Design and biological characterization of hybrid compounds of curcumin and thalidomide for multiple myeloma

Article abstract of DOI:10.1039/c3ob40595h

In our efforts to develop effective treatment agents for human multiple myeloma (MM), a series of hybrid molecules based on the structures of thalidomide (1) and curcumin (2) were designed, synthesized, and biologically characterized in human multiple myeloma MM1S, RPMI8226, U266 cells, and human lung cancer A549 cells. The biological results showed that two hybrid compounds, 5 and 7, exhibited significantly improved lethal effects towards all three human MM cell models compared to 1 or 2 alone, as well as the combination of 1 and 2. Furthermore, mechanistic studies in U266 cells demonstrated that 5 and 7 can induce the production of reactive oxygen species (ROS) and cause G1/S arrest, thus leading to apoptosis and cell death. Additionally, they exhibited inhibitory effects on NFκB activation in A549 cells. Collectively, the results obtained from these hybrid compounds strongly encourage their further optimization as new leads to develop effective treatment agents for human MM.

Full text of DOI:10.1039/c3ob40595h

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Design and biological characterization of hybrid
compounds of curcumin and thalidomide
Cite this: DOI: 10.1039/c3ob40595h
Received 25th March 2013,
Accepted 7th June 2013
for multiple myeloma†
Kai Liu,‡a Datong Zhang,‡b Jeremy Chojnacki,a Yuhong Du,c Haian Fu,c
DOI: 10.1039/c3ob40595h
Steven Grantd and Shijun Zhang*a
www.rsc.org/obc
In our efforts to develop effective treatment agents for human to control morning sickness during pregnancy in the 1950s,
multiple myeloma (MM), a series of hybrid molecules based on but was withdrawn due to severe teratogenicity.6,7 1 has been
the structures of thalidomide (1) and curcumin (2) were designed, recently reintroduced as an effective MM treatment either as a
synthesized, and biologically characterized in human multiple stand-alone therapy or in combination with other chemothera-
myeloma MM1S, RPMI8226, U266 cells, and human lung cancer peutic agents, due to its activities in modulating the immune
A549 cells. The biological results showed that two hybrid com- system and disturbing the microenvironment of tumor cell
pounds, 5 and 7, exhibited significantly improved lethal effects growth in bone marrow.8–11 Although the response rate and
towards all three human MM cell models compared to 1 or 2 patient survival of MM patients have significantly improved
alone, as well as the combination of 1 and 2. Furthermore, upon treatment with 1, certain toxicities are associated with it,
mechanistic studies in U266 cells demonstrated that 5 and 7 can such as venous thromboembolism,12 that need to be managed.
induce the production of reactive oxygen species (ROS) and cause Curcumin (2, Fig. 1), a yellow spice and pigment isolated from
G1/S arrest, thus leading to apoptosis and cell death. Additionally, the rhizome of Curcuma longa, has been traditionally used as a
they exhibited inhibitory effects on NFκB activation in A549 cells. food coloring additive.13 Recently, 2 has attracted extensive
Collectively, the results obtained from these hybrid compounds interest as both a preventive and treatment agent in a variety
strongly encourage their further optimization as new leads to of disease models, such as arthritis, cancer, and Alzheimer’s
develop effective treatment agents for human MM.
disease (AD).14–18 Notably, 2 has been shown to exhibit cyto-
toxic effects in MM models and to potentiate the effects of
other therapeutic agents, including 1, in MM disease
models.10
Multiple myeloma (MM), an incurable plasma cell malignancy,
is characterized by disordered growth of terminally differen-
tiated plasma cells and is the second most common hemato-
poietic cancer.1,2 In the United States, 50 000 patients are
currently affected by MM. Approximately 10 000 of these
patients die each year.3 With the advances in understanding
the molecular mechanisms of MM, novel agents with more
defined molecular targets have been successfully developed
and added to the armamentarium for treatment of MM, such
as immunomodulatory drugs (IMiDs) including thalidomide
(1, Fig. 1) and proteasome inhibitors.4,5 1 was first introduced
Recently, the “hybrid molecule” strategy has drawn
increased attention in drug design and development.19–22 Con-
ceptually, this strategy incorporates structural features that are
essential to the biological activities of different drug structures
into a single molecule. Compared to the combination of mul-
tiple drugs, hybrid molecules may provide certain advantages:
(1) enhanced potency by self-synergy within one molecule that
may not be achievable by a traditional combination of separ-
ately dosed agents that may miss the ideal timing window; (2)
reduced risk of developing drug resistance; and (3) improved
pharmacokinetic properties and reduced toxic side effects
compared to the administration of multiple agents. Addition-
ally, such hybrid molecules may provide the advantages of
reduced cost and improved patient compliance, which are
sometimes as significant as drug resistance and toxicity.
