Design, Synthesis, and Biological Evaluation of a Novel Water-soluble Prodrug of Docetaxel with Amino Acid as a Linker

Article abstract of DOI:10.1111/cbdd.12762

The synthesis and preliminary evaluation of derivatives of docetaxel with novel amino acid as a linker named as LK-193?LK-196 was described. The C2′-modified compound LK-196 behaves as a prodrug; that is, docetaxel is generated upon exposure to human plasma. The compound was also found to have greatly improved water solubility. The pharmacodynamic results showed LK-196 had the self-evident inhibitory effect on tumor growth in vivo, which is a promising candidate for further biological evaluation.

Full text of DOI:10.1111/cbdd.12762

Chem Biol Drug Des 2016
Research Article
Design, Synthesis, and Biological Evaluation of a
Novel Water-soluble Prodrug of Docetaxel with Amino
Acid as a Linker
1
2
2
Huan Ma , Gang Chen , Tao Wang ,
(8,9). A direct 7-O-glucosyl docetaxel analogue was
1
,
1,
Qingeng Li * and Yan Liu *
reported to be twice as water soluble as docetaxel and
with similar activity (10). Amino acid conjugates linked to
1
0
School of Pharmacy, Chongqing Medical University,
Chongqing 400016, China
R&D Department, Jiangsu Nhwa Luokang Pharmaceutical
Corporation Ltd., Xu Zhou 221000, China
Corresponding authors: Qingeng Li,
3908387568@vip.163.com; Yan Liu, y.liu@cqmu.edu.cn
the 2 -hydroxyl of docetaxel were also prepared and
tested in vivo (11). Malic acid linked to different hydroxyl
groups of docetaxel and their sodium salts was also syn-
thesized and evaluated in vivo (12). Some of the deriva-
tives had improved water solubility and showed biological
activity, but no further reported.
2
*
1
The synthesis and preliminary evaluation of derivatives
of docetaxel with novel amino acid as a linker named
as LK-193~LK-196 was described. The C2 -modified
compound LK-196 behaves as a prodrug; that is, doc-
etaxel is generated upon exposure to human plasma.
The compound was also found to have greatly
improved water solubility. The pharmacodynamic
results showed LK-196 had the self-evident inhibitory
effect on tumor growth in vivo, which is a promising
candidate for further biological evaluation.
0
2
-hydroxy is the essential pharmacophore in docetaxel’s
0
structure, and its small steric hindrance is useful to the
group’s departure, so it is often chosen as a good site for
the synthesis of prodrugs. Our group previously designed
several monocarboxylic acid ester derivatives of taxoids,
but all the derivatives were found difficult to release the
active drugs in vitro. To make it easier for the departure of
side chain, we tried to extend the length of the side chain
0
of 2 -hydroxy.
Key words: biological evaluation, Prodrug of docetaxel,
Then, we obtained a derivative named as LK-193
synthesis, water-soluble
(Figure 1). The antitumor activity in vitro was not satisfac-
tory, which might be caused by incomplete decomposi-
tion. Considering the electronic and steric effects, a
derivative named as LK-194 (Figure 1) was synthesized by
introducing a methoxy in the a-position of amino acid lin-
ker to weaken the ester bond, the results were also not
ideal, but better than LK-193. Based on the above results,
we introduced a fluorine atom in the a-position of amino
acid linker to further strengthen the electronic effects;
then, LK-195 and LK-196 were synthesized (Figure 1).
Received 28 January 2016, revised 31 March 2016 and
accepted for publication 5 April 2016
Taxol is a taxane diterpenoid derivative which was first iso-
lated from Taxus brevifolia by Wani et al. in 1971 (1). Doc-
etaxel, which is a semi-synthetic analogue from taxol, is an
important chemotherapeutic drug widely used for the treat-
ment of various types of cancer. However, due to its poor
water solubility, clinical application of docetaxel is limited. In
addition, a variety of adverse effects, such as allergic reac-
tions, nephrotoxicity, neurotoxicity, cardiovascular toxicity,
and so on, were readily evoked by docetaxel (2–4).
Herein, we reported the synthesis and biological evaluation
of a novel derivative of docetaxel, in which an amino acid
0
was linked to hydroxyl group of C2 position. The target
1
compounds were determined by MS, HRMS, HNMR,
and CNMR. The solubility, stability, and antitumor activity
of LK-196 are also described in this study.
