicity against human normal
cells. It is noteworthy that all synthesized compounds have
displayed similar cytotoxicity against both BRAF and KRAS
mutated cancer cell lines which suggests that the desired
diarylpentanoids system may not be BRAF- or KRAS-specific
inhibitors. Further SAR study revealed that meta-hydroxyl and
adjacent dimethoxyl moieties are crucial for better cytotoxicity of
diarylpentanoids as 7, 8 and 9 have displayed improved activities
in comparison to that of other analogs. In contrast, para-
hydroxylphenyl was found to be an undesired fragment as
compounds with such substitution (5 and 6) have displayed much
lower cytotoxicity as compared to the rest of synthesized
compounds. These results are in consistent with our previous
findings in which the presence of meta-hydroxyl and adjacent
dimethoxyl
moieties
improved
the
cytotoxicity
of
diarylpentanoids while the insertion of para-hydroxyl group
reduced their anti-cancer potential.25 Interestingly, when a
comparison was made between the most active compounds (7, 8
and 9), meta-hydroxylphenyl was found to be a more desirable
substitution pattern than adjacent methoxy groups as 8, a meta-
hydroxylated diarylpentanoid has achieved lower IC50 values than
its dimethoxylated analogs
7 and 9. Noteworthy, 3,4-
difluorophenyl fragment may not be an interesting substitution
pattern as compound with such moiety (4) has displayed strong
toxicity against human normal cells. Thus, based on the promising
cytotoxicity and relatively higher chemotherapeutic index of 8, it
was selected for further colony formation and cell cycle
analysis.27,28 The results obtained were compiled in Figure 2.

Figure 2. Effects of 8 on colonies formation (A) and cell cycle (B) of RKO cells.
As depicted in Figure 2A, the colonies of RKO cells were
population of RKO cells from 20% to 50%. Thus, based on both
anti-proliferative and cell cycle analysis, the present results
suggest that 8 inhibits proliferation of RKO cells through G2/M-
phase cell arrest. To further investigate the underlying cytotoxic
mechanisms of 8 on RKO cell line, flow cytometry and Western
blot studies were performed and the results obtained were
summarized in Figure 3.29,30
completely inhibited by 8 at the testing concentrations of 1.25, 2.5
and 5 µM while only very little colonies were observed in cells
treated with 0.625 µM of the same compound. This dose-
dependent inhibition implies that
8 exhibits strong anti-
proliferative activity against RKO cell line. Subsequent cell cycle
analysis showed that 8 could induce G2/M arrest in RKO cells as
the treatment with 2.5 µM of 8 has drastically increased the G2/M
Figure 3. Representative annexin-V-based apoptosis (A) and intracellular ROS profiles (B) of 8-treated RKO cells at selected time points.
Western blot analysis on executioner caspases (C) initiator caspases (D) as well as pro-survival and pro-apoptotic (D) proteins in 8-treated
RKO cells at 24h, 48h and 72h of post-treatments.
As depicted in Figure 3A, density plots that represent cell
populations were found to shift from left to right and upper right
as the treatment concentrations of 8 increased. This observation
suggests that 8 is a dose-dependent apoptosis inducer as such
shifting pattern indicates the initiation and progression of cell
apoptosis. Meanwhile, similar shifting of cell populations was also
being observed when the treatment period was prolonged to 48h
and 72h. This implies that 8 is also a time-dependent apoptosis
inducer. In order to validate the apoptosis inducing ability of 8,
Western blot analysis on procaspases-3 and -7 were performed. As
shown in Figure 3C, the cellular pools of both procaspases-3 and
-7 were found to be depleted upon the treatment with 8. This
observation thus confirmed the presence of apoptosis in 8-treated
RKO cells as procaspases-3 and -7 are the two critical proenzyme
which will be cleaved into activated caspases-3 and -7 to initiate
cell apoptosis.31 In order to identify the type of apoptosis induced
by 8, its effects on caspases-8 and -9 were studied.32 As showed in
Figure 3D, treatment with 8 has successfully down-regulated and
up-regulated the expression of procaspase-9 and caspase-9,
respectively. This observation indicates that 8 could induce
intrinsic apoptosis in RKO cells. Meanwhile, the expression of
caspase-8 was found to be independent to the treatment of 8 which
suggests that extrinsic apoptosis is not responsible for the 8-
mediated cell death. Based upon these, 8 is therefore confirmed to
be an intrinsic apoptosis inducer.