Herein, we report the design and biological characterization of
a series of hybrid compounds of 1 and 2 as potential treatment
agents for MM.
aDepartment of Medicinal Chemistry, Virginia Commonwealth University, Richmond,
Virginia, USA. E-mail: szhang2@vcu.edu
bSchool of Chemistry and Pharmaceutical Engineering, Shandong Polytechnic
University, Jinan, Shandong, P.R. China
cDepartment of Pharmacology and Emory Chemical Biology Discovery Center,
Emory University, Atlanta, GA, USA
dDepartment of Internal Medicine and Massey Cancer Center,
Virginia Commonwealth University, Richmond, Virginia, USA
†Electronic supplementary information (ESI)
10.1039/c3ob40595h
available. See DOI:
Since the phenolic oxygen of 2 can be modified without a
significant influence on its biological activity, compound 3
‡These authors contributed equally to the manuscript.
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Fig. 1 Molecular design of curcumin–thalidomide hybrids.
was therefore designed to simply link 1 and 2 into one mole- The coupling reaction of 9 with 2 in the presence of EDC in
cule through an ester linkage (Fig. 1). Hybrid 4 was designed dichloromethane afforded compound 3 (Scheme 1). The
using the phthalimide moiety of 1 to replace one of the bromide intermediate 12, prepared by following a reported
4-hydroxy-3-methoxy-phenyl rings of 2. Hybrid 5 was con- method,24 was oxidized by IBX to afford the desired aldehyde
structed to incorporate the structural features of 1 and 2 13. To prepare compound 4, intermediate 11 prepared from
through a benzylidene connection at the methylene position vanillin 10 was first reacted with BF3·Et2O to form a complex,
between the two carbonyls of 2. The results from 4 and 5 will which was condensed with aldehyde 13 under Pabon reaction
shed light on optimizing the positions for hybridization, as well conditions to yield 14. Refluxing of 14 in the mixture of MeOH
as on whether both of the 4-hydroxy-3-methoxy-phenyl rings of and DMSO afforded 4. The condensation reaction of aldehyde
2 are needed for activity. Compound 6 will further confirm the 13 with 11, catalyzed by acetic acid and morpholine under
importance of the 4-hydroxy-3-methoxy-phenyl rings of 2 on bio- microwave irradiation, yielded compound 6 as the major
logical activity. Recently, a mono-ketone analog of 2 has been product. In the presence of piperidine and tributylborate, con-
designed and shown to be more potent than 2.23 Therefore, 7 densation of aldehyde 13 with curcumin 2 afforded 5. Com-
was designed to evaluate whether a mono-ketone hybrid will pound 7 was prepared by condensation of aldehyde 13 with
produce improved biological activities.
15, which was prepared from vanillin 10 and acetone, in the
The syntheses of the designed compounds were achieved presence of BF3·Et2O in dioxane.26
through the conditions listed in Schemes 1 and 2. Briefly, tha-
After synthesis, we initially tested these compounds in
lidomide carboxylic acid 9 was prepared from 1,2,4-tribenzene- human MM1S, U266, and RPMI8226 cells at a single concen-
carboxylic anhydride 8 by following reported procedures.25 tration of 10 μM to confirm their cytotoxic effects. 1 and 2
Scheme 1 Reagents and conditions: (a) ref. 25; (b) curcumin, EDC, DMAP, DCM, 46%.
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Scheme 2 Reagents and conditions: (a) i. B2O3, acetylacetone, EtOAc, ii. vanillin, (BuO)3B, nBuNH2, iii. 1 M HCl, 60%; (b) IBX, DMSO, 90%; (c) i. BF3·Et2O, EtOAc,
ii. aldehyde 13, (BuO)3B, nBuNH2, EtOAc, 39%; (d) MeOH, DMSO, 22%; (e) aldehyde 13, B2O3, AcOH, morpholine, microwave 200 W, 5 min, 25%; (f) curcumin,
(BuO)3B, piperidine, EtOAc, 10%; (g) acetone, NaOH, 87%; (h) compound 15, BF3·Et2O, dioxane, 25%.
Fig. 2 Antiproliferative activity of hybrid molecules. (A) RPMI8226 cells, (B) MM1S cells, (C) U266 cells were treated with indicated compounds at 10 μM for 48 h
and cell viability was analyzed by MTT (data are expressed as mean percentage viability with vehicle control set at 100% viability. Error bars represent SEM from
three independent experiments and at least each data point was tested in triplicate in each experiment); (D) IC50s (calculated based on the four parameter dose–
response analysis function in Prism to fit five doses of 0.3, 1, 3, 10, 30 μM and corresponding viability) of indicated compounds in RPMI8226, MM1S, and U266 cells.
