Synthesis and biological evaluation of novel 9-functional heterocyclic coupled 7-deoxy-9-dihydropaclitaxel analogue

Article abstract of DOI:10.1016/S0960-894X(00)00031-7

Novel 9-functional heterocyclic coupled 7-deoxy-9-dihydropaclitaxel analogues 17 and 22-24 synthesized from a natural taxoid 5-cinnamoyltriacetyltaxicin-I (3) and their biological evaluation in tubulin assembly activity and cytotoxicity in vitro against several human tumor cell lines are first presented. The biologically tested results show that 17, 22 and 23 are inactive in tubulin assembly assay and have no more remarkable cytotoxicities against human tumor cell lines SK-0V3, WIDR and MCF-7, though 22 and 23 exhibit more potent cytotoxicity against human liver cancer and human esophagus cancer cell lines (BEL-7402 and ECa-109) than paclitaxel. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00031-7

Bioorganic & Medicinal Chemistry Letters 10 (2000) 517±521
Synthesis and Biological Evaluation of Novel 9-Functional
Heterocyclic Coupled 7-Deoxy-9-Dihydropaclitaxel Analogue
Qian Cheng, a,* Takayuki Oritani, a Tohru Horiguchi, a Teiko Yamada a
and Yan Mong b,c
aLaboratory of Applied Bioorganic Chemistry, Division of Life Science, Graduate School of Agricultural Science,
Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981, Japan
bGraduate School of Medicine, Tohoku University, Aoba-ku, Sendai 980, Japan
cInstitute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College,
Beijing 100021, People's Republic of China
Received 10 December 1999; accepted 14 January 2000
AbstractÐNovel 9-functional heterocyclic coupled 7-deoxy-9-dihydropaclitaxel analogues 17 and 22±24 synthesized from a natural
taxoid 5-cinnamoyltriacetyltaxicin-I (3) and their biological evaluation in tubulin assembly activity and cytotoxicity in vitro against
several human tumor cell lines are ®rst presented. The biologically tested results show that 17, 22 and 23 are inactive in tubulin
assembly assay and have no more remarkable cytotoxicities against human tumor cell lines SK-0V3, WIDR and MCF-7, though 22
and 23 exhibit more potent cytotoxicity against human liver cancer and human esophagus cancer cell lines (BEL-7402 and ECa-
109) than paclitaxel. # 2000 Elsevier Science Ltd. All rights reserved.
The diterpenoid paclitaxel (Taxol1, 1), originally iso-
lated from the Paci®c yew tree Taxus brevofolia in
1971,1 exhibits remarkably high cytotoxicity and strong
antitumor activity against di€erent tumors resistantly
treated by existing anticancer drugs.2 It has been
approved for treatment of advanced ovarian and breast
cancers,3,4 and it is currently in clinical trials for treat-
ment of lung, skin, and head and neck cancers with
encouraging results.5 Since its discovery in the 1960s,
structural complexity, important biological activity and
novel mechanism of action6,7 of pacitaxel have stimu-
lated extensive chemical, biological and medicinal
research.8,9 Up to date, numerous analogues have been
prepared among many studies of structural modi®-
cations of paclitaxel by contractions and changes to
A-ring,10,11 B-ring,12,13 C-ring,14,15 D-ring,16,17 and the
side-chain,18 which have led to the discovery of the new
and potent bioactive taxoid docetaxel19 (Taxotere1 2).
while benzoyloxy and acetoxy at C-2 and C-4 respec-
tively plus the oxetane ring in the `southern hemisphere'
and the side chain at C-13 are essential for biological
activity.8,9,20,21 However, only a few modi®cations of C-
9 such as dihydrogenation and decarboxylation have
been reported.22 Recently, further chemical and SAR
studies of C-9 have few appeared in the literature. In
addition, twin drugs combining two biologically active
components into a single molecule have been reported
in numerous domains of medicinal chemistry.23 Thus,
according to the previous SAR studies which show 7-
dehydroxylation having no signi®cant e€ect on the
activity of pacitaxel, we expected to explore the possi-
bility of new taxoids combined with the functional
heterocyclic such as AZT, which is the ®rst therapeutic
drug for AIDS in clinical medicine, possessing potent
cytotoxicity or other biological activity.
Recently, the semisyntheses of 7-deoxypaclitaxel analo-
gues have been reported,24±27 but all investigations have
been carried out by using taxine B and isotaxine B28 as
starting materials. So far attention has never been paid
to 5-cinnamoyltriacetyltaxicin I (3),29 the major taxoid
isolated in abundant yield from the needles of di€erent
Taxus species, such as Japanese yew T. cuspidata, as a
precursor for the synthesis of either paclitaxel or its
analogues. In this communication, we report our e€orts
A large number of the structure±activity relationships
(SAR) studies of paclitaxel have led to the general con-
clusions that the function groups at C-7, C-9 and C-10 in
the `northern hemisphere' have little e€ect on bioactivity,
*Corresponding author. Fax: +81-22-717-8783; e-mail: chengq@
biochem.tohoku.ac.jp
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00031-7

