Synthesis and biological evaluation of novel 3′-N-tert-butylsulfonyl analogues of docetaxel

Article abstract of DOI:10.1016/j.bmcl.2008.07.101

Novel 3′-N-tert-butylsulfonyl analogues 10a-c of docetaxel were synthesized and their biological evaluation in cytotoxicity in vitro against several human tumor cell lines were presented. The biologically tested results showed that N-oxide pyridyl substit

Full text of DOI:10.1016/j.bmcl.2008.07.101

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4783–4785
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel 30-N-tert-butylsulfonyl analogues
of docetaxel
b
b,
*
Bowen Ke a, Yong Qin a, , Fengyan Zhao , Yi Qu
*
a Department of Chemistry of Medicinal Natural Products, Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education,
West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
b Department of Pediatrcs, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Novel 30-N-tert-butylsulfonyl analogues 10a–c of docetaxel were synthesized and their biological evalu-
ation in cytotoxicity in vitro against several human tumor cell lines were presented. The biologically
tested results showed that N-oxide pyridyl substituted10b–c had potent cytotoxicities against human
tumor cell lines Eca-109, SKOV3, SMMC-7721, HCT-8, PC3, MCF-7, HeLa and KB.
Ó 2008 Elsevier Ltd. All rights reserved.
Article history:
Received 27 June 2008
Revised 23 July 2008
Accepted 25 July 2008
Available online 29 July 2008
Keywords:
Docetaxel analogue
Synthesis
Antitumor activity
Paclitaxel (Taxol, Fig. 1), a naturally occurring diterpenoid, iso-
lated from the bark of Pacific yew tree Taxus brevofolia in 1971 (Fig.
1),1 has shown remarkably high antitumor activity.2 It has been
considered as one of the most important antitumor agents3 and
was approved by FDA for the treatment of advanced ovarian cancer
and breast cancer in 1992 and 1994, respectively. Clinical trials
have demonstrated that paclitaxel also was of utility for treatment
of lung, skin, and head and neck cancers.4 Docetaxel (Taxotere, Fig.
1),5 a semisynthetic analogues, has also exhibited encouraging
clinical usage and was approved by FDA for the treatment of breast
cancer in 1996. The anti-cancer activity of these compounds is as-
cribed to their unique mechanism of action as promoters of tubulin
assembly and inhibitors of microtubule disassembly.6 Although
both paclitaxel and docetaxel possess potent antitumor activity,
utility of these drugs results in some undesirable side effects, such
as low tumor selectivity, development of multi-drug resistance
(MDR),7 and poor solubility in aqueous solutions.8 Therefore,
development of new anticancer agents with fewer side effects, im-
proved pharmacological properties and activity against various
cancers has been a long term effort by medicinal chemists.
Extensive structure–activity relationship (SAR) studies over the
past two decades have led to several promising clinical candidates
of paclitaxel and docetaxel analogues. These SAR studies were
mainly focused on changes to A, B, C, D-rings9–12 and the side-
chain.13
SAR studies so far indicate that the C-13 side chain is essential
for antitumor activity. The stereochemistry of the side chain at the
C20 and C30 is crucial for biological activity.14 Deletion of either 20-
hydroxy group or 30-phenyl group leads to analogues with reduced
biologic activity.15 It is also known that analogues without a 30-N-
acyl group are significantly less active than paclitaxel and aliphatic
and heteroaromatic 30-N-acyl analogues are slightly more active
than paclitaxel.16
Although a large number of 30-N-acyl analogues were investi-
gated, SAR studies of 30-N-sulfonyl analogues have received little
attention. A few of paclitaxel analogues with 30-N-phenylsulfonyl
group were reported with significant loss of antitumor activity.17
In this letter, we report our efforts on the synthesis and biological
evaluation of several novel 30-N-tert-butylsulfonyl docetaxel ana-
logues 10a–c.
The synthesis of novel 30-N-tert-butylsulfonyl analogues 10a–c
of docetaxel was accomplished by following two synthetic proce-
O
R2O
O
OH
7
R1
Ph
NH
O
11
9
2'
O13
B
3 C
A
5
3'
O
D
OAc
OH
HO1
H
OBz
2
Paclitaxel, R1=Ph, R2=Ac
Docataxel, R1=tert-BuO, R2=H
* Corresponding authors. Tel./fax: +86 28 85503842.
