An orally antitumor chalcone hybrid inhibited HepG2 cells growth and migration as the tubulin binding agent

Article abstract of DOI:10.1007/s10637-019-00737-z

Liver cancer is a kind of high mortality cancer due to the difficulty of early diagnosis. It is necessary to develop the anticancer agents to treat liver cancer. Here, a novel chalcone derivative was synthesized and evaluated for anticancer activity in vi

Full text of DOI:10.1007/s10637-019-00737-z

Investigational New Drugs
https://doi.org/10.1007/s10637-019-00737-z
SHORT REPORT
An orally antitumor chalcone hybrid inhibited HepG2 cells growth
and migration as the tubulin binding agent
1
1
1
1
1
Wang Yan & Chen Xiangyu & Li Ya & Wang Yu & Xu Feng
Received: 16 November 2018 /Accepted: 31 January 2019
#
Springer Science+Business Media, LLC, part of Springer Nature 2019
Summary
Liver cancer is a kind of high mortality cancer due to the difficulty of early diagnosis. It is necessary to develop the anticancer
agents to treat liver cancer. Here, a novel chalcone derivative was synthesized and evaluated for anticancer activity in vitro against
liver cancer cell lines (HepG2, SNU-423, SMMC7221, and SNU-398). The chalcone hybrid 9 displayed the antiproliferative
effect against HepG2, SNU-423, SMMC7221 and SNU-398 cells with IC50 values of 0.9 μM, 2.7 μM, 6.2 μM and 4.6 μM,
respectively. Cellular mechanisms showed that derivative 9 could obviously inhibit HepG2 cells growth and colony formation in
a concentration-dependent manner. Analogue 9 inhibited the migration by regulating the expression levels of migration-releated
markers and transcription factors (Snail and Slug). Tubulin polymerization inhibition assay illustrated that chalcone hybrid 9
might be a potent tubulin polymerization inhibitor. Importantly, compound 9 displayed the antitumor activity against liver cancer
HepG2 cells in vivo with the low toxicity toward mice. Therefore, compound 9 as a novel tubulin polymerization inhibitor
deserves further investigation to treat liver cancer.
.
.
.
.
Keywords Chalcone Liver cancer Cell growth Migration Tubulin
Introduction
against HepG2 cells [11]. Natural chalcone 2 arrested cell cycle
at G2/M phase against HER2-overexpressing breast cancer
cells by inhibiting phosphorylation of Cdc2 and Cdc25C [12].
Chalcone 3 inhibited cell growth and induced apoptosis against
MCF-7/ADR cells in a dose-dependent manner [13]. Chalcone
4 as a phosphate salt inhibited tumor growth in xenograft
models in vivo without apparent toxicity [14].
Molecular hybridization is a rational design strategy to ob-
tain new ligands based on the recognition of pharmacophoric
subunits in the molecular structure of two or three known
bioactive derivatives [15, 16]. Based on the anticancer activity
of chalcones, we designed and synthesized a novel chalcone-
1,2,3-triazole hybrid 9 by the molecular hybridization strate-
gy. In this work, we tested its antiproliferative activity against
liver cancer cells and explored its anticancer mechanisms.
Liver cancer is highly fatal, and death rates in the United
States are increasing faster than for any other cancer [1–3].
Recently, there have been progresses to help patients with
hepatocellular carcinoma by the liver resection or chemical
drugs [4]. However, patients usually present with underlying
advanced liver disorders and the successful treatment of liver
cancer remains a challenge [5]. Therefore, it is very necessary
to discovery novel antiproliferative agents to treat liver cancer.
Chalcone bearing an α,β-unsaturated carbonyl moiety has
been used as the antitumor agent against a variety of cancer cell
lines [6–10]. Chalcone 1 (Fig. 1) could activate intracellular
reactive oxygen species levels and activate programmed death
via the caspase-dependent intrinsic mitochondrial pathway
Electronic supplementary material The online version of this article
(
https://doi.org/10.1007/s10637-019-00737-z) contains supplementary
Materials and methods
material, which is available to authorized users.