13
It is known that docetaxel is a little more water soluble
than paclitaxel, but just 6–7 lg/mL in aqueous solution
(paclitaxel: 0.25 lg/mL) (5–7). To improve water solubility,
a series of docetaxel prodrugs had been carried out
0
through the introduction of solubilizing moieties to C2 , C7,
Methods and Materials
and C10 positions (8–17). The solubilizing moieties can be
carboxylic acids, phosphates, sulfonates, amines, sugar
derivatives, or polyethylene glycol. Previously, some glyco-
syl derivatives of docetaxel were prepared and evaluated
General
AB204-E analytical balance (Mettler-Toledo Shanghai,
Shanghai, China); Delta-320 pH meter (Mettler-Toledo
ª 2016 John Wiley & Sons A/S. doi: 10.1111/cbdd.12762
1

Ma et al.
HO
OH
O
H
O
OH
O
NH
O
O
O
O
O
O
OBz
O
R1
A
.
N
1
LK-193: R = H, A = hydrochloric acid
1
LK-194: R = OCH , A = hydrochloric acid
3
1
LK-195: R = F, A = hydrochloric acid
Figure 1: The structure of LK-193~LK-
96.
1
LK-196: R = F, A = methanesulfonic acid
1
Shanghai); 1200 series high-performance liquid chro-
matography (Agilent Technologies, Palo Alto, CA, USA);
Stability in PBS buffer and human plasma
The derivatives LK-193, LK-194, LK-195, and LK-196
were dissolved in water and vortex and centrifuged. A
total of 10 lL of the above fluid was mixed with 900 lL
of PBS buffer (pH 7.4) or human plasma (heparin). The
solutions were incubated at 37 °C, and at different points
(for PBS buffer, T = 0, 5, 30, 60, 120, 180 min; for
human plasma, T = 0, 2, 5, 10, 15, 30, 60 min), 100 lL
mixture was precipitated with 900 lL acetonitrile and
then extracted with 2000 lL of dichloromethane. After
mixing for 3 min (using a vortex), this mixture was cen-
trifuged (10 min, 3000 9 g) and evaporated. The samples
were dissolved in 100 lL acetonitrile and analyzed by
HPLC (12).
2
010A mass spectrometer (Shimadzu Corporation, Kyoto,
Japan); probe BBO500 nuclear magnetic resonance spec-
trometer (Bruker Corporation, Karlsruhe, Germany).
Docetaxel (Zhuhai United Laboratories Co., Ltd., Zhuhai,
China); N,N-dimethyl-c-amino butyric acid hydrochloride
(homemade); N,N-dimethyl-a-methoxy-c-amino butyric
acid hydrochloride (homemade); N,N-dimethyl-a-fluoro-c-
amino butyric acid hydrochloride (homemade); 4-dimethy-
laminopyridine, iodomethane, N-sodiohexamethyldisila-
zane, diethylaminosulfurtrifluoride (J & K Technology Co.,
Ltd., Shanghai, China); thionyl chloride (Shanghai Crystal
Pure Industrial Co., Shanghai, China); human prostate
cancer PC-3 cells line (by the Shanghai Institute of Mate-
riaMedica, Shanghai, China); sodium chloride, anhydrous
sodium sulfate, ammonium dihydrogen phosphate, methy-
lene chloride, acetone, isopropyl ether, hydrochloric acid
by Chengdu Kelong Chemical reagent Factory. All
reagents were of analytical grade or more. Experimental
water is ultra-pure water.
Cytotoxicity assay in vitro
The cytotoxic activity in vitro was measured using the
MTT assay. The MTT solution (final concentration:
0.5 mg/mL) in RPMI-1640 was added after cells were
treated with the drug for 48 h, and cells were incubated
for further 4 h at 37 °C. The purple formazan crys-
tals were dissolved in 100 lL DMSO. After 5 min,
the plates were read at 570 nm by an automated
Biological methods
microplate
spectrophotometer.
The
concentration
required for 50% inhibition of cell viability (IC50) was cal-
culated using the software ‘Dose–Effect Analysis with
Microcomputers’. The cancer cell lines’ panel consisted
of A375, IGROV, H226, and MCF-7. In all of these
experiments, three replicate wells were used to deter-
mine each point, and all of the experiments were per-
formed in triplicate.
