Discovery of FZU-03,010 as a self-assembling anticancer amphiphile for acute myeloid leukemia

Article abstract of DOI:10.1016/j.bmcl.2016.12.071

Recently various drug candidates with excellent anticancer potency have been demonstrated, whereas their clinical application largely suffers from several limitations especially poor solubility. Ursolic acid (UA) as one of ubiquitous pentacyclic triterpenes in plant kingdom exhibited versatile antiproliferative effects in various cancer cell lines. However, the unfavorable pharmaceutical properties became the main obstacle for its clinical development. With the aim of development of novel derivatives with enhanced potency, a series of diversified UA amphiphiles have been designed, synthesized, and pharmacologically evaluated. Amphiphile 10 (FZU-03,010) with significant improved antiproliferative effect can self-assemble into stable nanoparticles in water, which may serve as a promising candidate for further development.

Full text of DOI:10.1016/j.bmcl.2016.12.071

Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of FZU-03,010 as a self-assembling anticancer amphiphile
for acute myeloid leukemia
a,
Yingyu Chen a,b,1, Cailong Li a,1, Yunquan Zheng a, Yu Gao a, Jianda Hu b, , Haijun Chen
⇑
⇑
a College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
b Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Recently various drug candidates with excellent anticancer potency have been demonstrated, whereas
their clinical application largely suffers from several limitations especially poor solubility. Ursolic acid
(UA) as one of ubiquitous pentacyclic triterpenes in plant kingdom exhibited versatile antiproliferative
effects in various cancer cell lines. However, the unfavorable pharmaceutical properties became the main
obstacle for its clinical development. With the aim of development of novel derivatives with enhanced
potency, a series of diversified UA amphiphiles have been designed, synthesized, and pharmacologically
evaluated. Amphiphile 10 (FZU-03,010) with significant improved antiproliferative effect can self-assem-
Received 6 October 2016
Revised 12 December 2016
Accepted 28 December 2016
Available online xxxx
Keywords:
Ursolic acid
Poor aqueous solubility
Amphiphile
Self-assembling
Nanoparticles
ble into stable nanoparticles in water, which may serve as
development.
a promising candidate for further
Ó 2016 Elsevier Ltd. All rights reserved.
Recently, natural products attract increasing attention in
academic institutions and pharmaceutical industry due to their
unparalleled resources, and diverse interesting biological charac-
teristics.1–3 Among them, pentacyclic triterpene compounds
widely exist throughout nature, possessing considerable pharma-
cological activities, especially anticancer potency.4,5 Therefore,
they are expected to serve as a pivotal resource to develop novel
promising drug candidates targeting diverse signaling pathways.6,7
Ursolic acid (UA, Fig. 1) as one of the pentacyclic triterpenes is
ubiquitous in plant kingdom.8 UA is particularly valuable for its
versatile bioactivities including anti-inflammatory, antioxidative,
anticancer, antibacterial, and sedative activities.9 Its significant
anticancer and fascinating chemoprevention effects have been
intensively studied. Recent studies revealed that UA is involved
in a series of the activities of anticancer, such as induction of can-
cer cell apoptosis, prevention of tumorigenesis, and inhibition of
cancer cell proliferation.10 In addition, UA has been demonstrated
to significantly enhance immune function of human body.11 All
these findings indicate that UA has great potential for clinical
application. However, UA suffers from poor water solubility, rapid
metabolism and low bioavailability, limiting its further clinical
development.12,13
Despite these limitations, UA possesses the common structural
characteristic of the plant-derived triterpenoids bearing two polar
groups separated by a non-polar spacer of appropriate length.14
This inherent amphiphilic feature renders it as one of the ideal
building blocks for development of self-delivering amphiphiles
with improved anticancer potency through self-assembly. Due to
the diversity spacers and unique spatial structure arrangements,
Bag, Ju and Hu, as well as Mezzenga studied the assembly behav-
iors of triterpenoids especially focusing on supramolecular recog-
nition, assembly and diverse supramolecular architectures
(including fibers, vesicles, flowers, helices, and spheres).15–17 For
example, Ju reported a novel uracil-appended glycyrrhetinic acid
conjugate and fully investigated its gelation characteristics as well
as the gel-to-sol phase transition process.17
Recently, construction of complex amphiphilic drugÀdrug con-
jugates (ADDCs) is considered as an emerging strategy for the
enhancement of therapeutic efficacy via simple conjugation of a
hydrophilic anticancer drug with a hydrophobic one through a
biodegradable bond.18 For example, Yan and Zhu synthesized
IrÀCb conjugate consisting of the hydrophilic anticancer drug
irinotecan (Ir) and the hydrophobic anticancer drug chlorambucil
(Cb) via a hydrolyzable ester linkage.19 This complex conjugate
could self-assemble into nanoparticles in water and facilitated
the accumulation of drugs in tumor tissues, eventually resulting
in significant improvement of therapeutic efficacy.19
⇑
Corresponding authors.