General procedure for the synthesis
of chalcone-1,2,3-triazole derivative 9
*
Xu Feng
doctorxuyfy@163.com
1
Chalcones 7 (5 mmol), 3-azidoprop-1-ene (5 mmol), propar-
Department of Gastroenterology, The First Affiliated Hospital of
Zhengzhou University, Zhengzhou 450052, China
gyl bromide (6 mmol), CuSO .5H O (1 mmol) and sodium
4
2

Invest New Drugs
Fig. 1 Chemical structures of anticancer chalcones
ascorbate (0.5 mmol) were dissolved in THF/H O (15 mL/
120.57, 114.73, 77.23, 62.17, 52.89. HRMS (ESI) calcd. For
2
+
1
5 mL) and stirred for 10 h at room temperature. The crude
C H C N O [M + H] : 414.0776, found: 414.0779.
21 18 l2 3 2
product was filtered and purified with column chromatogra-
phy on silica gel (EtOAc/hexane = 8/1). The yield to get com-
pound 9 is 86%.
MTT assay
Liver cancer cell lines (HepG2, SNU-423, SMMC7221, and
SNU-398) were from shanghai research science limited com-
pany. Cells were cultured with RPMI 1640 medium in an
(E)-1-(4-((1-allyl-1H-1,2,3-triazol-4-yl)methoxy)
phenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (9)
atmosphere containing 5% CO . We added 10,000 cells in
2
each well of 24 wells plate. All wells were added 100uL
3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium
bromide (MTT) solution to culture 1 h. The next steps were
processed according to the reported reference [17].
1
White solid, yield: 86%; m.p.:175–177 °C; H NMR
(
400 MHz, CDCl ) δ 8.09 (d, J = 15.7 Hz, 1H), 8.03 (d, J =
.8 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.48(d, J =
5.7 Hz, 1H)7.47(d, J = 6.8 Hz, 1H), 7.30 (dd, J = 8.5, 2.0 Hz,
H), 7.09 (d, J = 8.8 Hz, 2H), 6.03 (s, 1H), 5.37 (m, 2H), 5.31(s,
H), 5.01 (d, J = 6.2 Hz, 2H). C NMR (100 MHz, CDCl ) δ
3
8
1
1
1
1
1
Colony formation assay
13
3
88.26, 162.17, 143.66, 138.66, 136.29, 135.99, 132.01,
31.17, 130.98, 130.12, 128.49, 127.53, 124.85, 122.66,
1000 HepG2 cells were selected and added in each well of
6 wells plate. The next day, derivative 9 at different
4 2 2
Scheme 1 Reagents and conditions: (a) NaOH, EtOH, reflux. (b) Propargyl bromide, CuSO .5H O, sodium ascorbate, THF:H O (1:1), r.t

Invest New Drugs
Fig. 2 The cell viability and IC50 values of compound 9 for 72 h
concentrations (0 μM, 0.1 μM and 0.5 μM) was added and
cells were cultured for 1 week. Then, all cells were washed
by PBS solution and stained by crystal violet solution for
membrane was left to dry. The detailed method was referenced
the report [19].
1
h. The system was washed by water and took photos. The
detailed method was referenced the report [18].
Animals study in vivo
Migration assay
Animals were treated according to protocols established
by the ethics committee of zhengzhou university and the
in vivo experiments were carried out in accordance with
the approved guidelines. Mice were subcutaneously im-
Migration assay was assessed by the 24-well cell culture plate
4
(
BD Falcon, NJ). The top chambers were seeded with 2 × 10
7
HepG2 cells in 400 μL serum-free 1640 medium containing
derivative 9. The bottom chambers were filled with 700 μL
complete medium. After 24 h incubation, top chambers were
washed with PBS. The bottom chambers were fixed with 4%
paraformaldehyde and stained with 0.4% crystal violet for 1 h.