Water solubility
Docetaxel and derivatives were suspended in water until a
concentration was reached of 6 mg/mL. Suspension was
vortex for 15 min and centrifuge (3000 9 g) for 10 min. The
above fluid was analyzed, using HPLC. In the same way,
the solubility of docetaxel and derivative was analyzed (12).
2
Chem Biol Drug Des 2016

A Novel Water-soluble Prodrug of Docetaxel
Acute toxicity test in mice intravenously
Select fifty qualified health of SPF Kunming mice pur-
chased from laboratory animals center of Chongqing
Medical University, male and female, weighing 18–22 g.
The mice were randomly divided into five groups. Each
vacancy was ten. Intravenous administration LK-196,
HO
OH
O
O
OH
HO
O
H
O
O
NH
OH
O
O
O
O
NH
N
.
O
Cl
HCl
H
O
O
R1
O
O
OBzO
O
OH
O
O
OH OBz
DMAP/CH Cl
2 2
R1
O
A
N
.
Scheme 1: Synthesis of LK-193~LK-196. Reagents and conditions: Dichloromethane,4-dimethylaminopyridine.
a
OH
OH
Cl
b
H N
2
N
N
O
·HCl
O
·HCl
O
1c
2c
3c
O
N
O
OH
OH
O
1
a
c
O
O
N
O
O
F
OH
O
O
O
O
f
d
N
N
O
O
O
3
a
2a
O
O
1b
e
e
O
O
F
F
OH
OH
OH
a
OH
a
H N
2
N
H N
HCl
N
HCl
2
·
HCl
O
·
HCl
O
O
·
O
F
·
5a
3b
2b
4
a
b
b
O
Cl
Cl
N
N
·
HCl
O
·HCl
O
6a
4b
Scheme 2: Synthesis of Linkers. Reagents and conditions: (a) Formic acid, formaldehyde, 80 °C; (b) thionyl chloride, 50 °C; (c) thionyl
chloride, methanol, r.t.; (d) iodomethane, N-sodiohexamethyldisilazane, tetrahydrofuran; (e) 6 mol/L hydrochloric acid, 90 °C; (f)
diethylamino-sulfur trifluoride, tetrahydrofuran, r.t.
Chem Biol Drug Des 2016
3

Ma et al.
dosing capacity 0.2 mL/10 g. Animals were kept at
conditions. 2-methoxy-4-phthalimidoaminobutyric acid
methyl ester (1b) was synthesized by 2-hydroxy-4-phthali-
mido aminobutyric acid methyl ester (2a) with iodomethane
and N-sodiohexamethyldisilazane under anhydrous condi-
tions. Hydrolysis of 2-fluoro-4-phthalimido aminobutyric
acid methyl ester (3a) was carried out in the presence of
2
4 ꢀ 1 °C and 55 ꢀ 10% humidity, with 12 h of light (arti-
ficial illumination; 08:00-20:00) for 1 week, free access to
water and food, recorded the death of animal. Calculate
LD50 by Bliss method program.
6
mol/L hydrochloric acid to give the corresponding 2-
Pharmacodynamics
fluoro-4-amino butyric acid hydrochloride (4a); in the same
way, 2-methoxy-4-amino butyric acid hydrochloride (2b)
was given. N,N-dimethyl-c-aminobutyric acid hydrochloride
(2c) was afforded by Leuckart reaction with formic acid
and formaldehyde from c-aminobutyric acid (1c); in the
same way, N,N-dimethyl-a-fluoro-c-aminobutyric acid
hydrochloride (5a) and N,N-dimethyl-a-methoxy-c-amino-
butyric acid chloride hydrochloride (3b) were afforded. N,
N-dimethyl-c-aminobutyric acid chloride hydrochloride (3c)
was synthesized by N,N-dimethyl-c-aminobutyric acid
hydrochloride (5a) with thionyl chloride; in the same way,
Select sixty BALB/cA nude mice purchased from Shanghai
Slac Laboratory Animal Co. Ltd. (Shanghai, China), male,
weighing 18–22 g. Under sterile conditions, the human
prostate cancer PC-3 cells were inoculated subcuta-
neously in the right armpit male nude mice. After the
3
tumor grew to 100–200 mm , the mice were randomly
divided into four groups of six. Docetaxel control divided
into 14 and 7 mg/kg group and LK-196 divided into 16.8
and 33.6 mg/kg group. The rest were in negative control
group. Inject once a week for 3 weeks. Tumor volume
was recorded at each time-point.
