Synthesis and biological evaluation of 4-deacetoxy-1,7-dideoxy azetidine paclitaxel analogues

Article abstract of DOI:10.1016/S0960-894X(03)00054-4

Three novel 4-deacetoxy-1,7-dideoxy azetidine paclitaxel analogues were synthesized through a convenient route that employed hydroboration-amination and intramolecular S_N2-type substitution reaction from a natural taxoid taxinine. All analogues have been tested for cytotoxicity against three human tumor cell lines. None of them showed remarkable cytotoxicity compared to paclitaxel against tested tumor cell lines.

Full text of DOI:10.1016/S0960-894X(03)00054-4

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1075–1077
Synthesis and Biological Evaluation of 4-Deacetoxy-1,7-dideoxy
Azetidine Paclitaxel Analogues
Qian Cheng,y Hiromasa Kiyota,* Marina Yamaguchi, Tohru Horiguchi{ and
Takayuki Oritani
Laboratory of Applied Bioorganic Chemistry, Division of Life Science, Graduate School of Agricultural Science, Tohoku University,
1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Received 27 January 2002; accepted 8 January 2003
Abstract—Three novel 4-deacetoxy-1,7-dideoxy azetidine paclitaxel analogues were synthesized through a convenient route that
employed hydroboration-amination and intramolecular SN2-type substitution reaction from a natural taxoid taxinine. All analo-
gues have been tested for cytotoxicity against three human tumor cell lines. None of them showed remarkable cytotoxicity com-
pared to paclitaxel against tested tumor cell lines.
# 2003 Elsevier Science Ltd. All rights reserved.
ies so far indicated that the oxgen functions at 7, 9, 10-
positions were not essential for paclitaxel’s activity,6
while the 13-side chain and 2-benzoyloxy group were
crucial7 (He et al.8 reported that m-azido group at
2-benzoyloxy group could be a substitute for the 13-side
chain, on the contrary to our results9). Although the
necessity of 1-OH group is still unclear,10 the presence
of oxetane ring and 4-acyloxy group11 was shown to be
essential: azetidine type12 or 4-deacetoxyl analogues lost
the activity.13 On our continuing efforts to evaluate
SAR of paclitaxel,9,14 we planned to prepare novel
4-deacetoxy paclitaxel analogues bearing azetidine ring.
Here we report a convenient synthesis and antitumor
activity of some 4-deacetoxy-1,7-dideoxy azetidine
paclitaxel analogues, such as 2, from naturally abun-
dant taxinine (3).
Paclitaxel1 (1, Taxol1) and docetaxol2 (Taxotere1) are
clinically used in the treatment of advanced ovarian and
breast cancers. Both also exhibit potent antitumor
activity against various cancer cells which have been
uneffectively treated by existing chemotherapeutic
drugs.3 Paclitaxel has also been approved for the sec-
ond-line treatment of AIDS related Kaposi’s sarcoma in
1997.4 Since its discovery at the end of 1960s, a number
of chemical, biological and medicinal researches as well
as the structure–activity relationships (SAR) of pacli-
taxel have been carried out, especially in the recent dec-
ade.5 Therefore, several major problems have been
emerged such as low aqueous solubility, multi-drug
resistance (MDR), scarcity of the drug and little activity
for oral administration. To overcome these problems,
searching for novel promising paclitaxel analogues as
anticancer drug candidates is still necessary. SAR stud-
Synthetic protocol to 1-deoxypaclitaxel azetidine analo-
gues included the synthesis of the known taxane 415
which could be prepared through 2 steps from naturally
abundant taxinine 3 isolated from the Japanese yew,
Taxus cuspidata (2 g/kg from the bark). As the synthetic
protocol depicted in Scheme 1, 4 was converted to bis-
O-silyl compound 5. The double bond at C-4(20) was
subjected to hydroboration-amination to form primary
amine 6 in 86% yield.16 Protection of the amino group
and selective deprotection of the TES group gave alco-
hol 7. Mesylation of the resulting hydroxyl group of 7
followed by alkaline treatment yielded a key inter-
mediate azetidine taxane 8.12,17 Deprotection of the
13-TBS group and subsequent esterification with
*Corresponding author. Tel.: +81-22-717-8785; fax: +81-22-717-8783;
e-mail: kiyota@biochem.tohoku.ac.jp
yCurrent address: Department of Chemistry and Biochemistry, Florida
State University, Tallahassee, FL 32306, USA.
{Current address: Department of Chemistry, Colorado State Uni-
versity, Fort Collins, CO 80523, USA.
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00054-4