Then the chambers were washed with water, and the
planted with HepG2 cells (1 × 10 cells per mouse) on
the right flank of nude mice. The mice were randomly
divided into corresponding saline and 9 (70 mg/kg) treat-
ment groups (n = 5 mice for each group). The treatment
group received intragastric administration of 9 per day for
a period of 21 days.
a
b
Fig. 3 Colony formation (a) Representative images of HepG2 cells colonies after the treatment of derivative 9 for a week (b) Colony formation rate

Invest New Drugs
a
b
Fig. 4 Derivative 9 inhibited the migration against HepG2 cells (a) Representative images of HepG2 cells migration (b) migration rate. *: p < 0.05 verse control
Results
the claisen-schmidt condensation reaction based on reported
references [20–22]. 1,2,3-Triazole fragment is widely applied
in organic chemistry and medicinal chemistry because of its
anticancer activity [23–25]. The 1,2,3-triazoles might increase
the antitumour activity of chemical compounds [26, 27].
Based on these findings, chalcone-1,2,3-triazole analogue 9
was designed and synthesized. Chalocne intermediate 7 was
Synthesis
The synthesis of chalcone-1,2,3-triazole hybrid 9 in this work
was shown in Scheme 1. Acetophenone 5 was reacted with the
aromatic aldehyde 6 to obtain the chalcone intermediate 7 via
a
b
c
d
e
f
Fig. 5 Expression changes of migration releated biomarkers and
transcription factors (a) Analogue 9 regulated the expression levels of
migration-releated markers and transcription factors in HepG2 cells (b-
f) Statistical analysis of protein expression levels. *: p < 0.05 verse
control, **: p < 0.01 verse control

Invest New Drugs
Colony formation was used to investigate whether derivative
could inhibit HepG2 cells growth and proliferation [29]. The
9
colony formation results were shown in Fig. 3. Compared
with the control group, HepG2 cells with the treatment of
derivative 9 at 0.1 μM and 0.5 μM exhibited fewer colonies
obviously. From the colony formation results, chalcone-1,2,3-
triazole derivative 9 could significantly inhibit HepG2 cells
growth in a concentration-dependent manner.
Analogue 9 inhibited HepG2 cells migration
Fig. 6 Tubulin polymerization activity of derivative 9
The effect of migration about chalcone-1,2,3-triazole deriva-
tive 9 was explored by the reported method [30]. HepG2 cells
were treated with derivative 9 at different concentrations
reacted with 3-azidoprop-1-ene 8 to form (E)-1-(4-((1-allyl-
1
H-1,2,3-triazol-4-yl)methoxy)phenyl)-3-(2,4-
(
0 μM, 0.5 μM, 1 μM and 2 μM) for 24 h and were stained
by hematoxylin. The migration rates at 0.5 μM, 1 μM and
μM were about 62%, 21% and 4%, respectively. All migra-
dichlorophenyl)prop-2-en-1-one 9 in the yield of 86%.
2
Antiproliferative activity of analogue 9
tion results in Fig. 4 indicated that chalcone-1,2,3-triazole de-
rivative 9 could inhibit HepG2 cells migration by a
concentration-dependent manner.
MTT assay was performed to investigate the antiproliferative
activity of chalcone derivatives against liver cancer cells for
7
1
2 h [28]. The antiproliferative activity results of chalcone-
,2,3-triazole hybrid 9 against liver cancer cells (HepG2,
Analogue 9 regulated the expression levels
of migration-releated markers and transcription
factors
SNU-423, SMMC7221, and SNU-398) were listed in Fig. 2.
