Effects of C7 substitutions in a high affinity microtubule-binding taxane on antitumor activity and drug transport

Article abstract of DOI:10.1016/j.bmcl.2011.06.034

Some C-7 modified analogs of 3, a taxane with high affinity for binding to microtubules, were prepared through multistep transformations. Most of the analogs, bearing less lipophilic C-7 substituents than propionyl in 3, exhibited comparable binding affin

Full text of DOI:10.1016/j.bmcl.2011.06.034

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4852–4856
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Effects of C7 substitutions in a high affinity microtubule-binding taxane
on antitumor activity and drug transport
Xi Xiao a,1, Ju Wu a,1, Chiara Trigili b, Hui Chen a, Joseph W. K. Chu c, Ying Zhao a, Peihua Lu c, Li Sheng a,
Yan Li a, Frances J. Sharom c, Isabel Barasoain b, J. Fernando Diaz b, Wei-shuo Fang a,
⇑
a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences,
Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China
b Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain
c Department of Molecular and Cellular Biology, University of Guelph, Guelph ON NIG 2W1, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 November 2010
Revised 8 June 2011
Accepted 10 June 2011
Available online 17 June 2011
Some C-7 modified analogs of 3, a taxane with high affinity for binding to microtubules, were prepared
through multistep transformations. Most of the analogs, bearing less lipophilic C-7 substituents than pro-
pionyl in 3, exhibited comparable binding affinities to microtubules but less cytotoxicity against drug-
sensitive as well as multidrug-resistant tumor cells overexpressing P-glycoprotein. In addition, these
C7 modifications increased P-glycoprotein-mediated drug transport in both directions in a Caco-2 cell
assay.
Keywords:
Paclitaxel
Ó 2011 Elsevier Ltd. All rights reserved.
Taxane
Microtubule
P-glycoprotein
Cytotoxicity
Drug transport
The antitumor agent paclitaxel (1a, Fig. 1) and its analog doce-
taxel (2) has demonstrated their success in the chemotherapy of
solid tumors.1 However, both of them suffer from low water solu-
bility, poor oral bioavailability, and drug resistance.
not observed directly in these studies. Indirect measurements such
as rhodamine 123 uptake experiments were also used to probe the
Pgp interactions of these compounds modified at C-10 and C-7.10–
13
Its water solubility has been significantly improved by new
formulations.2 In contrast, although extensive structural modifica-
tions of 1a led to a number of drug candidates entering phases I–III
clinical trials,3 very few have shown promising results in patients
bearing drug-resistant tumors.
Multidrug resistance (MDR) is one of the most challenging
problems in cancer chemotherapy, and arises through different
mechanisms, including ABC transporter overexpression, alteration
in apoptosis pathways, etc.4 For microtubule (MT)-targeting drugs
such as 1a, there are also additional resistance mechanisms spe-
cific to this class of agents, such as mutations in b-tubulin, overex-
pression of the b-III tubulin isotype, etc.5
Improvement in cytotoxicity against various MDR tumor cells
and antitumor efficacy in animals through structural modifications
of 1a have been well documented.6 It is believed that these effects
are realized by decreasing the interactions of these compounds
with Pgp, although the modulation of interactions with Pgp were
We have proposed to overcome Pgp-mediated MDR by enhanc-
ing the binding affinity of taxanes to MTs.7 It would be interesting
to know, for the high affinity taxane such as LX2-32C (3),8 if the
cytotoxicity against MDR tumors could be further enhanced
through modulation of their interactions with Pgp, and possibly
improved oral bioavailability as demonstrated in early studies.9
Regarding a possible strategy to evade Pgp-mediated export, it
has been proposed14 that the ability of Pgp to transport small mol-
ecules can be reduced by decreasing their lipophilicity. Hence, we
designed a series of analogs of 3 bearing less lipophilic groups at C7
(Fig. 2).