518
Q. Cheng et al. / Bioorg. Med. Chem. Lett. 10 (2000) 517±521
In order to achieve the combination of taxoid 13 with
biologically active compound AZT, the succinyl group
was introduced as a bridge to connect the above two
molecules. Compound 13 was treated with an excess of
succinic anhydride to provide the succinate 14 as the only
reaction product uneventfully, subsequently which was
reacted with AZT in the presence of DMAP to give 15 in
85% yield. Reduction of 15 and subsequent esteri®cation
with (2S, 4S, 5R)-3-benzoyl-2-(p-methoxyphenyl)-4-
phenyl-1,3-oxazolidine-5-carboxylic acid 16 and acid
hydrolysis a€orded the desired product 1732 in 51% all
yield from 15 according to the developed established
methods.33
Chart 1.
on the synthesis and biological evaluation of several
new 7-deoxy-9-dihydropaclitaxel analogues 17 and 22±
24 from 5-cinnamoyltriacetyltaxicin I (3).
As depicted in Scheme 1, a natural taxoid 3 underwent
deacetylation and selective protection of 9,10-dihydroxy
with acetone catalyzed by CuSO4 to give 4 in 73%
The mechanism of action studies of paclitaxel indicate
that the anticancer activity is believed to be mediated by
a combination of its primary action on microtubule
assembly and secondarily by inhibiting DNA synthesis
and promoting DNA fragmentation of the cell.28 These
actions are found to be related to the nucleotide which
is a basic unit in the formation of nucleic acids DNA
and RNA. In order to explore the possibility of new
taxoids which are expected to have highly biological
activities, three novel 9-functional nucleotide coupled
7-deoxy-9-dihydropaclitaxel analogues 22±24 were
synthesized by introduction of functional nucleotides
(Scheme 2).
24
yield. Further protection of 1,2-dihydroxy with tri-
phosgene followed by hydrolysis of the cinnamate ester
using hydroxylamine30 led to 5-hydroxy±taxoid 6. Con-
struction of the oxetane ring from 6 was achieved fol-
lowing the previously established methods24±27 leading
to 10. We expected that the isopropylidene group could
be removed independently from the 1,2-cyclic carbonate
and oxetane ring. This attempt was accomplished by
treatment of 10 with a mixture of HOAc:H2O:THF (v/v
4:2:l) at 40 ꢀC to a€ord 4, 9, 10-trihydroxy taxoid 11 in
71% yield. In fact, this selective acid hydrolysis in this
taxoid series has already been reported.24 Acetylation of
11 by means of Ac2O/DMAP gave 4- and 10-diacety-
lated 12,31 which subsequently was treated with phenyl-
lithium in THF at 78 ꢀC to furnish compound 13.
After esteri®cation of succinyl taxoid 14 by benzyl
alcohol which gave a corresponding ester 18, subse-
quently this was reduced to give 13a-hydroxy taxoid 19
Scheme 1. Reagents and conditions: (i) NaOCH3, CH3OH/CH2Cl2, 0 ꢀC, 86%; (ii) Acetone, CuSO, 73%; (iii) (Cl3CO)2CO (2 eq), CH2Cl2:Pyridine
(2:1), 0 ꢀC, 92%; (iv) NH2OH.HCl, NaOAc, EtOH/H2O, re¯ux, 65%; (v) OsO4 NMO, THF:H2O (2:1). rt, 86%; (vi) TBDMSCl, imidazole, DMF,
rt, 95%; (vii) MsCl, pyridine, 81%; (viii) a: TBAF, THF, b: Bu4N+ OAc, butanone, re¯ux, 75%; (ix) HOAc:H2O:THF (v/v 4:2:1), 40 ꢀC, 71%; (x)
Ac2O, DMAP, 0 ꢀC to rt, 76%; (xi) PhLi, THF, 78 ꢀC, 84%; (xii) Succinic anhydride, DMAP, DMF, 85 ꢀC. 48 h, 69%; (xiii) AZT, DCC, DMAP,
toluene, 85%; (xiv) NaBH4, CH3OH. rt, 78%; (xv) a: DCC, DMAP, toluene; b: 0.1 N HCl, CH3OH, 65%.