In this work, 5-fluorouracil (5-Fu) was used as the control
drug. The IC50 values of 5-fluorouracil against HepG2,
SNU-423, SMMC7221 and SNU-398 cells were 9.2 μM,
Epithelial-mesenchymal transition (EMT) as a biologic process
displayed a pivotal role during the embryonic development and
carcinoma progression [31]. Due to the migration inhibitory
effect of derivative 9 against HepG2 cells, we examined the
expression level of the typical proteins of epithelial-
mesenchymal transition. As shown in Fig. 5, chalcone-1,2,3-
triazole derivative 9 could upregulate the expression level of E-
cadherin. Meanwhile, this compound decreased the mesenchy-
mal cells’ biomarkers, N-Cadherin and Vimentin. The expres-
sion levels of upstream transcription factors, Snail and Slug
were both decreased. These results indicated that chalcone-
1
0.3 μM, 15.1 μM, and 17.9 μM, respectively. From MTT
assay, chalcone 7 showed the weak inhibitory activity with
IC50 values >20 μM against all four cancer cell lines.
However, chalcone-1,2,3-triazole hybrid 9 displayed the po-
tently antiproliferative activity with IC50 values from 0.9 μM
to 6.2 μM against all four cancer cell lines. These resuts illus-
trated that the 1,2,3-triazole unit might be very important for
antiproliferative activity.
Analogue 9a inhibited HepG2 cells growth
1,2,3-triazole derivative 9 could inhibit liver cancer cells migra-
Based on the best antiproliferative activity result of chalcone-
tion by regulating EMT related biomarkers (E-cadherin, N-
Cadherin and Vimentin) and inhibiting the expression of up-
stream transcription factors (Snail and Slug).
1
,2,3-triazole derivative 9 against HepG2 cells, HepG2 cell
line was selected to do anticancer mechanisms in vitro.
Fig. 7 The in vivo antitumor activity of chalcone-1,2,3-triazole derivative 9 (a) Tumor volumes of mice (b) Tumor weight from each group (c)
Body weights of mice. **P < 0.01 verse control

Invest New Drugs
Funding This work was supported by the fund of The First Affiliated
Hospital of Zhengzhou University.
Chalcone analogue 9 inhibited tubulin polymerization
Microtubules as an important framework supporting cellular
morphology in interphase are the major components of the
mitotic spindle which allows the controlled segregation of the
chromosomes during mitosis [32]. Recently, a series of
phenstatin/isocombretastatin-chalcone conjugates were syn-
thesized and screened as potent tubulin polymerization inhib-
itors [33]. These phenstatin/isocombretastatin-chalcones pos-
sess the structural similarity with our target compounds. Based
on these findings, the tubulin activity of chalcone hybrid 9 was
detected using the tubulin polymerization inhibition assay [34].
The IC50 value of chalcone hybrid 9 was 2.34 μM against
tubulin polymerization. All these results indicated that deriva-
tive 9 was a novel tubulin polymerization inhibitor (Fig. 6).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Informed consent Informed consent was obtained from all individual
participants included in the study.
Publisher’s note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
Analogue 9 inhibited HepG2 cells growth in vivo
References
To evaluate the potential anticancer effects of chalcone-1,2,3-
triazole derivative 9 in vivo, a HepG2 xenograft model was
established in nude mice by subcutaneously injecting HepG2
cells. Tumor bearing mice were then randomly assigned to
two groups (control, 70 mg/kg 9) with 5 mice per group.
The growth rate of HepG2 xenograft tumors from mice which
were treated with chalcone-1,2,3-triazole derivative 9 was
lower than those from the control group (Fig. 7). The average
tumor weights of control and 70 mg/kg 9 were 1.311 ± 0.216 g
and 0.524 ± 0.172 g (inhibitory rate: 60.03%), respectively.
Importantly, there is no significant difference in mean body
weights between control and treated group. All these results
demonstrated the potent antitumor activity of chalcone-1,2,3-
triazole derivative 9 against liver cancer HepG2 cells in vivo
and low toxicity toward mice.
1. Yen CJ, Kim TY, Feng YH, Chao Y, Lin DY, Ryoo BY, Huang
DCL, Schnell D, Hocke J, Loembé AB, Cheng AL (2018) A
phase I/randomized phase II study to evaluate the safety, phar-
macokinetics, and efficacy of Nintedanib versus Sorafenib in
Asian patients with advanced hepatocellular carcinoma. Liver
Cancer 7(2):165–178
2
.