Based on our previously reported approach,7 the 20-OH and 7-
OH in cephalomannine (4), a natural congener of 1a, were pro-
tected with a silyl group to furnish taxoid 6, which underwent
debenzoylation and re-esterification with 3-azido benzoic acid, in
the presence of N,N0-dicyclohexylcarbodiimide (DCC) and pyrroli-
dinopyridine (PP)15 to afford 8. Taxoid 8, after removal of two silyl
protective groups at the C20 and 7 positions and re-silylation of the
20-OH with the t-butyldimethylsilyl (TBS) group, was converted
into 10. The C10 deacetylation in 10 was performed with aqueous
hydrazine in ethanol,16 affording the 7,10-dihydroxyl compound
⇑
Corresponding author. Tel.: +86 10 63165229; fax: +86 10 63017757.
E-mail addresses: wfang@imm.ac.cnin, wfang@imm.ac.cn (W.-s. Fang).
These authors equally contributed to this work.
1
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.034

X. Xiao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4852–4856
4853
O
RO
O
O
O
HO
O
HO
O
NH
O
OH
O
O
NH
O
NH
O
OH
O
O
O
O
O
O
OH
OH
OH
HO
H
O
O
O
O
HO
H
O
O
HO
H
O
O
O
O
O
O
1a R = Ac
1b R = COCH2CH2COOH
N3
2
3
Figure 1. Structure of taxanes 1–3.
11, which was selectively protected at C10 with the trimethylsilyl
(TMS) group to furnish 12.17 Both 11 and 12 were subjected to C7
acylation, as shown in Schemes 1 and 2.
those of taxanes, was applied in the determination of dissociation
constants (Kd) for these high affinity taxanes. This approach was
used instead of the fluorescent probe Flutax, which has lower rel-
ative affinity for MTs, since our competition approach for measur-
ing Kd necessitates the use of a probe with an affinity within one
order of magnitude of the tested compounds.18
Taxoid 12 was primarily applied to the preparation of taxoids
14a, 14d, and 14j, whereas 11 was also used in the preparation
of 14c, 14e, 14f, and 14h when modification of 12 was not success-
ful. After modification at C7, the derivatives were desilylated with
aqueous hydrofluoride and subjected to chromatographic purifica-
tion, furnishing several C7 modified taxanes 14 (see Table 1).
When both C7 esterifications of 11 or 12 were unsuccessful in
the preparation of 14k and 14l, t-butoxycarbonyl (Boc) was chosen
as a more stable protecting group instead of TMS to finish the syn-
thesis. The Boc group was first introduced into C10 in 11 in a
selective manner,17 and then the imidazolyl carbonyl group to
C7. Carbamate formation in 17 was realized by treating 16 with
methylamine or dimethylamine in alcohol. Deprotection of 10-
Boc and 20-TBS were then successively performed to furnish the
C7 carbamates 14k and 14l (Scheme 3).
After making many attempts, we were not able to prepare tax-
oids 14b, 14g, and 14i successfully, partly due to the poor stability
of these compounds. With these C7 analogs of 3 available, we
started to explore the influence of C7 modification on their cyto-
toxicity, as well as drug transport mediated by Pgp. In the initial
experiments, it was found that the tested C7-modified taxanes
14 bind with high affinity to MTs. So, epothilone B (EPO-B), a high
affinity probe that binds to sites within tubulin overlapping with
It has generally been recognized that C7 modification does not
make a significant contribution to the interaction of paclitaxel ana-
logs with MTs.4,6 We and others have also found6,7 that unless both
C7 and C10 are occupied simultaneously by large-sized substitu-
ents, either C7 or C10 modification usually led to a minor reduction
or enhancement of cytotoxicity, within one order of magnitude.
In our present study, we found that the dissociation constant Kd
values for 14, are generally comparable to 3 itself, displaying from
2-fold less to 1.5-fold more potent affinity for binding MTs.