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Q. Cheng et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1075–1077
Table 1. Results of biological assays in vitro on the cytotoxicity of
compounds 2, 11, 13, 14 and 15
a,b,c
Compd
Cytotoxicity against tumor cell (ED50/ED50)
SK-OV3
MCF-7
A549
Paclitaxel (1)
2
11
13
14
15
1.01.01.0
4.6
4.7
9.3
10.2
5.8
4.9
3.8
8.6
9.3
3.6
4.5
3.2
6.8
6.9
2.9
aED50 is the concentration of 50% inhibition of proliferation after 72
h of incubation.
bRatio of ED50 relative to paclitaxel is 1.0.
cSK-OV3: ovarian cancer cell lines, MCF-7: breast cancer cell lines,
A549: lung cancer cell lines.
All new 4-deacetoxy-1,7-dideoxy paclitaxel azetidine
analogues 2, 11, 13, 14 and 15 were evaluated in vitro on
the cytotoxicity against three tumor cell lines: SK-OV3
(ovarian cancer), MCF-7 (breast cancer) and A549
(lung cancer). As presented in Table 1, compared to
paclitaxel (1), all the tested compounds showed a
decrease of cytotoxicity against three tumor cell lines.
This demonstrates that the 4-acetoxy group and the
oxetane ring are essential for activity. However, com-
pared to the former azetidine analogue 12 and the 4-dea-
cetoxy analogue 13, our analogues with the original 13-
side chain (2, 11 and 15) still retained some activity. We
think that the azetidine NH group could compensate the
polarity of the original circumstances of paclitaxel. In
addition, the results also support the hypothesis that 1-
OH group is not essential for the activity.
Scheme 1. Reagents and conditions: (i) (a) NaBH4, CeCl3, MeOH, rt,
73%; (b) TBSCl, imidazole, DMF, rt, 91%. (ii) (a) BH3ꢁ THF, THF,
rt, (b) NH2OH, NaOCl, rt, 86%; (iii) (CF3CO)2O, DMAP, Py, rt,
82%; (iv) AcOH–H2O–THF (4:3:11), rt, 12 h, 84%; (v) MsCl, pyri-
dine, CH2Cl2, rt, 20h, 83%; (vi) DMSO, K 2CO3, rt, 56%; (vii) TBAF,
THF, rt, 98%; (viii) (a) 10, DCC, DMAP, toluene, 70 ꢂC; (b) TFA–
H2O, 65% two steps.
(2R,4S,5R)-3-benzoyl-2-(p-methoxyphenyl)oxy-4-phenyl-
1,3-oxazolidine-5-carboxylic acid (10) followed by acid
hydrolysis afforded the expected 4-deacetoxy-1,7-
dideoxy paclitaxel azetidine compound 11 according to
the previously established methods.14cꢀd
As shown in Scheme 2, the compound 9 was reduced
using NaBH4 to give a free azetidine 12 in 66% yield.
Esterification of the azetidine 12 with the carboxylic
acid 10 provided ester 13, which was hydrolyzed to
afford 4-deacetoxy-1,7-dideoxy paclitaxel azetidine ana-
logue 2 in 88% yield. Additionally, N-acetyl derivatives
of the azetidine ring, compounds 14 and 15, were pre-
pared in the similar manner.
Acknowledgements
JSPS fellowship to Q.C., and Dr. Y. Meng (Graduate
School of Medicine, Tohoku University) for biological
assays are gratefully acknowledged.
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