Delord JP, Ravaud A, Bennouna J, Fumoleau P, Favrel S, Pinel MC,
Ferré P, Saliba F (2013) Phase I and pharmacokinetic study of IV
vinflunine in cancer patients with liver dysfunction. Investig New
Drugs 31(3):724–733. https://doi.org/10.1007/s10637-012-9878-7
3. Said R, Kurzrock R, Naing A, Hong DS, Fu S, Piha-Paul SA,
Wheler JJ, Janku F, Kee BK, Bidyasar S, Lim J, Wallace M,
Tsimberidou AM (2015) Dose-finding study of hepatic arterial in-
fusion of irinotecan-based treatment in patients with advanced can-
cers metastatic to the liver. Investig New Drugs 33(4):911–920.
https://doi.org/10.1007/s10637-015-0251-5
4. Zhang X, Zhang S, Sun Q, Jiao W, Yan Y, Zhang X (2018)
Compound K induces endoplasmic reticulum stress and apopto-
sis in human liver Cancer cells by regulating STAT3. Molecules
2
3(6):1482
5
6
7
8
.
.
.
.
Piscaglia F, Ogasawara S (2018) Patient selection for Transarterial
chemoembolization in hepatocellular carcinoma: importance of
benefit/risk assessment. Liver Cancer 7(1):104–119
Szliszka E, Czuba ZP, Mazur B, Paradysz A, Krol W (2010)
Chalcones and Dihydrochalcones augment TRAIL-mediated apo-
ptosis in prostate Cancer cells. Molecules 15(8):5336–5353
Malek SNA, Phang CW, Ibrahim H, Abdul Wahab N, Sim KS
Discussion
A novel chalcone-1,2,3-triazole derivative 9 displayed the po-
tent inhibitory effect against HepG2 cells with an IC50 value
of 0.9 μM. Analogue 9 obviously inhibited HepG2 cells
growth and migration in a concentration-dependent manner.
In addition, compound 9 was a novel tubulin polymerization
inhibitor. Importantly, derivative 9 effectively inhibited the
liver cancer cells growth in vivo with no signs of adverse side
effects. In summary, derivative 9 deserves further investiga-
tion as a lead compound to treat liver cancer.
(
2011) Phytochemical and cytotoxic investigations of Alpinia
mutica rhizomes. Molecules 16(1):583–589
Saxena HO, Faridi U, Kumar JK, Luqman S, Darokar MP, Shanker
K, Chanotiya CS, Gupta MM, Negi AS (2007) Synthesis of
chalcone derivatives on steroidal framework and their anticancer
activities. Steroids 72(13):892–900. https://doi.org/10.1016/j.
steroids.2007.07.012
Sashidhara KV, Kumar A, Kumar M, Sarkar J, Sinha S (2010)
Synthesis and in vitro evaluation of novel coumarin–chalcone hy-
brids as potential anticancer agents. Bioorg Med Chem Lett 20(24):
7205–7211. https://doi.org/10.1016/j.bmcl.2010.10.116
9
.
Acknowledgments So thanks the supports from The First Affiliated
Hospital of Zhengzhou University.
1
0. Modzelewska A, Pettit C, Achanta G, Davidson NE, Huang P,
Khan SR (2006) Anticancer activities of novel chalcone and bis-
chalcone derivatives. Bioorg Med Chem 14(10):3491–3495.
https://doi.org/10.1016/j.bmc.2006.01.003
Author’s contribution Wang Yan., Chen Xiangyu., Li Ya., and Wang Yu.
performed the design work and experiments. Wang Yan., and Xu Feng.
witten the paper. All authors read and approved the final manuscript.