In contrast, C7 modification resulted in much less interaction
with Pgp. It was found (Table 2) that 3 (bearing C7 propionyl)
exhibited a 14-fold weaker binding to Pgp compared to paclitaxel
1a, whereas 10-deacetyl paclitaxel (bearing C7 OH) showed only
3-fold weaker binding (Kd 0.094 l
M).19 After the replacement of
C7 propionyl by other less lipophilic groups, Kd values 4- to 12-fold
higher were observed. It should be remembered that, in general, Kd
values within a factor of 2 should not be considered different from
each other. However, our data did show that C7 modifications sig-
nificantly decreased interactions with Pgp. Hence, in addition to
C10 modification, C7 modification represents another option to
O
C
O
C
14a
R=
R=
R=
14b
14d
O
C
O
14c
14e
R=
R=
N
NHBoc
Cl
O
HO
O
NH
O
OR
O
O
C
C
O
14f
Cl
R=
R=
OH
HO
H
O
O
C
F
F
F
O
O
F
O
C
O
14g R=
14h
O
F
F
N3
O
C
O
C
R=
14i
14j
14l
O
O
R=
R=
O
C
O
C
14k
N
R=
N
H
Figure 2. Sturcture of taxanes 14.

4854
X. Xiao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4852–4856
O
O
O
AcO
AcO
AcO
O
O
O
O
NH
NH
O
O
NH
OH
O
OH
O
OTES
O
a
O
O
b
c
O
OTBS
OH
OTBS
HO
H
HO
H
HO
H
O
O
O
O
O
O
O
O
O
O
O
O
4
5
6
O
O
AcO
O
AcO
AcO
O
O
NH
O
O
NH
O
OH
O
O
NH
OTES
O
OTES
O
O
O
O
OTBS
e
d
f
OH
OTBS
HO
H
HO
H
HO
HO
H
O
O
O
O
O
O
O
O
O
O
7
8
9
N3
N3
O
O
O
AcO
HO
TMSO
O
O
O
NH
O
NH
O
NH
O
OH
O
OH
O
OH
O
O
O
O
h
g
OTBS
OTBS
OTBS
HO
H
HO
O
H
HO
H
O
O
O
O
O
O
O
O
O
O
O
10
11
12
N3
N3
N3
Scheme 1. Reagents and conditions: (a) TBS-Cl, imidazole, DMF; (b) TES-Cl, imidazole, DMF, 89% for two steps; (c) Triton B, CH2Cl2, dry ice-acetone bath, 85%; (d) m-N3-
benzoic acid, DCC, PP, toluene, 82.9%; (e) HF-Py, CH3CN, 88.6%; (f) TBS-Cl, imidazole, DMF, 92.9%; (g) Hydrazine hydrate (85%), anhydrous ethanol, 89%; (h) LHDMS, BSTFA,
THF, directly used for the reactions in Scheme 2 without further purification.
O
R10
O
R10
O
O
O
HO
O
O
O
O
O
O
NH
NH
NH
OR7
O
OH
O
OR7
O
a
b
O
O
O
OTBS
OTBS
OTBS
HO
H
HO
H
HO
H
O
O
O
O
O
O
O
O
O
O
O
O
N3
N3
N3
11 R10=H
14
13
Scheme 2. Reagents and conditions: (i) see Table 1; (j) 40% aq HF, Py, CH3CN.