E-mail addresses: drjiandahu@163.com (J. Hu), chenhaij@gmail.com (H. Chen).
Owing to the unique properties of self-assembled nanoparticles
and higher accumulation in tumors via the enhanced permeation
1
These authors contribute equally to this work.
http://dx.doi.org/10.1016/j.bmcl.2016.12.071
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Chen Y., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2016.12.071

2
Y. Chen et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Design of new amphiphilic UA derivatives
with improved anticancer effects
Intensive researches demonstrated that various biological prop-
erties of pentacyclic triterpenes are related to the C-3 hydroxyl
group.20–23 In this respect, a variety of structure modifications of
UA on C-3 position have been conducted to improve the biological
activity.24–26 The heterocyclic ring derivatives have been proved
possess highly anticancer effects. To date, increasing studies have
demonstrated that a variety of UA derivatives with structural mod-
ifications on A ring possess effective improvement of anticancer
effects.27,28 Accumulating investigation revealed that pentacyclic
triterpenes with thiazole and pyrazole moiety at A-ring are
expected to possess enhanced anticancer potency.29,30 In addition,
accumulating evidence indicated that the introduction of suitable
moieties at the 28-position of UA would significantly enhance
the anticancer activity.31,32 Therefore, our efforts first focused on
modification at C-2 and C-3 positions followed by introduction of
the privileged fragments at the 28-position (Fig. 1) to synthesize
amphiphilic UA derivatives.
The synthetic routes to new UA derivatives reported in this
work are outlined in Scheme 1. Following the literature proce-
dures, the key intermediate 3-keto UA (2) was prepared by the oxi-
dation of UA (1) with Jones reagent in 90% yield. The compounds 3
and 4 were obtained in a two-step synthesis starting from 3-keto
UA (2). The C-28 chloride of UA analogues was easily prepared
from 3-keto UA (2) in oxalyl chloride in CH2Cl2, and then treated
with piperazine or diethanolamine to give the corresponding ana-
logues 3 and 4, respectively. Notably, the moieties of piperazine
and diethanolamine have been demonstrated to enhance potency
and drug-like properties.24,33 Bromination of 2 with PyHBr3 in
THF led to obtain the intermediate 5 in 88% yield. Hantzsch reac-
tion of 5 with thiourea or allyl thiourea in the refluxing ethanol
directly afforded corresponding derivatives 6 and 7 in the yield
of 62% and 60%, respectively. Compound 8 was obtained by Claisen
Modification on ring A
OH
O
E
Me
Me
28
introduction of
Me
Me
A
2
heterocyclic ring
C
17
D
3
HO
B
Introduction of
soluble moieties
Me
Me
Me
Effectively self-assembles into nanoparticles in water?