E-mail address: yongqin@scu.edu.cn (Y. Qin).
Figure 1. The Structures of Paclitaxel and Docataxel.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.101

4784
B. Ke et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4783–4785
Table 1
Cytotoxicity data (IC50, l
M) for taxoids 10a–c against human cancer cell linesa
Taxoids
Eca-109
SKOV3
SMMC-7721
HCT-8
PC3
MCF-7
Hela
KB
K562
Paclitaxe
Docetaxel
10a
10b
10c
2.73 ( 0.28)
2.60 ( 0.24)
7.14 ( 0.54)
1.95 ( 0.21)
2.52 ( 0.23)
2.43 ( 0.26)
2.35 ( 0.24)
7.09 ( 0.22)
2.28 ( 0.24)
2.41 ( 0.26)
2.86 ( 0.26)
2.73 ( 0.25)
>10
2.54 ( 0.25)
2.45 ( 0.26)
3.29 ( 0.30)
3.07 ( 0.26)
9.12 ( 0.88)
2.85 ( 0.29)
3.03 ( 0.27)
2.85 ( 0.28)
2.77 ( 0.28)
6.83 ( 0.45)
1.98 ( 0.22)
2.64 ( 0.27)
2.98 ( 0.27)
3.29 ( 0.30)
7.88 ( 0.56)
2.11 ( 0.18)
2.68 ( 0.28)
3.11 ( 0.28)
3.03 ( 0.31)
9.54 ( 0.87)
2.54 ( 0.23)
2.67 ( 0.28)
2.54 ( 0.22)
2.35 ( 0.29)
7.68 ( 0.56)
2.12 ( 0.23)
2.32 ( 0.22)
3.65 ( 0.35)
2.96 ( 0.28)
>10
2.89 ( 0.26)
3.33 ( 0.23)
a
Values are means of three experiments, standard deviation is given in parentheses.
O
R
O
S
O
COOH
O
S
TrocO
R
NH
O
O
O
S
OTroc
BocO
N
OBn
b
2
R
OBn
OBoc
N
O
HO
a
a
+
O
3a-c (dr>99:0:0:0)
1a R=Ph
H
OBz
OCH3
OCH3
HO
OAc
1b R=2-Py
1c R=3-Py
7a-c
8
O
S
O
TrocO
O
OTroc
S
NH
O
NH
O
O
O
R
O
O
d
c
R
N
OBn
R
OBn
OBoc
b, c
OH
5a-c
O
S
O
O
O
H
OBz
4a R=Ph
4b R=2-Py N-oxide
4c R=3-Py N-oxide
HO
OAc
Ar
9a-c
R
COOBn
R
COOH
O
S
HO
O
OH
O
S
O
S
N
O
N
O
NH
O
O
R
e
10a, R=Ph
O
O
O
10b, R=2-Py N-oxide
10c, R=3-Py N-oxide
O
H
OBz
OH
HO
10a-c
OAc
OCH3
OCH3
6a-c
OCH3
OCH3
Scheme 2. Reagents and conditions: (a) DCC or DPC, DMAP, toluene, 80 °C, 18 h,
45–72%; (b) TFA, CH2Cl2, rt, 2 h, 58–63%; (c) Zn, AcOH, MeOH, 60 °C, 2 h, 50–63%.
7a-c
Scheme 1. Reagents and conditions: (a) LiHMDS, THF, ꢀ78 °C, 3 h, 72–97%; (b) m-
CPBA, MeOH, 60 °C, 2 h, 50–63%; (c) TFA, CH2Cl2, rt, 1 h; (d) 3,4-dimethoxybenz-
aldehyde dimethyl acetal, toluene, PPTS, 76–85%; (e) Pd(OH)2, AcOEt, 1 atm H2, 2 h,
93–99%.
The synthesized taxoids 10a–c were tested for their cytotoxicity
against various cancer cells. As a result of in vitro studies, 10b–c
showed the same level of potencies against human cancer cell lines
such as Eca-109, SKOV3, SMMC-7721, HCT-8, PC3, MCF-7, HeLa
and KB, while 10a showed less cytotoxic activity in comparison
to paclitaxel and docetaxel (Table 1).
dures: (1) asymmetric synthesis of side chain oxazolidines 7a–c
and (2) condensation of the side chain 7a–c with 7,10-ditrocbacc-
atin III.