12 R10=TMS
Table 1
Preparation of analogs 14
Starting materials
Reagents and conditions
Products and yields
R7 in 14
12
11
12
11
11
11
12
c-C3H5COOH, DCC, DMAP, rt
N,N-Dimethylglycine, DCC, DMAP, rt
Boc-glycine, DCC, DMAP, rt
14a (72% for two steps)
14c (41% for two steps)
14d (18% for two steps)
14e (45% for two steps)
14f (34% for two steps)
14h (33% for two steps)
14j (28% for two steps)
–CO-cyclopropane
–COCH2NMe2
–COCH2NHBoc
–COCH2Cl
–COCH2CH2Cl
–COCH2CF3
Chloroacetic anhydride, DCC, rt
3-Chloropropionic acid, DCC, DMAP, rt
3,3,3-Trifluoropropionic acid, DCC, DMAP, rt
Ethyl chloroformate, i-Pr2NEt DMAP, rt
–COOEt

X. Xiao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4852–4856
4855
O
O
O
BocO
BocO
HO
O
O
O
O
O
NH
O
O
NH
O
NH
O
O
OH
O
OH
O
N
c or d
O
a
O
O
b
N
OTBS
OTBS
OTBS
HO
O
HO
O
HO
H
H
H
O
O
O
O
O
O
O
O
O
15
11
16
N3
N3
N3
O
HO
O
O
HO
BocO
O
O
O
O
NH
O
O
NH
O
OR
O
NH
OR
OR
O
O
O
e
f
OTBS
OH
OTBS
HO
H
HO
HO
O
H
H
O
O
O
O
O
O
O
O
O
O
O
O
17a,17b
18a,18b
14k,14l
N3
N3
N3
O
O
17a,18a,14k
R=
N
H
17b,18b,14l
R=
N
Scheme 3. Reagents and conditions: (a) (Boc)2O, CeCl3, THF, 90%; (b) CDI/DMAP/toluene; (c) Methylamine (25–30% alcohol solution), 2-propanol, 82.7%; (d) Dimethylamine
(70% alcohol solution), 2-propanol, 68%; (e) TFA, PhOCH3, CH2Cl2, 30.9%; (f) HF/Py, CH3CN, 30% (for 14k), 33% (for 14l)
Table 2
Binding of modified taxanes to MTs and Pgp, and cytotoxicity data
R7
Kd for MTs (nM)
Kd for Pgp (nM)
IC50 A2780 (nM)
IC50 A2780AD (nM)
R/Sa
1a
3
56
1.1 0.5
35 3.0
498 81
0.62 0.3
2.7 0.6
1900 400
14 3.8
3064
5.2
–COEt
14a
14c
14d
14e
14h
14j
14k
14l
–CO-cyclopropane
–COCH2NMe2
–COCH2NHBoc
–COCH2Cl
–COCH2CF3
–COOEt
0.95 0.058
1.48 0.13
0.81 0.10
0.62 0.099
0.66 0.040
0.90 0.044
2.15 0.11
2.45 0.16
2150 34
22
7.2 1.1
15.5 0.3
17.25
33 2.4
11.2 0.6
7.4 0.9
26 0.3
6
293
3200 700
875
710 69
1300 300
170 10
1400 340
950 30
7
13.3
444.4
56.4
41.2
39.4
15.2
189.2
36.5
2380 610
6340 1960
2750 730
4310 1000
1420 300
3150 710
5290 130
4
–CONHMe
–CONMe2
a
Resistance index R/S = IC50 (A2780/AD)/IC50 (A2780)
significantly decrease the interaction with Pgp, while not making a
negative contribution to the interaction with MTs.
affinity for Pgp, we were interested in determining how this af-
fected drug transport through Caco-2 cell membranes, which ex-
press high levels of Pgp.
Next, the C7-modified taxanes, as well as 1a and 3, were evalu-
ated for their cytotoxicity against the drug-sensitive tumor cell line
A2780, and its MDR counterpart A2780AD (Table 2). It was found
that the cytotoxicity of 14 for drug-sensitive tumor cells decreased
10- to 50-fold compared to 1a, whereas for MDR cells it increased
as much as 10-fold. As we observed in an early study8 that cytotox-
icity of taxanes against sensitive tumor cells reached a plateau
when Kd for binding to MTs increased greatly (<1 nM), the lower
cytotoxicity for 14 may be due to differences in their ability to per-
meate through the cell membrane. Unfortunately, C7-modified
taxanes 14, although interacting less with Pgp, did not enhance
cytotoxicity against Pgp-overexpressing MDR tumor cells com-
pared to taxane 3. Instead, one to two orders of magnitude lower
cytotoxicity was observed. The resistance index (R/S) for the C7-
modified taxanes was 3- to 85-fold higher when compared to 3.