N,N-dimethyl-a-methoxy-c-aminobutyric
acid
chloride
hydrochloride (4b) and N,N-dimethyl-a-fluoro-c-aminobuty-
ric acid chloride hydrochloride (6a) were synthesized. The
chemical synthesis details and structure data were pre-
sented as Appendix S1.
Pharmacokinetics of rats
Healthy male Sprague Dawley rats weighting 180–220 g
were purchased from laboratory animals center of
Chongqing Medical University. Intravenous administrate a
dose of 5 mmol/kg LK-196. At different time-points after
administration (T = 0.083, 0.17, 0.5, 1, 2, 4, 8, 12, 24 h),
blood was collected from the tail vein to determine plasma
concentrations by LC/MS/MS and then calculated phar-
maco-kinetic parameters by the software of 3p97.
Solubility and stability
Solubility of synthesized compounds was measured by
HPLC. Results are listed in Table 1. Chemicophysical
properties demonstrated that the derivatives greatly
improved water soluble compared to docetaxel (200–2060
times). We considered that it is possible to prepare them
in the form of lyophilized powder for injection clinically
without any surfactant such as Tween-80. Therefore, the
strong allergic reactions caused by Tween-80 could be
avoided.
Results and Discussion
Chemistry
In Scheme 1, LK-193 was synthesized by N,N-dimethyl-c-
amino butyric acid chloride hydrochloride with docetaxel in
ice bath. With the same strategy, LK-194 and LK-195
were synthesized. LK-196 was obtained by converting salt
type with LK-195.
Table 2: The stability of docetaxel derivatives in PBS buffer
Sample points decomposition rate% (min)
In Scheme 2, 2-hydroxy-4-phthalimido aminobutyric acid
methyl ester (2a) was synthesized by treatment in 2-
hydroxy-4-phthalimido aminobutyric acid (1a) and metha-
nol with thionyl chloride as catalyst. 2-fluoro-4-phthalimido
aminobutyric acid methyl ester (3a) was obtained by
Compound
0
5
30
8.2
11.3
97.6
99.4
60
120
180
LK-193
LK-194
LK-195
LK-196
0
0
0
0
2.8
4.2
71
15.4
20.1
21.3
33.6
36.8
48.3
77.4
2
-hydroxy-4-phthalimido aminobutyric acid methyl ester
(
2a) with diethylamino sulfur trifluoride under anhydrous
Table 3: The stability of docetaxel derivatives in human plasma
Table 1: The solubility of docetaxel derivatives
Sample points decomposition rate% (min)
Compound
Solubility (mg/mL)
Compound
0
2
5
10
15
30
60
LK-193
LK-194
LK-195
LK-196
Docetaxel
1.2
1.4
2.8
12.4
6 9 10
LK-193
LK-194
LK-195
LK-196
0
0
0
0
1.3
4.7
75.4
81.6
3.6
6.3
17.8
9.4
20.2
20.7
38.8
40.1
61.6
10.5
97.2
99.8
ꢁ3
4
Chem Biol Drug Des 2016

A Novel Water-soluble Prodrug of Docetaxel
Table 4: Cytotoxicity of docetaxel derivatives in cell lines
Cell line (IC50 lg/mL)
Compound
A375
IGROV
H226
MCF-7
Docetaxel
LK-193
LK-194
LK-195
LK-196
3.2 ꢀ 0.3
20.4 ꢀ 3.2**
15.4 ꢀ 1.4**
4.7 ꢀ 0.3*
3.0 ꢀ 0.2
2.8 ꢀ 0.2
9.4 ꢀ 0.7**
8.3 ꢀ 1.3**
2.4 ꢀ 0.3
2.7 ꢀ 0.3
9.7 ꢀ 0.4
27.6 ꢀ 4.4**
21.6 ꢀ 2.3**
21.4 ꢀ 3.1**
9.5 ꢀ 1.0
2.3 ꢀ 0.2
13.7 ꢀ 0.8**
11.1 ꢀ 1.2**
5.6 ꢀ 0.3*
2.5 ꢀ 0.2
,a
a
Statistical analysis was evaluated using a one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison test.
*p < 0.05; **p < 0.01 compared with docetaxel.
Table 5: Acute toxicity LD50 of mice after intravenous injection of
LK-196
The test of stability in PBS buffer showed that LK-193
and LK-194 were more stable than LK-195 and LK-196
(
Table 2). Besides, LK-195 and LK-196 almost completely
Dose
group
Number
Logarithmic of
decomposed into docetaxel when it was incubated in
human plasma within 5 min (Table 3). Apparently, LK-196
acted as the prodrug of docetaxel.
Mortality Probit
(mg/kg) dose (X)
animals
Deaths rate (%)
(Y)
1
8
6
5
4
00.0
0.0
4.0
1.2
1.0
2.0000
1.9031
1.8062
1.7093
1.6128
10
10
10
10
10
10
7
4
2
0
100
70
40
20
0
3.4191
4.2995
5.1799
6.06.03
6.9368
Cytotoxicity
All compounds were screened for their cytotoxicity in vitro
against human cancer cell lines (A375, IGROV, H226,
and MCF-7). The results are listed in Table 4. LK-193 and
LK-194 were significantly less active against most tested
cancer cell lines. LK-196 showed similar activity compared
to docetaxel and superior to LK-195. LK-196 was chosen
as the optimal compound for further studies.
Mice intravenous acute toxicity test results
The dose LD50 of LK-196 for injection in mice was
6
6.99 mg/kg, and a 95% confidence range of its LD50
was 60.42–74.27 mg/kg as shown in Table 5. Poisoned
mice were found that their behaved with tremor, erect tail,
piloerection, spontaneous acting decreased, dysphoria,
tachypnea, and dyspnea right after administration LK-196
and died finally.
Pharmacodynamic results
Figure 2: Effects of docetaxel and LK-196 on the weight of
tumor-bearing nude mice.
LK-196 (16.8, 33.6 mg/kg, i.v., single) significantly inhib-
ited the growth of human prostate tumor PC-3 in nude
Table 6: Effects of docetaxel and LK-196 on prostate tumor PC-3 in nude mice
3
3
Group
Dose (mg/kg)
No. of animals
Tumor volume D
0
(mm )
Tumor volume D20 (mm )
p-Value D20
Inhibition rate (%)
Control
12
6
6
6
6
110.5 ꢀ 4.4
111.5 ꢀ 1.3
111.7 ꢀ 4.6
115.9 ꢀ 2.9
113.7 ꢀ 2.9
870.5 ꢀ 60.5
81.4 ꢀ 25.1
542.7 ꢀ 72.5
83.8 ꢀ 11.4
26.6 ꢀ 12.4
Docetaxel
Docetaxel
LK-196
14
7
16.8
33.6
0.000
0.005
0.000**
0.000**
127
43
128
177
,
a
LK-196
a
Statistical analysis was evaluated using a one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison test.
**p < 0.01, compared with Docetaxel (7 mg/kg); Student’s t-test was used to compare the inhibition rate. The number of mice: treatment
group n = 6, control group n = 12.
Chem Biol Drug Des 2016
5

Ma et al.
Figure 3: The tumor photograph of the
effect of docetaxel and LK-196 on prostate
tumor PC-3 in nude mice.
were 43% and 127%, respectively. The high dose group
showed partial remission (PR) rate of tumor is 4/6, and
complete remission (CR) rate is 1/6. Results in high dose
LK-196 group and high dose docetaxel group, the weigh
LK-196
Docetaxel
6 6
was reduced by 12.5% (D ) and 13.6% (D ), respectively,
and returned faster to normal weight after discontinuation
of drugs. According to the current dose regimen, the toxi-
city of these two drugs was similar. From the Table 7 and
Figure 4, we can see that, compared with docetaxel, LK-
1
96 showed significant therapeutic effect on human pros-
tate tumor PC-3 in nude mice, its action were stronger
than docetaxel, and the toxicity did not increase obviously
(
Figure 2). Therefore, LK-196 was worthy of further devel-
Time (h)
opment, such as the antitumor activity against other tumor
strains (Table 6 and Figure 3).
Figure 4: The concentration–time curve of LK-196 and
docetaxel.
Rat pharmacokinetic results
mice in a dose-dependent manner, inhibition rates are
After intravenous injection 5 mmol/kg LK-196, the original
drug was not detected within 5 min, while docetaxel was
detected. The distribution of serum concentrations of LK-
196 and docetaxel met three-compartment model. The
results were depicted in Table 5 and Figure 4. The plasma
concentrations of metabolites reached the peak very
1
28% and 177%, respectively. The low dose group
showed that partial remission (CR) rate is 5/6, and the high
dose group showed that partial remission (PR) rate of
tumor is 3/6, complete remission (CR) rate is 3/6. The inhi-
bition rates of docetaxel (7, 14 mg/kg, i.v., single) groups
Table 7: Metabolites docetaxel and LK-196 on pharmacokinetic parameters after rat intravenous injection of 5 mmol/kg LK-196
t
1/2a (h)
t
1/2b (h)
AUC0?t (nmol h/mL)
CL (lmol/kg/h)
LK-196
Docetaxel
1.05 ꢀ 0.45
2.11 ꢀ 1.30
27.62 ꢀ 6.75
2.53 ꢀ 0.12
2.84 ꢀ 0.96
1172.8 ꢀ 135.35
423.19 ꢀ 312.12
278.89 ꢀ 214.48
6
Chem Biol Drug Des 2016

A Novel Water-soluble Prodrug of Docetaxel
rapidly, AUC0?t to 2.84 ꢀ 0.96 nmol h/mL, which was
equivalent to 112.2% of unchanged drug. Therefore, LK-
solutions in PVC bags and polyolefine containers.
Pharm World Sci;21:137–141.
1
96 had the potential to be prodrug. It was concluded that
6. Vyas D.M., Wong H., Crosswell A.R., Casazza A.M.,
Knipe J.O., Mamer S.W., Doyle T.W. (1993) Synthesis
and antitumor evaluation of water soluble taxol phos-
phates. Bioorg Med Chem Lett;3:1357–1360.
LK-196 would quickly decomposed to docetaxel to play
efficacy in vivo (Table 7).
7
. Skwarczynski M., Sohma Y., Kimura M., Hayashi Y.,
Kimura T., Kiso Y. (2003) O-N Intramolecular acyl
migration strategy in water-soluble prodrugs of taxoids.
Bioorg Med Chem Lett;13:4441–4444.
Conclusion
In conclusion, we have synthesized some novel water-solu-
ble docetaxel derivatives in good yields and LK-196 was
screened out. It may be caused by the strong electron-with-
drawing effect of fluorine atom in a-position of amino acid
linker so that the ester bond of LK-196 is more easily broken
than LK-193 and LK-194. LK-196 showed similar activity
in vitro and significant inhibition on the growth of human
prostate tumor PC-3 in vivo, in addition to the excellent
water solubility, compared with docetaxel. Through prelimi-
nary evaluation, we confirmed LK-196 had a very potential
to be a prodrug of docetaxel. Further studies about LK-196
are in progress. This study provided the basis for the further
development of novel water-soluble docetaxel derivative.
8. Rodrigues M., Carter P., Wirth C., Mullins S., Lee A.,
Blackburn B. (1995) Synthesis and b-lactamase-
mediated activation of a cephalosporin-taxol prodrug.
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producing thereof. European Patent 0882732.
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L.O. (2003) Semi-synthesis of an O-Glycosylated doc-
etaxel analogue. Bioorg Med Chem;11:1551–1556.
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Acknowledgments
1
1
1
This study was supported by Shanghai Institute of Mate-
riaMedica. We also thank the Centre for Innovative Drug
1
13
Research of Chongqing University for H NMR, C NMR,
and ESI-MS spectra.
6
1:799–801.
4. Abraham E.M., Magdalena R.M., Jyoti P.N., Richard
H.H., Valentino J.S. (1992) Synthesis and evaluation of
some water-soluble prodrugs and derivatives of taxol
with antitumor activity. J Med Chem;35:145–151.
Conflict of Interest
None declared.
1
1
5. Deutsch H.M., Glinski J.A., Hernandez M., Haugwitz
R.D., Narayanan V.L., Suffness M., Zalkow Leon H.
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Appendix S1 General procedure.
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