Oxazolidines 7a–c were synthesized via a five-step route from
benzyl O-Boc-a-hydroxyacetate2 (Scheme 1). The substituted
In conclusion, we have synthesized the novel 30-N-tert-butylsul-
fonyl docetaxel analogues 10a–c and found that N-oxide pyridyl
substituted 30-N-tert-butylsulfonyl analogues 10b–c showed po-
tent activities against human cancer cell lines used in our study.
isoserines 3a–c with SR,2R,3S absolute configurations were pre-
pared in 72–97% yields by a diastereoselective enolate addition
of 2 with (SR)-tert-butylsulfinylimine 1a–c by adopting our pre-
vious methord.18 Oxidation of 3a–c to the corresponding sulfon-
amides 4a–c with m-CPBA, followed by deprotection of Boc
group in 4a–c with TFA afforded alcohols 5a–c. Alcohols 5a–c
were condensed with 3,4-dimethoxybenzaldehyde dimethyl ace-
tal in the presence of PPTS to afford oxazolidines 6a–c as a dia-
stereomeric mixture in a 3:1 ratio. Removal of the benzyl group
in 6a–c afforded the corresponding carboxylic acids 7a–c by
hydrogenolysis with 5% Pd(OH)2 (Pearlman’s catalyst). Coupling
of acids 7a–c with 7,10-ditrocbaccatin III (8)19 was carried out
by using DCC or DPC as coupling reagents to afford 9a–c in
45–72% yields (Scheme 2). Treatment of 9a–c with TFA, followed
by removal of Troc groups with Zn/AcOH at 60 °C provided tax-
oids 10a–c20 in 50–63% yields.
Acknowledgments
This work was supported by NSFC (Nos. 20632030 and
20772083) and Doctoral Program of Ministry of Education of China
(No. 20050610094). The authors thank the Analytic and Testing
Centre of Sichuan University for recording spectra.
References and notes
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Org. Lett. 2006, 8, 2301.
20. Compound 10a: 1H NMR (100 MHz, CDCl3) d 8.07 (d, J = 7.6 Hz, 2H), 7.62 (t,
J = 7.4 Hz, 1H), 7.49 (t, J = 7.4 Hz, 2H), 7.31–7.42 (m, 5H), 6.14 (t, J = 8.3 Hz, 1H),
5.68 (s, 1H), 5.64 (d, J = 7.2 Hz, 1H), 5.18 (s, 1H), 4.90 (d, J = 2 Hz, 1H), 4.57 (s,
1H), 4.19 and 4.28 (2d, J = 8.8, 8.4 Hz, 2H), 3.85 (d, J = 8.4 Hz, 1H), 2.50–2.58 (m,
1H), 2.31 (s, 3H), 2.21–2.27 (m, 2H), 2.17 (s, 3H), 1.99–2.06 (m, 1H), 1.74 (s,
3H), 1.26 (s, 9 H), 1.20 (s, 3H), 1.04 (s, 3H) ppm; 13C NMR (400 MHz, CDCl3) d
200.8, 170.1, 169.9, 166.8, 162.7, 153.2, 153.1, 149.8, 148.8, 142.7, 139.6, 133.7,
131.8, 130.0, 129.6, 129.1, 128.7, 128.6, 128.5, 128.3, 128.1, 127.8, 127.5, 120.9,
111.0, 110.6, 83.7, 83.6, 80.5, 79.1, 79.0, 77.4, 77.1, 76.4, 76.2, 74.3, 72.1, 66.8,
61.4, 56.1, 55.9, 55.8, 46.9, 43.1, 35.8, 33.9, 33.2, 26.3, 24.1, 21.7, 21.1, 15.3,