Fig. 1. Drug design self-delivery strategy for new amphiphilic UA derivatives with
improved anticancer effects.
and retention (EPR) effect, amphiphiles with improved anticancer
potency can enhance permeability and reduce side effects.18 The
skeleton of UA is lined with readily accessible A ring and carboxyl
group at the position 28, which allows for the facile introduction of
functional moieties to promote reversible and directional interac-
tions and engender supramolecular assemblies. With these consid-
erations in mind, we hypothesized that amphiphilic UA derivatives
consisting of the hydrophilic privilege fragments around A-ring
and hydrophobic tail at the 28-position might solve the limitation
of poor solubility of UA.
In this work, we designed and synthesized a series of novel
amphiphilic UA derivatives with favorable physicochemical prop-
erties which were associated with incorporating nitrogen into
the core scaffold and evaluated their anticancer activities. Among
them, UA derivative 10 (FZU-03,010) could be a promising anti-
cancer agent for its highly inhibitory activity against human leuke-
mia cells. To our knowledge, such a promising strategy through
development of amphiphilic UA derivatives to self-assemble into
its own nanostructures for the enhancement of anticancer efficacy
has not been reported to date.
OH
OH
OH
H
H
H
d
Br
S
N
O
O
R1
O
O
HO
6-7
1
5
H
N
H2N
R1
=
c
a
6
7
OH
OH
e
OH
f
H
N
H
H
H
N
O
O
HO
O
H
O
O
O
O
2
8
12
OH
N
N
f
R2
=
b
NH
3, 10
4, 11
OH
R2
R2
OH
H
H
H
b
O
O
O
N
N
N
H
N
O
H
3-4
10-11
9
Scheme 1. Reagents and conditions: (a) Jones reagent, acetone, rt, 2 h, 90%; (b) (i) oxalyl chloride, CH2Cl2, rt, 24 h; (ii) corresponding amines, EtOAc, rt, 3 h, 38–67%; (c)
PyHBr3, THF, rt, 16 h, 88%; (d) corresponding thioureas, EtOH, reflux, 5 h, 60–62%; (e) CH3ONa, ethyl formate, benzene, rt, 12 h, 80%; (f) corresponding hydrazines, EtOH,
reflux, 6 h, 80–85%.
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Y. Chen et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
3
Table 1
Effects of newly synthesized compounds on proliferation of human promyelocytic leukemia (HL-60) cells.
No
cLogPa
TPSAb
Inhibitory effect (%)c
IC50 (l
M)c
0.63
lM
1.25
lM
2.5
lM
5
lM
10
l
M
20
lM
40 lM
1
2
3
4
6
7
8
9
6.48
6.37
5.82
5.23
6.73
7.70
5.98
6.61
6.07
5.41
6.63
57.5
54.4
49.4
77.8
76.2
62.2
74.6
66.0
61.0
89.4
72.2
N/Ad
N/A
N/A
N/A
22.5
8.43
N/A
0.33
18.5
7.54
66.4
2.47
20.7
N/A
N/A
43.7
12.4
N/A
4.73
33.9
8.55
86.0
19.3
28.8
N/A
N/A
82.2
26.7
N/A
13.4
50.3
16.3
91.6
64.8
41.7
N/A
N/A
92.7
53.7
N/A
20.3
67.0
79.5
95.0
86.8
61.7
N/A
N/A
N/A
N/A
>40
>40
10.6e
9.32
N/A
92.5
86.5
12.9
34.7
72.4
93.2
93.5
94.0
69.7
94.8
92.7
59.2
49.8
89.8
94.7
94.0
93.6
93.1
2.64 0.12
7.04 1.37
ꢀ40
N/A
>40
9.03
5.36
14.7
3.54
9.96
5.44 0.08
6.26 1.61
0.91 0.05
5.21 1.41
5.64 1.33
10
11
12
Doxorubicin (ADR)
80.8
82.5
85.6
95.4
>99
>99
>99
<0.63
a
b
c
Average cLogP: http://146.107.217.178/lab/alogps/start.html.
TPSA: http://www.molinspiration.com/cgi-bin/properties.
The values are the mean SE of at least three independent experiments.
