Isolation and cytotoxicity evaluation of taxanes from the barks of Taxus wallichiana var. mairei

Article abstract of DOI:10.1016/j.bmcl.2015.01.056

Fifteen taxanes (1-15) including a new taxane glucoside, 7β,9α,10β-triacetoxy-13α-hydroxy-5α-O-(β-d-glucopyranosyl)taxa-4(20),11-diene (1), were isolated from the barks of Taxus wallichiana var. mairei. Compounds 1-15 representing three sub-types of 6/8/6-taxane were evaluated in vitro for anti-proliferative activity against a panel of parental and drug-resistant cancer cells. Potent compounds were found while several exhibited selective cytotoxicity. Especially, 3, 8, and 10 showed selective inhibition to breast carcinoma cell line MCF-7, while 13 selectively inhibited taxol resistant human ovarian carcinoma cell line A2780/TAX (IC₅₀ = 0.19 μM), being more potent than the clinical drugs taxol (IC₅₀ = 4.4 μM) and docetaxol (IC₅₀ = 0.42 μM), and less cytotoxic to mouse embryonic fibroblast cell line NIH-3T3, a cell line close to normal cell line. The possible P-glycoprotein evasion mechanism of 13 against A2780/TAX and the preliminary structure-activity relationships (SARs) of this group of compounds were also discussed.

Full text of DOI:10.1016/j.bmcl.2015.01.056

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1240–1243
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Isolation and cytotoxicity evaluation of taxanes from the barks
of Taxus wallichiana var. mairei
Zhang-Hua Sun a, , Yu Chen a, , Yan-Qiong Guo a, Jie Qiu b, Cui-Ge Zhu a, Jing Jin a, Gui-Hua Tang a,
Xian-Zhang Bu a, , Sheng Yin a,
⇑
⇑
a School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, People’s Republic of China
b School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Fifteen taxanes (1–15) including a new taxane glucoside, 7b,9a,10b-triacetoxy-13a-hydroxy-5a-O-(b-D-
Received 12 November 2014
Revised 7 January 2015
Accepted 23 January 2015
Available online 30 January 2015
glucopyranosyl)taxa-4(20),11-diene (1), were isolated from the barks of Taxus wallichiana var. mairei.
Compounds 1–15 representing three sub-types of 6/8/6-taxane were evaluated in vitro for anti-prolifer-
ative activity against a panel of parental and drug-resistant cancer cells. Potent compounds were found
while several exhibited selective cytotoxicity. Especially, 3, 8, and 10 showed selective inhibition to
breast carcinoma cell line MCF-7, while 13 selectively inhibited taxol resistant human ovarian carcinoma
Keywords:
Taxus wallichiana var. mairei
Taxanes
Cytotoxicity
Drug resistant
cell line A2780/TAX (IC50 = 0.19
lM), being more potent than the clinical drugs taxol (IC50 = 4.4 lM) and
docetaxol (IC50 = 0.42 M), and less cytotoxic to mouse embryonic fibroblast cell line NIH-3T3, a cell line
l
close to normal cell line. The possible P-glycoprotein evasion mechanism of 13 against A2780/TAX and
the preliminary structure–activity relationships (SARs) of this group of compounds were also discussed.
Ó 2015 Elsevier Ltd. All rights reserved.
Structure–activity relationships
The discovery of paclitaxel (taxol) as a potent anticancer drug,
initially isolated from Taxus brevifolia, has spurred several groups
all over the world to conduct research work on other Taxus species,
to isolate potentially more effective paclitaxel derivatives or as
starting materials for semisynthesis. So far more than 550 taxanes
have been identified, and new taxanes continue to be isolated from
the needles, bark, stem, and roots of Taxus species.1 Although taxol
and its derivatives are widely used in clinical applications, the
chemotherapy often fails due to its acquired-drug resistance,
neuro-cytotoxicity, and low oral bioavailability. Thus, there is
continuously demanding of new information facilitating the novel
taxane-based drug design and discovery. However, previous phar-
maceutical study on taxanes mainly focused on the modification of
the taxol prototype with a 6/8/6-ring system,2–7 and systematically
evaluation of the anticancer properties of taxanes with different
sub-types remains scarce.