Q. Cheng et al. / Bioorg. Med. Chem. Lett. 10 (2000) 517±521
519
Scheme 2. Reagents and conditions: (i) PhCH2OH, DCC, DMAP, toluene, 90%; (ii) NaBH4, CH3OH, rt, 83%; (iii) DCC, DMAP, toluene, 86%:
(iv) H2, Pd/C (10%), EtOAc, rt, 73%; (v) a: 6-Chloropurine riboside, DCC, DMAP, toluene; b: TFA, H2O, rt, 73% from 21; (vi) a: ( )-5-Bro-
mouridine, DCC, DMAP, toluene; b: TFA, H2O, rt, 69% from 21; (vii) a: N4-Benzoyl-20-deoxycytidine, DCC, DMAP, toluene; b: TFA, H2O, rt,
75% from 21.
followed by treatment with carboxylic acid 16 which
a€orded the reaction product 20. Removal of the benzyl
group by hydrogenation in the presence of Pd (10% on
activated carbon) gave the C-13 side-chain protected
acid 21 in 73% yield. Combination of the acid 21 with
6-chloropurine riboside using DCC and a catalytic
amount of DMAP in toluene, followed by acid hydro-
lysis with tri¯uoroacetic acid and water, a€orded the
desired product 22 in 73% yield. A similar combination
of the acid 21 with ( )-5-bromouridine and N4-benzoyl-
20-deoxycytidine and followed by acid hydrolysis gave
the compounds 23 and 24 in 69 and 75% yields,
respectively.
The results are presented in Table 1. Compared to
paclitaxel, 17, 22 and 23 showed a marked decrease of
tubulin assembly activity and 24 remained at half of the
tubulin assembly activity of paclitaxel in our experi-
mental conditions. This implies that the functional
group at C-9 may be one e€ective factor of the micro-
tubulin binding site beside another two key micro-
tubulin binding regions involving the C-13 ester side
chain and the oxetane ring of paclitaxel.35 In cytotoxi-
city assay 17 and 22±24 showed less cytotoxicity against
three human cancer cell lines (SK-OV3, WIDR and
MCF-7) than paclitaxel, though both 22 and 23 showed
more potent cytotoxicity against human liver cancer
(BEL-7402) and human esophagus cancer (ECa-109)
cell lines than paclitaxel. What reasons result in this
inconsistency between tubulin polymerisation activity
and cytotoxicity of 22 and 23 against BEL-7402 and
ECa-109 is as yet unclear, but it might be explained
either by the success of 22 and 23 to gain access to the
Biological activities of the novel 7-deoxy-9-dihy-
dropaclitaxel analogues 17 and 22±24 were evaluated in
two assay systems, i.e. in vitro cytotoxicity against ®ve
human tumor cell lines (SK-OV3, WIDR, MCF-7, BEL-
7402, ECa-109) and microtubule assembly activity.34
Table 1. Biological assays in microtubule assembly activity and cytotoxicity of 17 and 22±24
Compound
Cytotoxicity against tumor
a,b,c
Microtubule assembly
assay (ED50 mM)d
cell (Ed50/ED50
)
SK-OV3
3.41
2.24
4.06
1.98
WIDR
2.62
2.16
3.87
2.43
MCF-7
3.13
3.68
2.64
1.63
BEL-7402
7.32
0.24
ECa-109
3.54
0.18
0.16
1.03
Ð
17
22
23
24
>20
>15
>15
0.9
0.13
1.45
Paclitaxel
1.00
1.00
1.00
1.00
1.00
0.4
aED50 is the concentration which produces 50% inhibition of proliferation after 72 h of incubation.
bRatio of ED50 relative to paclitaxel is 1.00.
cSK-OV3: human ovarian cancer; WIDR: human colon cancer MCF-7: human breast cancer; BEL-7402: human liver cancer; ECa-109: human
esophagus cancer.
dED50 is the concentration which causes polymerization of 50% of the tubulin present at 37 ꢀC.

520
Q. Cheng et al. / Bioorg. Med. Chem. Lett. 10 (2000) 517±521
cells or by some biotransformations of 22 and 23 to an
active metabolite. These compounds are likely to induce
cell death via apoptosis, a process characterized by
cytoskeletal changes, chromatin condensation, and
genomic DNA fragmentation as paclitaxel.36 In fact,
this di€erence between tubulin polymerisation activity
and cytotoxicity in paclitaxel analogues has already
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Acknowledgements
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Financial support of this work by Grant-in-Aid for sci-
enti®c research from the Ministry of Education, Science
and Culture of Japan and JSPS Fellowship to Dr.
Cheng are gratefully acknowledged.
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J=4.0 Hz, OH-20), 2.70 (m, 4H, 2CH2), 2.38 (m, 2H, CH2),
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