N/A: no activity.
d
e
The values are mean of at least three independent experiments.
condensation of 2 with ethyl formate in 80% yield. Treatment of 8
with hydrazine in EtOH under reflux for 6 h afforded pyrazole
derivative 9. To access compounds 10 and 11, the pyrazole deriva-
tive 9 was submitted to the same reaction condition as the synthe-
sis of 3 and 4. Treatment of 8 with acetohydrazide provided
compound 12 in the yield of 85%.
The calculated lipophilicity (cLogP) and topological polar sur-
face area (TPSA) values of synthesized UA derivatives are listed
in Table 1. The result suggests that most of these new compounds
are conformed to the criteria of Lipinski’s ‘‘Rule of Five” and may
have good physicochemical properties. In the present study, to
explore a meaningful SAR and examine how the substitutions on
the key moieties affect biological activities of newly UA derivatives,
the antiproliferative potency of these analogues was evaluated on
the proliferation of human promyelocytic leukemia (HL-60)
cells.34,35 The capability of novel synthesized analogues to inhibit
the growth of HL-60 cells is summarized in Table 1.
The key intermediate 2 did not show any antiproliferative effect
even at 40 lM. After introduction of soluble moieties into the
derivative 2 at position 28, compound 3 with piperazine moiety
exhibited significantly improved antiproliferative effect with an
IC50 value of 2.64 lM and compound 4 showed a slightly enhanced
potency, indicating that appropriate modifications on 28-position
may improve the antiproliferative activity. It was disappointed to
find that the thiazole derivatives 6 and 7 were inactive with a dra-
matic loss of antiproliferative activity. Therefore, more extensive
SAR study on thiazole ring was not pursued. Noteworthy, the pyra-
zole derivative 9 displayed significantly enhanced potency. Thus
we turned our extensive SAR efforts on the scaffold of compound
9. As expected, amphiphilic UA derivative 10 (FZU-03,010) with
Fig. 2. (A) Relationship between the storage on diameter and time of FZU-03,010
(10) nanoparticles; inset: a digital photograph of FZU-03,010 (10) nanoparticle
solution, exhibiting a stable, transparent bluish solution. (B) DLS plot of FZU-03,010
(10) nanoparticles (placed at room temperature for 25 days), which shows the
average size (Dh = 179.9 nm).
piperazine moiety displayed an IC50 value of 0.91
60 cells, while derivative 11 showed a slight enhanced potency
with an IC50 value of 5.21 M. Notably, compound 12 also exhib-
lM against HL-
l
ited significant improved antiproliferative effect, suggesting fur-
ther structural modifications are needed.
(data derived from the sample placing at room temperature for
25 days). Besides, the DLS measurements were performed at differ-
ent time intervals. The results demonstrated that nanoparticles of
UA derivative 10 were stable enough for more than three-week
storage. All results demonstrated that compound 10 can self-
assemble into stable and well-defined nanoparticles. It also noted
that UA is a little different to effectively form nanoparticles at
the same condition for a large amount of solid was precipitated.
One potential reason is that the water solubility of UA is extraordi-
narily poor, while compound 10 displayed favorable water
After adding deionized water into the DMSO solution of com-
pound 10, DMSO was removed by dialysis and a stable and bluish
nanoparticle solution with the final concentration of 1.5 mg/mL
was obtained (Fig. 2A). To confirm that UA derivative 10 can form
nanoparticles, the dynamic light scattering (DLS) measurement
was used to study the size of nanoparticles. The DLS results in
Fig. 2B showed that compound 10 in aqueous solution forms
aggregates and the average hydrodynamic diameter aggregates
was about 179.9 nm with a narrow unimodal size distribution
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Y. Chen et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Fig. 4. Western blot analysis of biochemical markers for apoptosis induction and
inhibition by UA, FZU-03,007 (9), and FZU-03,010 (10) in the HL-60 cell line. Cells
were treated with UA, FZU-03,007 (9), and FZU-03,010 (10) at different concentra-
tions, respectively. Levels of procaspase-3, cleaved caspase-9, PARP, Bcl-2, P-
P70S6K, and p-Akt were probed by specific antibodies. Actin was used as the
loading control.