have led to the isolation a number of taxanes, some of which
showed significant cytotoxicity.9–14 In our screening program
aimed at the discovery of structurally unique and biologically sig-
nificant taxanes from Taxus plants, a new taxane glucoside,
7b,9a,10b-triacetoxy-13a-hydroxy-5a-O-(b-D-glucopyranosyl)
taxa-4(20),11-diene (1), and 14 known analogues (Fig. 1),
2-deacetoxytaxinine J15 (2), 2-deacetoxyaustrospicatine16 (3),
cephalomannine17 (4), 10-deacetyl-7-epi-taxol18 (5), taxol19 (6),
7-xylosyl-10-deacetyl taxol20 (7), 7-b-xylosyl-cephalomannine20
(8), 7-b-xylosyl-taxol20 (9), 7-b-xylosyl-10-deacetyl-cephaloman-
nine20 (10), 7-xylosyl-10-deacetyl taxol C20 (11), taxinine M21
(12), taxacin22 (13), 10-deacetylbaccatin III23 (14), and baccatin
III17,20 (15) were isolated from the barks of T. wallichiana var.
mairei.
Subsequent cytotoxic screening against a panel of cancer cell
lines revealed that some of the 6/8/6-taxanes with different sub-
types exhibited selective inhibition to some of the cell lines, such
as the MCF-7 and taxol-resistant A2780/TAX. Herein, details of
the isolation, structural elucidation, cytotoxic activity as well as a
preliminary structure–activity relationship (SAR) of these
compounds are described.
Taxus wallichiana var. mairei (Lemée & H. Léveillé) L. K. Fu & Nan
Li, also known as Taxus chinensis (Pilger) Rehder var. mairei (Lemee
& H. Léveillé) W.C. Cheng & L.K. Fu, an evergreen tree that is only
distributed in China.8 Previous phytochemical studies on this plant
The air-dried barks of T. wallichiana var. mairei was extracted
with refluxing MeOH to yield an extract, which was partitioned
into EtOAc-soluble and EtOAc-insoluble fractions. After a series of
column chromatography (CC) steps over silica gel and reversed-
phase silica gel, followed by preparative TLC, the EtOAc-soluble
⇑
Corresponding authors. Tel./fax: +86 020 39943054 (X.-Z.B.); tel: +86 020
39943090/31; fax: +86 020 39943090 (S.Y.).
E-mail addresses: phsbxzh@mail.sysu.edu.cn (X.-Z. Bu), yinsh2@mail.sysu.edu.cn
(S. Yin).
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.bmcl.2015.01.056
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

Z.-H. Sun et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1240–1243
1241
OAc
OAc
O
O
O
O
AcO
19
R1O
HO
O
R2
R3
18
13
B9
11
7
8
NH
O
O
16
O
18
12
13
C
R1O
A
10
17
9
3
5
15
17
OR2
HO
OH
7
Ph
O
14
H
H 1
20
OH
1'
16
5
15
HO
O
H
OBz
4'
6'
O
OH
1 R1 = H R2 = Glu
OAc
14
1
O
20
2 R1 = Ac R2 = Cinn
OH
3
R
1 = Ac R2 = a
Figure 2. Key HMBC (H?C) and 1H–1H COSY (
) correlations of 1.
4
5
6
7
8
R1 = Ac R2
R1 = H R2
=
=
=
=
=
=
=
=
=
β
α
-OH
-OH
-OH
R3 = b
R3 = Bz
3 = Bz
R1 = Ac R2
β
β
β
β
β
β
β
R
AcO
OBz
AcO
HO
OAc
namoyl unit in taxezopidine H was replaced by a glucose moiety in
1. This was supported by the downfield-shifted C-5 signal (dC 81.9)
in 1 due to the glycosylation shift effect (C-5 at dC 75.2 in taxezopi-
R1 = H
R2
R2
R2
R2
R2
-OXyl R3 = Bz
R1 = Ac
R1 = Ac
-OXyl
-OXyl
-OXyl
R
R
R
3 = b
3 = Bz
3 = b
9
O
OR
10
11
16
R
R
R
1 = H
1 = H
dine H). The D-configuration of the glucosyl unit was determined
O
H
H
by HPLC analysis.26 The gross structure of 1 was further confirmed
by detailed 2D NMR analysis including HMBC and COSY spectra
(Fig. 2).
-OXyl R3 = c
OAc
12
R = H
1 = Ac R2
-OH
R
3 = d
13 R = Cinn
O
HO
1'
OH
OH
OH
Cinn =
Bz =
Glu =
Xyl =
The relative configuration of 1 was determined by analysis of its
1H–1H coupling constant and NOESY data. The fusion patterns of A/
B/C ring system and the orientations of the substituents (acetyl and
hydroxyl groups) on rings A and B were assigned as the same as
those of taxezopidine H by comparison of their 1D NMR data.