10.7 ppm; Anal. Calcd for C42H53NO14S: C, 60.92; H, 6.45; N, 1.69. Found: C,
60.81; H, 6.38; N, 1.74; HRMS (FAB) calcd for C42H53NO14S (M+Na+) 850.3079,
found 850.3050. Compound 10b: 1H NMR (400 MHz, CDCl3)
d 8.26 (d,
J = 6.4 Hz, 1H), 8.10 (d, J = 7.4 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.50 (t,
J = 7.8 Hz, 2H), 7.33–7.37 (m, 4H), 6.22 (m, 1H), 5.68 (s, 1H), 5.56 (d,
J = 7.2 Hz, 1H), 5.18 (s, 1H), 4.93 (d, J = 2 Hz, 1H), 4.60 (s, 1H), 4.19 and 4.30
(2d, J = 8.8, 8.4 Hz, 2H), 3.87 (d, J = 8.4 Hz, 1H), 2.50–2.58 (m, 1H), 2.37 (s, 3H),
2.22–2.27 (m, 2H), 2.17 (s, 3H), 1.99–2.06 (m, 1H), 1.75 (s, 3H), 1.24 (s, 9 H),
1.18 (s, 3H), 1.04 (s, 3H) ppm; 13C NMR (400 MHz, CDCl3) d 211.1, 172.0, 170.6,
166.7, 159.8, 142.0, 138.8, 133.8, 132.2, 130.1, 129.8, 129.0, 128.9, 128.6, 127.5,
127.8, 126.8, 106.1, 83.5, 80.9, 79.1, 78.5, 77.4, 75.1, 74.0, 72.1, 68.3, 59.7, 56.3,
55.9, 46.9, 42.9, 35.5, 33.3, 26.5, 24.1, 22.4, 20.5, 14.8, 9.8 ppm; Anal. Calcd for
C
42H53NO14S: C, 58.28; H, 6.20; N, 3.32. Found: C, 58.11; H, 6.28; N, 3.21; HRMS
(FAB) calcd for C41H52N2O15S (M+Na+) 867.2880, found 867.2850. Compound
10c: 1H NMR (400 MHz, CDCl3) d 8.60 (s, 1H), 8.14 (d, J = 6.4 Hz, 1H), 8.11 (d,
J = 7.4 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.33–7.43 (m, 4H),
6.13 (m, 1H), 5.67 (d, J = 7.0 Hz, 1H), 5.64 (d, J = 7.2 Hz, 1H), 5.22 (s, 1H), 4.93 (d,
J = 9.3 Hz, 1H), 4.64 (s, 1H), 4.20 and 4.30(2d, J = 8.8, 8.4 Hz, 2H), 3.93 (d,
J = 8.4 Hz, 1H), 2.56–2.63 (m, 1H), 2.40 (s, 3H), 2.21–2.27 (m, 2H), 2.09 (s, 3H),
13. Miller, M. L.; Ojima, I. Chem. Rec. 2001, 3, 195.
14. Gueritte-Voegelein, F.; Guenard, D.; Lavelle, F.; Le Goff, M. T.; Mangatal, L.;
Potier, P. J. Med. Chem. 1991, 34, 992.
15. Kant, J.; Huang, S.; Wong, H.; Fairchild, C.; Vyas, D.; Farina, V. Bioorg. Med.
Chem. Lett. 1993, 3, 2471.
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17. Cassidy, P. B.; Moos, P. J.; Kelly, R. C.; Fitzpatrick, F. A. Clin. Cancer Res. 2002, 8,
846.
1.99–2.08 (m, 1H), 1.77 (s, 3H), 1.26 (s, 9 H), 1.20 (s, 3H), 1.15 (s, 3H) ppm; 13
C
NMR (400 MHz, CDCl3) d 211.4, 174.7, 170.3, 166.8, 159.8, 142.0, 138.8, 134.4,
132.2, 129.8, 129.0, 128.8, 128.5, 127.8, 127.5, 126.8, 106.1, 83.5, 80.9, 79.1,
78.5, 76.8, 75.1, 74.0, 72.1, 68.4, 60.3, 56.3, 55.9, 46.9, 42.9, 35.5, 33.3, 27.4,
23.9, 22.4, 20.5, 13.6, 9.9 ppm; Anal. Calcd for C42H53NO14S: C, 58.28; H, 6.20;
18. Wang, Y.; He, Q. F.; Wang, H. W.; Zhou, X.; Huang, Z. Y.; Qin, Y. J. Org. Chem.
2006, 71, 1588.
N, 3.32. Found: C, 58.13; H, 6.29; N, 3.43; HRMS (FAB) calcd for C41H52N2O15
S
(M+Na+) 867.2880, found 850.2861.