The Caco-2 cell model is commonly used to characterize drug
permeability and transport properties in vitro.20,21 The low oral
availability of 1a has been attributed to Pgp efflux into the intes-
tine, and decreasing the interaction with Pgp led to the discovery
of orally active taxanes.9 Since taxanes 14 exhibited much lower
In the Caco-2 assay, two reference compounds, atenolol (repre-
senting paracellular transport) and propranolol (representing pas-
sive transcellular transport) are usually screened alongside the
tested compounds. Chaturvedi et al.22 have suggested that com-
pounds with apparent permeability co-efficients (Papp) in the range
of <1 ꢀ 10ꢁ6, 1–10 ꢀ 10ꢁ6, and >10 ꢀ 10ꢁ6 cm/s can be classified as
poorly (0–20%), moderately (20–70%) and well (70–100%) ab-
sorbed drugs.
A bi-directional Caco-2 cell permeability assay was performed,
where transport of the compound was measured in both directions;
apical to basolateral (A–B) and basolateral to apical (B–A). The re-
sult is typically reported as an efflux ratio, Papp(B–A)/Papp(A–B), which
provides an indicator as to whether a compound undergoes active
efflux. An efflux ratio greater than 1.5 indicates that drug efflux is
occurring.
The absorptive Papp values and the B–A/A–B transport ratio
of tested compounds at 10 lM are listed in Table 3. Compa-
red with the low (atenolol; 4.1 ꢀ 10ꢁ5 cm/s) and high (propran-
olol; 192.5 ꢀ 10ꢁ5 cm/s) permeability markers, 3, 14e and 1a

4856
X. Xiao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4852–4856
Table 3
Bidirectional drug transport through the Caco-2 cell membrane
R at C7
Papp(AꢁB) (ꢀ10ꢁ5 cm/s)
Papp(BꢁA) (ꢀ10ꢁ5 cm/s)
Papp(BꢁA)/Papp(AꢁB)
1a
3
14a
14c
14d
14e
14h
14j
14k
14l
Atenolol
Propranolol
6.6
0.95
73.5
41.9
12.3
1.9
30.0
74.6
25.5
NDa
4.1
50.3
2.65
94.0
269.8
85.3
10.7
66.1
125.5
190.8
ND
7.62
2.79
1.28
6.44
6.93
5.63
2.20
1.68
7.48
—
–COEt
–CO-cyclopropane
–COCH2NMe2
–COCH2NHBoc
–COCH2Cl
–COCH2CF3
–COOEt
–CONHMe
–CONMe2
6.1
233.6
1.49
1.21
192.5
a
Not determined.
exhibited low permeability, with Papp(A–B) values of 0.95, 1.9, and
6.6 ꢀ 10ꢁ5 cm/s, respectively. In addition, the efflux ratios of all
tested compounds except 14a were greater than 1.5, indicating
that significant efflux transport takes place for most of the C7-
modified taxanes in Caco-2 cells.
The Caco-2 assay results showed that decreasing the interaction
of C7-modified taxanes with Pgp did increase Papp(A–B) in most
cases, as well as increasing Papp(B–A). Since we have observed that
3 is not orally active (unpublished results), we believe that trans-
port ratios Papp(B–A)/Papp(A–B) over 3 may indicate drugs with low
oral activity. Of the tested compounds, only 14a and 14j, which
have low transport ratios, are worthy of being explored for their
oral bioavailability.
In summary, C7-modified analogs of taxane 3, although retain-
ing high affinity for binding to MTs, exhibit much lower cytotoxic-
ity. Even though interactions of these analogs with Pgp were
greatly decreased, their cytotoxicity against MDR tumor cells was
not enhanced, instead, it was weakened by 10- to 100-fold com-
pared to 3. This observation discourages the introduction of less
lipophilic C7 groups compared to propionyl in 3 for antitumor drug
development. However, some of these compounds may be worthy
of investigation in the treatment of tauopathies,23 because they are
less cytotoxic, while retaining potent binding to MTs and showing
reduced interactions with Pgp. Thus they may possibly be able to
permeate the blood brain barrier, which is highly dependent on ex-
pressed Pgp.
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This work was supported in part by Canadian Cancer Society
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