The NOESY correlations of H-7/H-3 and CH3-19/H-6b indicated
that H-7, H-3, CH3-19, and H-6b adopted the axial bonds of the
quasi chair-conformational ring C. The small coupling constant of
H-5 [dH 4.23 (dd, J = 3.7 and 2.0 Hz)] indicated that H-5 adopted
equatorial bond and was in b-orientation. Thus, compound 1 was
O
4'
4'
O
RO
OH
6'
O
HO
1' O
O
OH
HO
OH
O
H
OBz
OAc
O
O
N
HO
a =
c =
b =
d =
Ph
14
R = H
15 R = Ac
O
O
assigned as 7b,9
pyranosyl)taxa-4(20),11-diene.
a,10b-triacetoxy-13a-hydroxy-5a-O-(b-D-gluco-
Figure 1. Structures of compounds 1–15 and clinical drug docetaxol (16).
The cytotoxicity of compounds 1–5 and 7–15 were evaluated by
sulforhodamine B (SRB) assay with docetaxol (16) and taxol (6)
used as positive controls (Supplementary data, experimental sec-
tion). Ten human cancer cell lines including human ovarian carci-
noma cell A2780 with the taxol resistant cell A2780/TAX, human
ileocecum carcinoma cell HCT-8 with the vincristine resistant cell
HCT-8/VCT, breast carcinoma cell line MCF-7 with the doxorubicin
resistant cell MCF-7/DOX, human lung carcinoma cell line A549
with the cis-platinum resistant cell A549/CDDP, colon carcinoma
cell SW480, and hepatoma carcinoma cell line HepG2 were chosen
for this biological activity assay. The experiments were conducted
in three independent replicates.
fraction afforded compounds 1–15 (Supplementary data, experi-
mental section).
Compound 124 was isolated as a colorless oil. The molecular for-
mula of C32H48O13 was determined by the HRESIMS ion at m/z
663.2959 [M+Na]+ (calcd for 663.2987) and 13C NMR data. The
1D NMR spectra (Table 1) resolved 32 carbon resonances attribut-
able to four methyls (dH 0.81, 1.01, 1.56, and 2.29; dC 13.7, 16.1,
27.7, and 31.5), three acetoxys (dH 1.93, 2.01, and 2.03; dC 21.0,
21.3, 21.4, 169.4, 170.2, and 170.7), a pair of exoethylene protons
[dH 4.86 (1H, s) and 5.16 (1H, s)], and a glucose moiety [dH 4.26
(1H, d, J = 7.7 Hz); dC 63.0 (CH2), 71.6 (CH), 74.2 (CH), 77.4 (CH),
77.5 (CH) and 104.8 (CH)]. The aforementioned data were similar
to those of the known taxane taxezopidine H25 except that the cin-
The bioassay results (Table 2) showed that most of the taxanes
exhibited moderate to good inhibitory activity (IC50 <10 lM)
against some of the cell lines, and compounds 4 and 5 sharing
the most structural features with taxol showed broad inhibitory
effects against most of the cell lines, with the activities comparable
Table 1
a
1H and 13C NMR data of 1 in acetone-d6
to those of the positive control (most IC50s <0.1 lM). Compared to
No. dH
dC
No.
dH
dC
4–6 and 16, the introduction of an O-b-xylose in R2 (7–11) or loss
of the C-13 ester side chain (14–15) greatly decrease their
activities, which is consistent with the reported SAR of taxol
analogues.27
1
2
3
4
5
1.80 (1H, m)
1.81 (1H, m)
2.96 (1H, d 4.7)
41.4
28.1
37.9
16
17
18
1.01 (3H, s)
1.56 (3H, s)
2.29 (3H, s)
0.81 (3H, s)
4.86 (1H, s)
5.16 (1H, s)
2.01 (3H, s)
31.5
27.7
16.1
13.7
112.9
150.7 19
Interestingly, despite of the general low activity, the O-b-xylose
bearing compounds 7–11 reserved their anti-proliferative activity
and showed selective cytotoxicity towards certain cancer cell lines.