bly, the changes of expression levels of Bcl-2 after the treatment
with UA and UA derivatives were different. Treatment with UA
increased Bcl-2 expression, while, pyrazole derivatives 9 and 10
markedly decreased the expression of Bcl-2. We next evaluated
whether UA derivatives (9 and 10) modulates PI3K/Akt signaling
pathway for constitutive PI3K/Akt activation is frequently
observed in AML.42–46 Compared with UA treatment group, UA
derivatives 9 and 10 markedly reduced phosphorylation of Akt at
Ser473 and inhibited mTOR downstream targeted protein p-
p70S6K. Our observation indicated that pyrazole derivatives 9
and 10 down-regulated the activation of crucial molecules in
PI3K/Akt pathway.
In summary, an appropriate chemical modification of UA scaf-
fold enabled us to identify several potent UA derivatives with
improved anticancer potencies as well as enhanced druglike prop-
erties. A series of novel diversified analogues displayed improved
antiproliferative effects. Among them, amphiphile 10 (FZU-
03,010) exhibited remarkably growth inhibitory effect against
HL-60 cells with an IC50 value of 0.91 lM, which is approximately
Fig. 3. The apoptotic cell percentages in HL-60 cells after incubation with 80 lM of
UA (1), 2 lM of FZU-03,010 (10), and 10 lM of FZU-03,007 (9) for 24 h, respectively.
100-fold more potent than UA. This most potent pyrazole deriva-
tive also has demonstrated to modulate the apoptotic signaling
pathway as well as PI3K/Akt pathway. Particularly, the data in this
study clearly showed that amphiphile 10 with favorable nanoscale
characteristics can self-assemble into nanoparticles in an aqueous
solution. Design of self-assembled derivatives based on the amphi-
philic building block is a promising strategy that can be both prac-
tical and inspiring, affording nanostructures with favorable
pharmaceutical properties that the initial skeleton structure does
not effectively possess.
solubility (as HCl salt, aqueous solubility >0.15 mg/mL, measured
by an HPLC method36). Through our preliminary studies, com-
pound 10 with favorable nanoscale characteristics was subjected
to further biological characterization.
To determine whether amphiphilic UA derivative 10 induces
cell apoptosis in HL-60 cells, we next used Annexin V-PE/7-AAD
staining assay to investigate the role of UA derivatives on the
induction of apoptosis. As shown in Fig. 3, compound 10 signifi-
cantly induced apoptosis at 2
showed the similar effects at 80
l
M, while UA and compound 9
Acknowledgements
l
M and 10 M, respectively.
l
Despite recent advances in the development of effective molecu-
larly targeted agents, acute myeloid leukemia (AML) still remains
a lethal and incurable disease due to drug resistance in the pro-
longed chemotherapy.37–39 Therefore, innovative single agent tar-
geting multiple aberrant signaling pathways in AML might
provide an additional therapeutic approach for AML.40,41 To further
investigate the potential mechanism of compound 10 induced
apoptosis, we next examined the apoptotic signaling pathways
involved in HL-60 cells. As shown in Fig. 4, the treatment with
UA or UA derivatives (9 and 10) reduced the expression level of
procaspase-3 and induced the cleavage of caspase-9 in a dose-
dependent manner. However, the cleavage of PARP, one of the
important caspase-3 substrates, was only slightly induced. Nota-
This work was supported by the National Natural Science Foun-
dation of China (Nos. 81402781 and 81571802), the Scientific
Research Foundation for the Returned Overseas Chinese Scholars,
Fujian Provincial Key Laboratory Foundation on Hematology
(2009J1004), National and Fujian Provincial Key Clinical Specialty
Discipline Construction Program.
A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.12.
071.
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Y. Chen et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
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