alone and the combination of 1 and 2 were compared as con- consistent with the literature report that a minimum of 50 μM
trols. As shown in Fig. 2A–2C, 2 (10 μM) decreased the cell concentration is needed for 1 to exhibit significant cytotoxic
growth of MM1S, U266, and RPMI8226 cells by 45.0%, 42.5%, effects in MM cells.4 The combination of 1 and 2 exhibited
and 58.6% respectively. However, 1 did not exhibit antiproli- comparable anti-proliferative activity as 2 alone. The ester
ferative activity at this concentration by itself. This is analog 3 (10 μM) decreased the cell viability of MM1S, U266,
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and RPMI8226 cells by 32.8%, 21.8%%, and 47.5%, respect- increase, respectively). This dose-independent mode of action
ively, i.e., is comparable to 2. Compound 4 also showed com- in ROS induction is possibly due to the unique mono-ketone
parable antiproliferative activities against MM1S, RPMI8226, structure of 7 and the antioxidant effects of the phenol group
and U266 cells to 2. This may suggest that replacement of one in this structure at higher concentrations, but further studies
of the 4-hydroxy-3-methoxy-phenyl rings of 2 with the phthal- are warranted to better understand such a dose-independent
imide moiety can retain antiproliferative activity. Notably, com- nature. The ROS level steadily decreased with the increase of
pound 5 significantly inhibited the cell growth of all three cell exposure time for both compounds, even to a level that is
lines by ≥90% at 10 μM. On the other hand, 6 exhibited no sig- lower than the control after 6 h treatment. ROS have also been
nificant activity against all three cell lines at this concen- demonstrated to induce apoptosis or necrosis in many cancer
tration, thus indicating that the 4-hydroxy-3-methoxy- cell models.27,30 Since our compounds induced significant oxi-
benzylidene moiety is essential to the antiproliferative activity dative stress in U266 cells, we next investigated whether 5 and
of 5. The mono-ketone hybrid 7 also significantly inhibited the 7 can induce apoptosis in U266 cells to investigate the
growth of all three cell lines compared to 5. With these results molecular mechanisms of their cytotoxicity. As demonstrated
in hand, we then tested 5 and 7 against MM1S, RPMI8226, and in Fig. 3, because the ROS level decreased to normal or even
U266 cells in dose–response studies to obtain potency infor- below control level after 6 h treatment, we decided to analyze
mation. As shown in Fig. 2D, 5 exhibited IC50s of 6.44 0.85, the apoptotic effects of 5 and 7 at 4, 6 and 24 h time points
4.55 0.40, and 3.96 0.84 μM for MM1S, RPMI8226, and and to see whether there is any association between ROS pro-
U266 cells, respectively, and 7 exhibited IC50s of 7.59 3.31, duction and induction of apoptosis if apoptotic effects are
5.62 2.92, and 2.33 0.63 μM for MM1S, RPMI8226, and observed. As shown in Fig. 4, 5 and 7 induced mainly early
U266 cells, respectively. In general, U266 cells are more sensi- apoptosis at 10 μM concentrations after 6 h treatment (26.7%
tive to these hybrid compounds; therefore, U266 cells were and 10.4% increase, respectively), but apoptosis was only
employed for the following mechanistic studies.
slightly induced at 3 μM concentrations for this time course.
Reactive oxygen species (ROS) can be double-edged swords, No apoptotic effects were observed at 4 h treatment (data not
depending upon their concentrations and cellular shown). Prolonged treatment (24 h) induced significant
localizations.27–30 Many anticancer agents, including 2, have apoptosis by both compounds at both 3 μM and 10 μM
been demonstrated to exert their cytotoxic effects through the concentrations (14.8% and 79.2% increase for 5; 9.1% and
generation of ROS.31 Therefore, we decided to investigate 54.1% increase for 7). Comparing the time course of ROS
whether 5 and 7 induce the production of ROS that could production and apoptosis induction, it may suggest that
potentially lead to the cytotoxic effects observed in U266 cells. ROS production triggers the apoptosis of U266 cells
As shown in Fig. 3, 2 dose-dependently increased ROS pro- upon treatment with compounds
5 and 7. To further
duction at 1 h treatment, and the level of ROS is reduced after confirm the association between ROS production and
longer exposure. Notably, 5 significantly increased the pro- apoptosis, an N-acetyl-cysteine (NAC, an ROS scavenger agent)
duction of ROS at 1 h treatment in U266 cells at both 3 and rescue experiment was performed. As shown in Fig. 5,
10 μM concentrations (1.6 and 2.2 fold increase, respectively). NAC (8 mM) did not induce apoptosis by itself; however, it
Compound 7 also significantly increased the production of completely blocked the apoptotic effects induced by 5 and 7
ROS at 1 h treatment in U266 cells at both 3 and 10 μM con- at this concentration, thus demonstrating that ROS production
centrations. Interestingly, ROS induction by 7 at 3 μM is stron- is a direct cause of 5- or 7-mediated apoptotic cell death
ger than that at 10 μM at this time point (1.9 and 1.7 fold of U266 cells.