Compounds 8 and 10 selectively inhibited MCF-7 with IC50 values
4.23 (1H, dd 3.7, 2.0)
81.9
36.9
20
6
1.75 (1H, m)
2.09 (1H, m)
7-OAc
9-OAc
10-OAc 1.93 (3H, s)
10
20
21.4, 170.2
7
8
9
5.60 (1H, dd 11.5, 5.3) 71.2
47.0
5.84 (1H, d 11.1)
2.03 (3H, s)
21.3, 170.7
21.0, 169.4
at 0.029 and 0.14 lM, respectively. Further analysis showed
N-butanoylphenylisoserine substitution at R3 in 8 and 10 led to
generally lower cytotoxicity to most of cell line but more selective
and cytotoxic to MCF-7, as compared to those with phenyl substi-
tution in 7 and 9. Meanwhile, 11 selectively inhibited drug
77.5
73.3
133.7 30
142.7 40
68.5
35.0
4.26 (1H, d 7.7) 104.8
10 6.20 (1H, d 11.1)
11
12
13 4.71 (1H, m)
14 1.19 (1H, m),
2.63 (1H, m)
15
3.21 (1H, m)
3.36 (1H, m)
3.33 (1H, m)
3.28 (1H, m)
3.63 (1H, m)
3.81 (1H, m)
74.2
77.4
71.6
77.5
63.0
50
60
resistant cell lines A549/CDDP (IC50 = 0.64
(IC50 = 1.5 M), respectively.
Compounds 1–3, 12, and 13, which possess
l
M) and A2780
l
4,20 terminal dou-
39.9
D
Data were recorded at 400 MHz for 1H NMR and 100 MHz for 13C NMR. (J in Hz,
d in ppm).
a
ble bonds, showed greatly decreased activities to most of cancer
cell lines. However, selective cytotoxicity was also observed within

1242
Z.-H. Sun et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1240–1243
Table 2
Antiproliferative activity of the compounds (1–16) towards cancer cells and NIH-3T3 cell
Compd
Cytotoxic activities IC50
(lM)
A549
A549/CDDP
MCF-7
MCF-7/DOX A2780 A2780/TAX HCT-8
HCT-8/VCT Sw480
HepG2
NIH-3T3
1
2
3
2.2 1.5
9.4 1.5
12 0.53
>25
7.1 2.3
14 3.4
>25
>25
>25
>25
>25
9.7 1.6
5.1 1.4
>25
>25
>25
>25
11 2.1
>25
>25
12 1.8
>25
16 3.1
>25
>25
6.1 2.8
>25
15 1.2
>25
15 4.7
10 1.0
0.040 0.021 >25
4
5
6
7
8
9
10
11
12
13
14
15
16
0.0080 0.001 0.0050 0.001 0.0040 0.004 7.0 1.9
0.011 0.003 0.024 0.011 0.012 0.0083 >25
0.0030 0.0006 0.0060 0.003 0.0030 0.002 6.2 1.5
0.013 0.0007 4.9 0.8
0.030 0.001 7.2 0.9
0.0060 0.002 4.4 0.4
>25
13 1.2
0.066 0.02 10 0.59
0.26 0.06 >25
>25
5.9 1.5
>25
8.5 0.6
>25
7.2 1.6
11 1.2
0.033 0.007 0.020 0.004 0.6 0.04
0.059 0.015 0.095 0.06 2.2 0.60
0.021 0.005 0.0090 0.005 0.58 0.16
2.1 1.2
2.2 0.54
0.39 0.24
1.9 0.49
19 6.4
12 2.5
15 1.0
21 1.4
>25
2.5 0.70
>25
0.92 0.07
3.1 0.19
0.64 0.18
>25
0.80 0.35
0.029 0.008 >25
0.16 0.028
0.14 0.11
>25
>25
>25
17 5.7
7.4 2.5
<0.002
1.4 0.31
1.6 0.18
>25
0.85 0.08
3.5 0.9
1.5 0.02
>25
>25
17 1.9
>25
>25
>25
16 2.0
7.2 0.8
5.6 1.2
20 1.7
>25
3.0 1.2
5.8 2.7
1.2 0.79
3.9 1.3
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
<0.002
>25
>25
16 1.1
ND
ND
>25
ND
ND
>25
6.6 1.1
>25
>25
>25
0.19 0.03 >25
25 0.06
24 0.29
<0.002
>25
>25
16 1.8
>25
>25
12 1.2
ND
ND
>25
<0.002
<0.002
0.42 0.07 <0.002
0.89 0.17 ND
ND
<0.002
ND: not determined.