Invest New Drugs
1. Ramirez-Tagle R, Escobar C, Romero V, Montorfano I, Armisén R,
1
23. Huang X, Shen Q-K, Zhang H-J, Li J-L, Tian Y-S, Quan Z-S (2018)
Design and synthesis of novel Dehydroepiandrosterone analogues
as potent Antiproliferative agents. Molecules 23(9). https://doi.org/
10.3390/molecules23092243
Borgna V, Jeldes E, Pizarro L, Simon F, Echeverria C (2016)
Chalcone-induced apoptosis through caspase-dependent intrinsic
pathways in human hepatocellular carcinoma cells. Int J Mol Sci
1
7(2):260
2. Jandial D, Krill L, Chen L, Wu C, Ke Y, Xie J, Hoang B, Zi X
2017) Induction of G2M arrest by Flavokawain A, a kava
24. Kamal A, Shankaraiah N, Devaiah V, Laxma Reddy K, Juvekar A,
Sen S, Kurian N, Zingde S (2008) Synthesis of 1,2,3-triazole-linked
pyrrolobenzodiazepine conjugates employing ‘click’ chemistry:
DNA-binding affinity and anticancer activity. Bioorg Med Chem
Lett 18(4):1468–1473. https://doi.org/10.1016/j.bmcl.2007.12.063
1
1
1
1
(
Chalcone, increases the responsiveness of HER2-overexpressing
breast Cancer cells to Herceptin. Molecules 22(3):462
3. Liu M, Yin H, Qian X, Dong J, Qian Z, Miao J (2017)
Xanthohumol, a Prenylated Chalcone from hops, inhibits the via-
bility and stemness of doxorubicin-resistant MCF-7/ADR cells.
Molecules 22(1):36
4. Yan J, Jie C, Zhang S, Hu J, Ling H, Li X (2016) Synthesis, eval-
uation, and mechanism study of novel indole-chalcone derivatives
exerting effective antitumor activity through microtubule destabili-
zation in vitro and in vivo. J Med Chem 59(11):5264–5283
5. Kakwani MD, Suryavanshi P, Ray M, Rajan MGR, Majee S,
Samad A, Devarajan P, Degani MS (2011) Design, synthesis and
antimycobacterial activity of cinnamide derivatives: a molecular
hybridization approach. Bioorg Med Chem Lett 21(7):1997–
2
5. Kumar A, Ahmad I, Chhikara BS, Tiwari R, Mandal D, Parang K
2011) Synthesis of 3-phenylpyrazolopyrimidine-1,2,3-triazole
(
conjugates and evaluation of their Src kinase inhibitory and anti-
cancer activities. Bioorg Med Chem Lett 21(5):1342–1346. https://
doi.org/10.1016/j.bmcl.2011.01.047
2
2
6. Penthala NR, Madhukuri L, Thakkar S, Madadi NR, Lamture G,
Eoff RL, Crooks PA (2015) Synthesis and anti-cancer screening of
novel heterocyclic-(2H)-1,2,3-triazoles as potential anti-cancer
agents. MedChemComm 6(8):1535–1543
7. Kamal A, Prabhakar S, Janaki Ramaiah M, Venkat Reddy P, Ratna
Reddy C, Mallareddy A, Shankaraiah N, Lakshmi Narayan Reddy
T, Pushpavalli SNCVL, Pal-Bhadra M (2011) Synthesis and anti-
cancer activity of chalcone-pyrrolobenzodiazepine conjugates
linked via 1,2,3-triazole ring side-armed with alkane spacers. Eur
J Med Chem 46(9):3820–3831. https://doi.org/10.1016/j.ejmech.
1999. https://doi.org/10.1016/j.bmcl.2011.02.022
1
6. Barbosa TP, Sousa SCO, Amorim FM, Rodrigues YKS, de Assis
PAC, Caldas JPA, Oliveira MR, Vasconcellos MLAA (2011)
Design, synthesis and antileishmanial in vitro activity of new series
of chalcones-like compounds: a molecular hybridization approach.