Fig. 3 ROS production in U266 cells. U266 cells were treated with indicated compounds at indicated concentrations for indicated intervals, then DCFH-DA (10 μM)
was loaded and fluorescence intensity was analyzed by flow cytometry. Data are expressed as mean percentage of ROS production with vehicle control set at 100%
from three independent experiments (at least each data point was tested in triplicate in each experiment). Error bars represent SEM. *p < 0.05, **p < 0.01, ***p <
0.001 vs. vehicle.
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Fig. 4 Apoptotic effects of 5 and 7 on U266 cells. U266 cells were treated with indicated compounds at indicated concentrations for 6 h and 24 h, and then the
cells were stained with Annexin V/PI and analyzed by flow cytometry. Data are expressed as mean value SEM from two independent experiments.
cells.40 Due to their well-defined cell morphology, we have
employed A549 cells as a model system and developed a highly
quantitative method to monitor the nuclear translocation as a
NFκB activation readout in an automated imaging-based high
content analysis (HCA) assay. Therefore we initially used this
well-defined quantitative assay in the A549 model system to
evaluate the effect of compounds 5 and 7 on NFκB activation.
Notably, as shown in Fig. 6B, both 5 and 7 inhibited the acti-
vation of NFκB in A549 cells upon stimulation with TNFα
(10 ng mL−1) with an IC50 of 5.2 and 5.6 μM, respectively, a
potency comparable to the potency of growth inhibition on
MM cells. Microscopy examination (Fig. 6C) also clearly
demonstrated that 5 dose-dependently inhibited the activation
and translocation of NFκB into the nucleus of A549 cells upon
stimulation with TNFα.
In summary, hybrid compounds of thalidomide (1) and cur-
cumin (2) were successfully designed and synthesized. The bio-
logical tests in human MM cells established that compounds 5
and 7, designed hybrids of 1 and 2, exhibited superior cyto-
Fig. 5 Protection of U266 cells from 5- and 7-induced apoptosis by NAC. U266
cells were treated with NAC (8 mM) and indicated compounds for 24 h, and
then cells were stained with Annexin V/PI and analyzed by flow cytometry. Data
are expressed as mean value SEM from two independent experiments.
toxic effects than 2 alone or the combination of 1 and 2.
Further mechanistic studies in U266 cells demonstrated that
both 5 and 7 can induce significant apoptotic cell death of
U266 cells that could be due to the induction of ROS pro-
duction and cell arrest at the S phase. Furthermore, 5 and 7
both exhibited potent inhibition on NFκB activation in A549
cells. Taken together, the results demonstrated that the hybrid
compounds exhibit all the properties reported for 1 and 2 but
are significantly more potent than both of them, thus
suggesting that the hybrid strategy in drug design could lead
to novel compounds with improved biological activities. Fur-
thermore, the results also strongly encourage further optimiz-
ation of 5 and 7 as new lead compounds to develop more
potent agents as treatment options for human MM.
ROS have also been implicated as having an important role
in the progression from G1 to S phase.32 Furthermore, 2 has
been reported to induce a G1/S arrest of cancer cells,33,34 and 1
to interfere with the cell cycle of MM cells.35 Therefore, we
determined the effects of 5 and 7 on the cell cycle of U266
cells. As shown in Fig. 6A, treatment with 5 or 7 (3 μM) signifi-
cantly arrested U266 cells at the S phase (21.67% and 23.98%
increase, respectively), an event accompanied by a decrease of
the G2/M population (16.36% and 22.74% decrease, respect-
ively). This may suggest that ROS-induced cell cycle arrest at
the S phase led to the apoptotic cell death of U266 cells upon
treatment with 5 or 7.
NFκB activation has been suggested to play a critical role in
the survival of MM cells and in the progression of MM.36,37
Furthermore, both 1 and 2 have been shown to inhibit NFκB
activation in cancer models.38,39 Our previous research has
Acknowledgements
demonstrated that the upregulated NFκB signaling pathway We thank Professor Glen E. Kellogg of the Department of Med-
can be blocked by curcumin analogues in lung cancer A549 icinal Chemistry, Virginia Commonwealth University for
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Fig. 6 Cell cycle arrest and inhibition of NFκB activation by 5 and 7. (A) U266 cells were treated with indicated compounds for 24 h, DNA content was then ana-
lyzed by flow cytometry (data are expressed as mean value from three independent experiments and error bars represent SEM); (B) A549 cells were treated with 5
or 7 at indicated concentrations for 30 min, followed by stimulation with TNFα (10 ng mL−1) for 30 min. Cells were fixed, stained, and analyzed by confocal
microscopy; (C) images of samples treated with 5 from B.
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