Figure 3. Detection of intracellular P-gp function by Rho123 accumulation and efflux assay. A2780 (a and b) and A2780/TAX (c and d) were incubated with 2
l
M Rho123 for
30 min at 37 °C, respectively. Then cells were washed and re-suspended in medium without Rho123 for 0, 15, 30, 60, 90, and 120 min at 37 °C, respectively. After
centrifugation the fluorescence of intracellular Rho123 was measured. Fluorescence distribution (a and c) and fluorescence intensity (b and d).
this sub-class. Compounds 3 and 13 showed excellent cytotoxic
activities against MCF-7 (IC50 = 0.040 M) and A2780/TAX
(IC50 = 0.19 M), respectively, implying that b-aminophenylpropa-
noic group might contribute the selectivity to MCF-7 in 1–3 while
cinnamoyloxy was important to the selectivity to A2780/TAX in 12
and 13.
much less active than the clinical drugs docetaxol (16). In
particular, comparing with taxol and docetaxol, 13 with a taxagi-
fine-type structural features (possessing C-12,17-ether ring and
l
l
D
4,20) exhibited stronger inhibitory activity on A2780/TAX but
weaker activity on NIH-3T3, suggesting it might be served as a
drug lead with little side effects to treat ovarian cancer.
To evaluate the preliminary safety of the active compounds, we
tested their cytotoxicity by using the mouse embryonic fibroblast
cell line NIH-3T3, a cell line close to normal cell line, as a model.
The results (Table 2) showed that the isolated compounds were
A main hurdle of taxol in clinical application is the acquirement
of drug resistance, and P-glycoprotein (P-gp) mediated drug efflux
was believed as the main cause of the taxol tolerance.28 To prelim-
inarily understand the underlying action mechanism of 13 in

Z.-H. Sun et al. / Bioorg. Med. Chem. Lett. 25 (2015) 1240–1243
1243
overcoming the drug tolerance of A2780/TAX, we examined the
Supplementary data
intracellular P-glycoprotein (P-gp) function by rhodamine 123
(Rho123) accumulation and efflux assay in A2780/TAX and its
parental cell line A2780, respectively (Supplementary data, exper-
imental section). The results (Fig. 3) showed that Rho123 accumu-
lated very well in A2780, and no obvious efflux was observed
during the examined time. In contrast, much lower Rho123 accu-
mulation was observed in A2780/TAX, and the accumulated
Rho123 was gradually eliminated by the time consumption. These
results validated A2780/TAX possessed a much elevated intracellu-
lar P-gp function. Reasonably, 13 possessing the potent activities
against A2780/TAX may evade the P-gp mechanism and exert its
effect. However, it should be pointed out that 13 showed no activ-
ity against drug sensitive cell line A2780, implying that there may
have other complex action mechanism for 13 to specifically exert
its effect in A2780/TAX, which is worth further extensively study-
ing in future.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.01.
056.
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Previous pharmaceutical study on taxanes mainly focused on
the modification of the substitutes on the taxol prototype, and
revealed that the C-13 esterification chain and oxetane ring
between C-5 and C-20 were prerequisite to the anticancer activ-
ity.2 In our current study, fifteen taxanes (1–15) representing three
sub-types of 6/8/6-taxane from T. wallichiana var. mairei, were sys-
tematically evaluated in vitro for cytotoxicity against ten human
cancer cell lines. Compound 13 with the C-12,17 oxygen bridge
but lack of the C-13 esterification chain and oxetane ring showed
selectively activity against A2780/T, with IC50 value of 0.19 lM,
being stronger than the clinical drugs taxol and docetaxol, while
3, 8, and 10 showed selective inhibition to MCF-7. The possible
P-gp evasion mechanism of 13 against drug-resistant cell line
A2780/TAX was explored and the preliminary structure–activity
relationships (SARs) of this group of compounds were also dis-
cussed. The selectivity of the different sub-types of 6/8/6-taxane
implied that these compounds may possess unique action mecha-
nism to certain cancer cell lines, which is worth exploring in future,
and 13 with potent activity to drug resistant cell line but weak
activity to normal cell line may serve as a drug lead for relative
cancer therapy.
23. Kingston, D. G. I.; Hawkins, D. R.; Ovington, L. J. Nat. Prod. 1982, 45, 466.
24. 7b,9
(1): Colorless oil; [
1437, 1371, 1256 cmꢀ1
32H48O13Na, 663.2987).
a
,10b-Triacetoxy-13
a
-hydroxy-5
a
-O-(b-
D
-glucopyranosyl)taxa-4(20),11-diene
20
a
]
D
+26.8 (c 0.5, MeOH); IR (KBr) mmax 3365, 2942, 1742,
;
HRESIMS m/z 663.2959 [M+Na]+ (calcd for
Acknowledgments
C
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The authors thank the National Natural Science Foundation of
China (Nos. 81102339, 81172931) and the Science and Technology
Foundation of Guangdong Province (No. 2012A080202013) for
providing financial support to this work.