Bioorg Med Chem 19(14):4250–4256. https://doi.org/10.1016/j.
bmc.2011.05.055
7. Patra T, Ghosh P, Alam N, Murmu N (2018) Supra-physiological
concentration of glyoxylate inhibits proliferation of human colon
cancer cells through oxidative stress. Life Sci 207:80–89. https://
doi.org/10.1016/j.lfs.2018.05.047
2
011.05.050
2
8. Crous-Masó J, Palomeras S, Relat J, Camó C, Martínez-Garza Ú,
Planas M, Feliu L, Puig T (2018) (−)-epigallocatechin 3-Gallate
synthetic analogues inhibit fatty acid synthase and show anticancer
activity in triple negative breast cancer. Molecules 23(5):1160
9. Xiao M, Li M, Reynolds CS (2018) Colony formation in the cya-
nobacterium Microcystis. Biol Rev 93(3):1399–1420
0. Mori T, Doi R, Koizumi M, Toyoda E, Ito D, Kami K, Masui T,
Fujimoto K, Tamamura H, Hiramatsu K (2004) CXCR4 antagonist
inhibits stromal cell-derived factor 1-induced migration and inva-
sion of human pancreatic cancer. Mol Cancer Ther 3(1):29–37
1. Li L, Su N, Zhou T, Zheng D, Wang Z, Chen H, Yuan S, Li W
1
1
1
2
2
2
3
8. Cevallos RR, Rodríguez-Martínez G, Gazarian K (2018) Wnt/β-
catenin/TCF pathway is a phase-dependent promoter of Colony
formation and Mesendodermal differentiation during human somat-
ic cell reprogramming. Stem Cells 36:683–695
3
3
9. Chang TT, More SV, Lu IH, Hsu J-C, Chen T-J, Jen YC, Lu C-K, Li
W-S (2011) Isomalyngamide A, A-1 and their analogs suppress
cancer cell migration in vitro. Eur J Med Chem 46(9):3810–3819.
https://doi.org/10.1016/j.ejmech.2011.05.049
0. Özdemir A, Sever B, Altıntop M, Kaya Tilki E, Dikmen M (2018)
Design, synthesis, and neuroprotective effects of a series of
Pyrazolines against 6-hydroxydopamine-induced oxidative stress.
Molecules 23(9). https://doi.org/10.3390/molecules23092151
1. Rampa A, Bartolini M, Pruccoli L, Naldi M, Iriepa I, Moraleda I,
Belluti F, Gobbi S, Tarozzi A, Bisi A (2018) Exploiting the
Chalcone scaffold to develop multifunctional agents for
Alzheimer’s disease. Molecules 23(8). https://doi.org/10.3390/
molecules23081902
(
2018) Mixed lineage kinase ZAK promotes epithelial–
mesenchymal transition in cancer progression. Cell Death Dis
(2):143. https://doi.org/10.1038/s41419-017-0161-x
9
2. Chen H, Lin Z, Arnst K, Miller D, Li W (2017) Tubulin inhibitor-
based antibody-drug conjugates for cancer therapy. Molecules
2
2(8):1281
33. Kamal A, Kumar GB, Vishnuvardhan MVPS, Shaik AB, Reddy
VS, Mahesh R, Sayeeda IB, Kapure JS (2015) Synthesis of
phenstatin/isocombretastatin–chalcone conjugates as potent tubulin
polymerization inhibitors and mitochondrial apoptotic inducers.
Org Biomol Chem 13(13):3963–3981. https://doi.org/10.1039/
C4OB02606C
2
2. Teng IJ, Tsai M-C, Shih S-F, Tsuei B-F, Chang H, Chuang Y-P,
Lin C-S, Chern C-Y, Chen S-J (2018) Chalcone derivatives
enhance ATP-binding cassette transporters A1 in human THP-
34. Wang Q, Arnst KE, Wang Y, Kumar G, Ma D, Chen H, Wu Z, Yang
J, White SW, Miller DD, Li W (2018) Structural modification of the
3,4,5-Trimethoxyphenyl moiety in the tubulin inhibitor VERU-111
leads to improved Antiproliferative activities. J Med Chem 61(17):
7877–7891. https://doi.org/10.1021/acs.jmedchem.8b00827
1
macrophages. Molecules 23(7). https://doi.org/10.3390/
molecules23071620