In order to further elucidate the apoptotic mechanism caused
by 8, its effects on intracellular ROS as well as pro-survival and
pro-apoptotic proteins were studied. As depicted in Figure 3B, the
fluorescence intensities of the treated cells were found to be
directly proportional to the concentrations of 8. This shows that 8
could trigger intracellular ROS production in dose-dependent
manners, which in turn implies that ROS is involved in the
apoptosis induction of 8 on RKO cells. Meanwhile, as shown in
the Western blot analysis on pro-survival proteins (Figure 3E),
24h treatment with 8 has successfully reduced the protein
expression of Bcl-2 and Bcl-xL which indicates that 8 could
inhibits both Bcl-2 and Bcl-xL proteins as early as 24h of post-
treatment. Noteworthy, a drastic increment of Bcl-xL expression
was observed when the compound treatment was prolonged to
72h. This selective up-regulation of Bcl-xL could be rationalized
by the activated defensive and survival machinery of 8-treated
RKO cells as Bcl-xL has been reported to be a more effective anti-
apoptotic protein against cell apoptosis.33 However, the activation
of proposed defensive and survival machinery in 8-treated RKO
cells may be overcome by the pro-apoptotic behavior of 8 as

treatment with such compound has successfully up-regulated both
Bad and Bax proteins. Taken all together, the present results
confirmed that 8 is a dose- and time-dependent apoptosis inducer
which could induce ROS-dependent intrinsic apoptosis through
the up-regulations of Bad and Bax as well as down-regulation of
Bcl-2 and Bcl-xL proteins. The results are summarized in Figure
4.
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Figure 4. Illustration of intrinsic apoptosis mechanism induced by
8 on RKO cells.
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In all, the present study has successfully optimized the anti-
cancer potential of diarylpentanoid system as compound 8, a new
diarylpentanoid analog was found to exhibit improved cytotoxicity
in comparison to that of previously reported compounds 7 and 9.
Apart from showing nano molar scale cytotoxicity, 8 was found to
possess strong anti-proliferative activity through G2/M cell cycle
arrest. On top of this, 8 was also found to induce intrinsic apoptosis
by altering both pro-apoptotic and pro-survival proteins. Thus,
based on present findings, it is plausible to conclude that 8, a
diarylpentanoid system containing both 3,4,5-trimethoxyphenyl
and meta-hydoxyphenyl moieties, is a potent anti-cancer candidate
which deserves further extensive studies including structural
modification on the cyclohexanone bridge as well as in-vivo
pharmacokinetic and pharmacodynamic analyses. The present
study not only successfully optimized the iarypentanoid structure
but also
10. Zhao C, Liu Z, Liang G. Promising Curcumin-based Drug
Design: Mono-carbonyl Analogues of Curcumin (MACs).
Curr Pharm Des. 2013. doi:10.2174/1381612811319110012
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Acknowledgments
13. Liang G, Shao L, Wang Y, et al. Exploration and synthesis
of curcumin analogues with improved structural stability
both in vitro and in vivo as cytotoxic agents. Bioorganic Med
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The authors thank the Newton-Ungku Omar Fund
(MR/P012795/1) and Universiti Putra Malaysia for supporting
SW. Leong under the post-doctoral programme.
Supplementary Material
14. Leong SW, Mohd Faudzi SM, Abas F, et al. Nitric oxide
inhibitory activity and antioxidant evaluations of 2-benzoyl-
6-benzylidenecyclohexanone analogs, a novel series of
curcuminoid and diarylpentanoid derivatives. Bioorganic
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Supplementary data to this article can be found online at
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curcumin, 1,5-bis(3-hydroxyphenyl)-1,4- pentadiene-3-one
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests: