Design, synthesis and biological evaluation of paclitaxel-mimics possessing only the oxetane D-ring and side chain structures

Article abstract of DOI:10.1016/j.fitote.2013.10.015

Two spiro paclitaxel-mimics consisting only of an oxetane D-ring and a C-13 side chain were designed and synthesized on the basis of analysis of structure-activity relationships (SAR) of paclitaxel. In vitro microtubule-stabilizing and antiproliferative assays indicated a moderate weaker activity of the mimics than paclitaxel, but which still represented the first example of simplified paclitaxel analogues with significant anti-tumor biological activity.

Full text of DOI:10.1016/j.fitote.2013.10.015

Fitoterapia 92 (2014) 111–115
Contents lists available at ScienceDirect
Fitoterapia
journal homepage: www.elsevier.com/locate/fitote
Design, synthesis and biological evaluation of paclitaxel-mimics
possessing only the oxetane D-ring and side chain structures
1
Xing-Xiu Chen , Feng Gao ,1, Qi Wang, Xing Huang, Dan Wang
⁎
Department of Chinese Traditional Herbal, Agronomy College, Sichuan Agricultural University, No. 211, Huiming Road, Wenjiang Region, Chengdu 611130, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 August 2013
Accepted in revised form 27 October 2013
Available online 6 November 2013
Two spiro paclitaxel-mimics consisting only of an oxetane D-ring and a C-13 side chain were
designed and synthesized on the basis of analysis of structure–activity relationships (SAR) of
paclitaxel. In vitro microtubule-stabilizing and antiproliferative assays indicated a moderate
weaker activity of the mimics than paclitaxel, but which still represented the first example of
simplified paclitaxel analogues with significant anti-tumor biological activity.
© 2013 Elsevier B.V. All rights reserved.
Keywords:
Paclitaxel
Paclitaxel-mimics
Spirocyclic oxetane
D-ring
Side chain
1. Introduction
Ojima et al. reported several paclitaxel-mimics with a simpli-
fied structure, in which the taxane core was substituted by an
The natural diterpenoid paclitaxel (Taxol®), and its semi-
synthetic derivatives docetaxel (Taxotere®) and cabazitaxel
(Jevana®) (Fig. 1), are important chemotherapeutics in current
clinical treatment of breast cancer, ovarian cancer, non-small cell
lung cancer and prostate cancer [1]. They accelerate microtubule
polymerization through a combination with tubulin and stabilize
cell division cycle at G2/M phase, stimulating the apoptosis
of tumor cells [2]. Due to their potent anti-cancer activities,
medicinal chemists have conducted in-depth research on the
SAR (Structure–Activity Relationship) of paclitaxel and have
developed a new generation of anti-cancer taxoids with higher
activity [3].
Current structural modification research on taxoids is mainly
focused on changes to the taxane core or the side chain. On
this basis, a large number of paclitaxel derivatives have been
synthesized, and the resulting SAR have been summarized [4].
Despite the limited number of studies on the simplification of
paclitaxel, some interesting results (Fig. 2) have been reported.
indolizidine scaffold, and the C-13 side chain was retained.
These compounds expressed modest cytotoxic activities, but
lost the activity to stabilize microtubules [5,6]. Kingston et
al. designed and synthesized macrocyclic paclitaxel-mimics,
which exhibited both cytotoxic and microtubule polymeri-
zation activity, based on the configuration study of T-Taxol
[7,8]. Guenard et al. synthesized a series of novel compounds
combining steroids with the side-chain of docetaxel, in
which the taxane skeleton was replaced by a steroid scaffold.
These compounds exhibited weak cytotoxic activities and
showed no microtubule disassembly inhibitory activity [9].
Beau et al. synthesized a series of paclitaxel-mimics via click
chemistry based on the study of the active three-dimensional
conformation of paclitaxel, but without bioactivity data [10].
Although researchers have not yet prepared strongly bioactive
paclitaxel-mimics, the bioactivities observed indicate their
potential for SAR research of paclitaxel as well as the discovery
of more active paclitaxel analogues [11–15].
Current SAR research on paclitaxel demonstrated that the
unique oxetane D-ring and side chains of paclitaxel were
indispensable active groups. A-seco-paclitaxel analogues syn-
thesized by Ojima et al. showed moderate activity, although
⁎
Corresponding author. Tel./fax: +86 28 86290870.
E-mail address: gaofeng@sicau.edu.cn (F. Gao).
The two authors contributed equally to this work.
1
0367-326X/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.fitote.2013.10.015

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X.-X. Chen et al. / Fitoterapia 92 (2014) 111–115
O
major reductions or even loss of activities [18–20]. In current
research, two novel paclitaxel-mimics consisting only of oxetane
D-rings and side chains, in which the taxane diterpenoid core
was replaced by 2-oxa-6-azaspiro[3.3]heptane, were synthe-
sized and their biological activities were evaluated.
R2O
O
H
OR1
R3
NH
O
Ph
O
B
A
1
HO
C
4
5
D
13
O
OH
2
2. Experimental
OAc
OBz
1 Paclitaxel
2 Docetaxel
3 Cabazitaxel
R1 = H, R2 = Ac, R3 = Ph
R1 = H, R2 = H, R3 = Ot bu
R1 = Me, R2 = Me, R3 = Ot bu
2.1. General
1H and 13C NMR spectra were recorded on a Varian Unity
INOVA 400/54NMR spectrometer in CDCl3 with tetramethyl-
silane (TMS) as the internal standard. Chemical shifts are given
as δ value and are referenced to residual solvent proton carbon
pick. Mass spectra were obtained on a VG Auto spec 3000 or on a
Finnigan MAT 90 instrument. Optical rotations were measured
on a Perkin-Elmer 341. Silica gel H (Qingdao Sea Chemical
Factory, Qingdao, PR China) was used for column chromatogra-
phy. Spots on TLC (silica gel GF254) were detected with H2SO4–
EtOH or UV. Commercially available reagents and solvents were
used without further purification. Biological activity evaluation
was carried out according to the protocols described previously
[21].
Fig. 1. Structures of paclitaxel, docetaxel and cabazitaxel.
less than paclitaxel [16]. C-seco-paclitaxel analogues, which
were also obtained by Ojima et al., showed favorable activities
against paclitaxel-resistant tumor cell lines [17]. In contrast,
paclitaxel analogues without a D-ring or a side chain showed
O
t-Boc
O
NH
O
O
N
Ph
NH
O
O
N
2.2. Preparation of N-tosyl-2-oxa-6-azaspiro[3.3]heptane (5)
Ph
O
OH
H
O
OH
H
OBz
To a solution of KOH (179 g, 3.2 mol) and p-tosylamide
(205 g, 1.2 mol) in 1500 mL ethanol, 3-bromo-2,2-bis
(bromomethyl)propan-1-ol (324 g, 1.0 mol) was added at
room temperature and the reaction mixture was heated to
reflux for 90 h. The solvent was removed by evaporation,
2000 mL 1 M KOH was added and the white suspension was
left to stir for another 2 h at room temperature. The mixture was
filtered and the white filter cake was rinsed with water until the
washing water was neutral. The filter cake was dried under high
vacuum to give N-tosyl-2-oxa-6-azaspiro[3.3]heptane (5, 192 g,
yield 76%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.69 (d,
2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 4.42 (s, 4H), 3.85 (s,
4H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 130.9,
130.2, 128.5, 79.1, 59.5, 37.3, 21.3.
OAc
R1
Ojima's mimic A
O
Ojima's mimic B
H
O
R2
O
HO
t-Boc
O
Bz
N
H
NH
OBz
O
OBz
O
Ph
H
X
OH
O
Roussi's mimic D
Kingston's mimic C
OH
H
t-Boc
NH
O
O
O
O
N
Ph
O
( )7
O
N
N
H
BzO
HO
O
Beau's mimic E
Fuji's mimic F
2.3. Preparation of 2-oxa-6-azaspiro[3.3]heptane oxalate (6)
Boc
Ph
A solution of N-tosyl-2-oxa-6-azaspiro[3.3]heptane (7.30 g,
0.0288 mol, 1.00 equiv) in MeOH (1000 mL) was sonicated,
and Mg powder (5.2 g, 0.2166 mol, 9.00 equiv) was added in
potions over 1 h. The crude mixture was concentrated in
vacuum, and suspended in Et2O (1000 mL) and Na2SO4 · 10H2O
(50 g) was added. The suspension was vigorously stirred at
room temperature for 1 h, then filtered, the filtrate dried
(Na2SO4), and filtered. To the filtrate was added under stirring
a solution of anhydrous oxalic acid (4.5 g, 0.05 mol) in EtOH
(10 mL), which immediately formed a white precipitate. The
solid was filtered and dried under reduced pressure to give
pure 2-oxa-6-azaspiro[3.3]heptane (3.22 g, 73%) of oxalate
mono-salt as an amorphous white powder. 1H NMR (400 MHz,
CDCl3): δ 4.65 (s, 4H), 4.12 (s, 4H); 13C NMR (100 MHz, CDCl3)
δ 79.2, 54.1, 39.3.
O
NH
O
HO
O
O
Ph
Bz
O
O
HO
NH
O
O
Zefirova's mimic G
Almqvist's mimic H
O
N
Bz
NH
NH
O
N
N
NH2
OH
O
Ph
O
Ph
O
O
OH
NH
O
Bz
OH OH
Howarth's mimic J
Klar's mimic I
Fig. 2. Structures of representative paclitaxel-mimics.

X.-X. Chen et al. / Fitoterapia 92 (2014) 111–115
113
2.4. Preparation of compounds 9 and 10
4.56 (1H, d, J = 7.2 Hz), 4.46 (1H, s), 4.43 (1H, d, J = 6.8 Hz),
4.27 (1H, d, J = 6.8 Hz), 3.99 (2H, t, J = 12.0 Hz), 3.81 (3H,
s),3.72(2H, t, J = 12.0 Hz);13C NMR (100 MHz, CDCl3) δ 160.0,
131.2, 128.3, 127.9, 127.9, 127.4, 126.1, 113.3, 91.1, 80.4, 80.3,
80.1, 61.9, 60.6, 57.7, 55.1, 37.38, 27.6.
Commercial (4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-
phenyl-5-oxazolidinecarboxylic acid (7, paclitaxel side chain,
2 g, 0.005 mol, 1.00 equiv) and HATU (3 g, 0.0079 mol, 1.50
equiv) were added to a solution of compound 6 (1 g, 0.0052 mol,
1.00 equiv) in THF (50 mL), and the reaction mixture was stirred
at room temperature for 24 h. Then 150 mL water and CH2Cl2
was added. The organic layer was washed with brine, dried
over MgSO4, and evaporated to give a residue which was
chromatographed over silica gel (Petroleum ether:EtOAc = 1:3)
to afford compound 9 as a white amorphous powder (2.252 g,
86%) as a pair of diastereoisomers.
Compound 10 was prepared through the coupling of
compounds 6 and commercial (4S,5R)-3-tert-butoxycarbony-2-
(4-methoxpheny)-4-phenyl-5-oxazolidinecarboxylic acid
(8, docetaxel side chain) in 95% yields by similar proce-
dures. Compound 10 is also a pair of diastereoisomers.
2.5. Preparation of compounds 11 and 12
p-Toluenesulfonic acid powder (0.15 g, 0.871 mmol) was
added in portions to a solution of compound 9 (400 mg,
0.826 mmol) in CH3OH (100 mL) at room temperature over
12 h. NaHCO3 was added to adjust PH to neutral. After addition
of water, the mixture was concentrated under reduced pressure
and extracted with AcOEt, the organic layer was washed with
brine, dried over MgSO4, and evaporated to give compound 11
(90 mg, 30.0%) after purification by column chromatography
over silica gel (chloroform:methanol = 20:1). Compound 12
was prepared in 36.0% isolated yield by similar procedures.
2.5.1. N-((1S,2R)-2-hydroxy-3-oxo-1-phenyl-3-(2-oxa-6-azaspiro
[3.3]heptan-6-yl)propyl)-benzamide (11)
2.4.1. (4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-
phenyloxazolidin-5-yl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)
methanone (9)
25
D
White amorphous powder, ½αꢀ
−15.6 (CHCl3, c 1.0);1H
White amorphous powder, 1H NMR (400 MHz, CDCl3): δ
6.88–7.31 (14H, Ar–H), 5.51 (1H, s),4.74 (4H, m), 4.69 (2H, s),
4.69 (2H, d, J = 10.0 Hz), 4.48 (2H, d, J = 10.0 Hz), 4.20 (2H, s),
3.81 (3H, s); 13C NMR (100 MHz, CDCl3) δ 167.5, 159.7, 135.4,
130.2, 129.5, 128.3, 128.3, 127.9, 127.6, 126.8, 113.4, 90.2, 80.4,
80.2, 60.8, 57.9, 55.0, 38.3.
NMR (400 MHz, CDCl3): δ 7.26–7.77 (10H, Ar–H), 5.49 (1H, br.
s), 4.52 (1H, br. s), 3.94 (1H, br.s), 3.68 (4H, m), 3.50 (4Η, m);
13C NMR (100 MHz, CDCl3) δ 171.1, 167.7, 138.2, 133.6, 130.0,
128.6, 128.6, 127.8, 127.1, 127.1, 80.2, 71.8, 63.5, 54.8, 39.5; MS
(ESI, MeOH) m/z 367 [M + H]+; HR-ESI-MS: 367.1634
[M + H]+, calcd. for C21H23N2O4 367.1657.
2.4.2. 4S,5R)-tert-butyl-2-(4-methoxyphenyl)-4-phenyl-5-(2-oxa-
6-azaspiro[3.3]heptane-6-carbonyl)oxazolidine-3-carboxylate (10)
White amorphous powder, 1H NMR (400 MHz, CDCl3): δ
6.89–7.37 (9H, Ar–H), 5.71 (1H, s),4.61 (1H, d, J = 7.2 Hz),
2.5.2. Tert-butyl(1S,2R)-2-hydroxy-3-oxo-1-phenyl-3-(2-oxa-
6-azaspiro[3.3]heptan-6-yl)-propylcarbamate (12)
25
D
White amorphous powder, ½aꢀ
−22.6 (CHCl3, c 1.0);1H
NMR (400 MHz, CDCl3): δ 7.32 (5H, Ar–H), 5.58 (1H, br. s),
Br
O
1) Mg / CH3OH / ultrasound
TsNH2 / KOH
S
O
Br
OH
N
2) anhydrous oxalic acid / Et2O
CH3CH2OH
Br
O
5
4
O
COOH
+
O
HN
HATU / Et3N / THF
2-
C2O4
N
+
R
2
O
6
7 R = Bz
8 R = Boc
O
R
H3CO
NH
O
O
O
p-TSA
CH3OH
Ph
N
N
N
HO
R
Ph
O
11 R = Ph
12 R = t BuO
O
9
R = Bz
10 R = Boc
Scheme 1. Synthesis of paclitaxel-mimics.

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X.-X. Chen et al. / Fitoterapia 92 (2014) 111–115
4.86 (1H, br. s), 4.60 (4H, m), 4.21 (1Η, br. s), 3.95 (4H, m),
1.38 (9Η, s); 13C NMR (100 MHz, CDCl3) δ 170.6, 155.4, 128.1,
127.4, 126.7, 80.2, 79.6, 72.0, 59.7, 57.6, 38.1, 28.0; MS (ESI,
represent the most significant microtubule disassembly
inhabitant activity in the reported paclitaxel-mimics. Interest-
ingly, compound 12 possessing the docetaxel side chain was
more active in tubulin assays than compound 11 consisting of
the paclitaxel side chain.
MeOH) m/z 363 [M + H]+; HR-ESI-MS: 363.1902 [M + H]+
,
calcd. for C19H27N2O5 363.1919.
Assays for anti-proliferative activity were also conducted
and indicated that paclitaxel-mimics 11 and 12 exhibited
moderate anti-proliferative activities (Table 2). It is particu-
larly worth mentioning that these two compounds showed
favorable activities against paclitaxel-sensitive tumor cell lines,
such as A2780 and BGC-823, and showed comparatively low
activities against paclitaxel-insensitive tumor cell lines, such
as Bel-7402, which suggests a probably similar anti-cancer
mechanism to that of paclitaxel. Of course, more pharmaco-
logical research should be done to interpret this interesting
result.
In summary, two paclitaxel-mimics 11 and 12 bearing
only an oxetane D-ring and C-13 side chain were designed on
the SAR of paclitaxel, and were readily prepared through four
simple reactions. In vitro stabilizing-microtubule and anti-
proliferative assays indicated that the two mimics 11 and 12
showed moderate anti-tumor activities. Interestingly, their
antiproliferative activity was consistent with that of paclitaxel,
i.e., exhibiting favorable activities against paclitaxel-sensitive
tumor cell lines while showing similar drug-resistance against
3. Results and discussion
The simplified scaffold 2-oxa-6-azaspiro[3.3]heptane, which
would replace the taxane core, was synthesized firstly. The
paclitaxel-mimics were then prepared by coupling different side
chains with the nitrogen atom using a known semi-synthetic
method of paclitaxel. Lastly, the paclitaxel-mimics were sub-
jected to stabilizing-microtubule and antiproliferative activity
assays.
Following the synthetic method for spirocyclic oxetanes
reported by Burkhard et al.[22], 6-tosyl-2-oxa-6-azaspiro
[3.3]heptane (5) was conveniently obtained by refluxing
tribromopentaerythritol (4) and p-toluenesulfonamide for
72 h in anhydrous ethanol under KOH. The protecting group
of tosyl was removed from 5 via ultrasonic-assisted reduction
with Mg powder, and the corresponding salt was formed with
oxalic acid to yield 2-oxa-6-azaspiro[3.3]heptane (6). Paclitaxel
oxetane D-ring analogues 9 and 10 were prepared by a coupling
reaction with the side chains of paclitaxel and docetaxel
(Scheme 1).
In most semi-synthesis of paclitaxel, the coupling reaction of
10-DAB (10-deacetylbacatin III) with different side chains was
conducted in the presence of DCC (dicyclohexylcarbodiimide)
and DMAP (4-dimethylamiopryidine) [20]. However, under
these conditions, the coupling reaction of 2-oxa-6-azaspiro[3.3]
heptane with iso-oxazolidine acid side chains (7 and 8) pro-
ceeded slowly. After testing various condensing agents, we
found that when DCC and DMAP were replaced by HATU
(2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) and triethylamine respectively, the
coupling reaction proceeded rapidly and gave high yields of
paclitaxel-insensitive tumor cell lines, which indicated
a
probably anti-cancer mechanism of mimics 11 and 12 with
paclitaxel. More interestingly, the varying trend stabilizing-
microtubule activity of mimics 11 and 12, which consisted of
paclitaxel's and docetaxel's side chain respectively, was also
consistent with those of paclitaxel and docetaxel, i.e., paclitaxel
and mimic 11 showed lower tubulin inhibit activity than
docetaxel and mimic 12, respectively. In future research, further
optimizing the 2-oxa-6-azaspiro[3.3]heptane core will be con-
ducted in the hope of getting more active paclitaxel-mimics with
simpler structures.
the corresponding products
9 and 10. The designed
Acknowledgments
paclitaxel-mimics 11 and 12 were prepared by removal of
the p-methoxybenzylidene protecting group with p-TSA
(p-toluenesulfonic acid). The two paclitaxel-mimics proved
to have good aqueous solubility, in contrast with the poor
aqueous solubility of anti-cancer taxoids (Scheme 1).
We are grateful to the National Natural Science Foundation
of China (No. 81001383), the Doctoral Foundation of Ministry
of Education of China (No. 20105103120009).
Mimics 11 and 12 were tested to determine the concen-
trations required to inhibit the rate of cold-induced micro-
tubule disassembly by 50% [23]. The ratios of IC50 (11 or 12):
IC50 (paclitaxel) gave the activities with 200 and 120 to
paclitaxel respectively (Table 1). These values, although low,
Appendix A. Supplementary data
Supplementary data to this article can be found online at
http://dx.doi.org/10.1016/j.fitote.2013.10.015.
Table 1
Microtubule disassembly inhibitor activity of paclitaxel, docetaxel, paclitaxel-
mimics 11 and 12.
Table 2
Antiproliferative activity of paclitaxel and paclitaxel-mimics 11 and 12.
Compound
Microtubule disassembly inhibitor activity
IC50:IC50 (Paclitaxel)
IC50 (nM)
Compd.
HCT-8
Bel-7402
BGC-823
A549
A2780
Paclitaxel
Docetaxel
11
1
0.5
200
120
Paclitaxel
11
12
37
128
135
100
768
538
7
75
64
19
85
76
6.3
32
45
12

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115
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