Synthesis and biology of 3'-N-acyl-N-debenzoylpaclitaxel analogues

Article abstract of DOI:10.1016/S0968-0896(99)00173-X

The 3'-N-acyl-N-debenzoylpaclitaxel analogues 1a-d were synthesized and evaluated on biological systems. Some of the analogues 1a-d exhibited higher cytotoxicities (up to 20-fold) and stronger abilities to induce apoptosis than paclitaxel. In an in vivo experiment against ip implanted B16 melanoma, the most cytotoxic compound 1b in vitro caused tumor growth inhibition more than paclitaxel.

Full text of DOI:10.1016/S0968-0896(99)00173-X

Bioorganic & Medicinal Chemistry 7 (1999) 2115±2119
Synthesis and Biology of 30-N-Acyl-N-debenzoylpaclitaxel
Analogues
Eun Joo Roh, a,b Choong Eui Song, a,* Deukjoon Kim, b Hyun-Ock Pae, c
Hun-Taeg Chung, c Kwan Sun Lee, d Ki-byung Chai, d Chong Ock Lee e
and Sang Un Choi e
aLife Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, 130-650, South Korea
bCollege of Pharmacy, Seoul National University, Shinrim-Dong, Kwanak-ku, Seoul, 152-742, South Korea
cDepartment of Microbiology and Immunology, Wonkwang University, School of Medicine, Iksan, Chonbuk 570-749, South Korea
dCentral Research Institute, Hanmi Pharm. Co., Ltd., Sampyong-dong, Boondang-ku, Kyonggi-do, 463-400, South Korea
eScreening Center, Korea Research Institute of Chemical Technology, PO Box 107, Yusong, Daejeon, 305-606, South Korea
Received 11 June 1999; accepted 15 June 1999
AbstractÐThe 30-N-acyl-N-debenzoylpaclitaxel analogues 1a±d were synthesized and evaluated on biological systems. Some of the
analogues 1a±d exhibited higher cytotoxicities (up to 20-fold) and stronger abilities to induce apoptosis than paclitaxel. In an in
vivo experiment against ip implanted B16 melanoma, the most cytotoxic compound 1b in vitro caused tumor growth inhibition
more than paclitaxel. # 1999 Elsevier Science Ltd. All rights reserved.
Introduction
Structure±activity studies16 of the paclitaxel analogues
have shown that both of the C-13 phenylisoserine side
chain and the diterpene part are essential for bioactivity.
The natural stereochemistry of the side chain at the 20
and 30-positions (20R,30S) is also essential for maximum
antitumor activity.17 Removal of the 20-hydroxy group18
or the 30-benzamide moiety19 produces paclitaxel ana-
logues with substantial reduced bioactivity. Deletion of
the 30-phenyl group leads to inactive derivatives,19
however, the compounds obtained by replacement of
the 30-phenyl group with lipophilic aliphatic substituents
such as cyclohexyl,20 isobutenyl group21 exhibited
excellent bioactivity. Although a large body of pacli-
taxel structure±activity relationships (SAR) has been
generated, a detailed investigation of aliphatic analo-
gues of similar size with phenyl group of 30-N-benzoyl
has received little attention. Only the analogues having
linear alkyl group instead of phenyl group were assayed
for microtubule binding anity and cytotoxicity.22 As
stated above, apoptosis along with cytotoxicity is an
important factor to evaluate chemotherapeutic agents.
The induction of apoptosis with tumor cell selectivity
may be more important than cytotoxicity involving
normal cell killing. Here we report the synthesis of 30-N-
acyl-paclitaxel analogues 1a±d (Fig. 1) which were
found to be highly cytotoxic and showed the strong
ability to induce apoptosis in vitro.
Paclitaxel (Taxol1), a highly functionalized diterpene
originally isolated from the paci®c yew (Taxus brevifo-
lia), is rapidly emerging as one of the most promising
antitumor compounds of the decade.1 This compound
promotes microtubule stabilization2±6 and also induces
cell death via apoptosis, a process characterized by
cytoskeletal changes, chromatin condensation, and
genomic DNA fragmentation.7 In the past few years,
the increasing evidences have suggested that the char-
acteristics of tumor cell death may be the most impor-
tant determinant for successful chemotheraphy.8±12
Multiple studies have concluded that paclitaxel arrests
the cell cycle at G1 or G2/M, with subsequent double-
stranded DNA breaks consistent with apoptosis and
correlate with cell death from this agent.13 Recent evi-
dence has supported these ®ndings and con®rmed the
presence of chemotherapy-induced apoptosis in epithe-
lial ovarian cancer after treatment with paclitaxel.14,15
Key words: 30-N-Acyl-N-debenzoylpaclitaxel analogues; cytotoxicity;
apoptosis; structure±activity relationship.
* Corresponding author. Tel.: +82-2-958-5143; fax: +82-2-958-5189;
e-mail: s1673@kistmail.kist.re.kr
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00173-X

2116
E. J. Roh et al. / Bioorg. Med. Chem. 7 (1999) 2115±2119
Figure 1.
Chemistry
cell line. As shown from the data in Table 1, the 30-N-
acyl-N-debenzoylpaclitaxel analogues 1a±d were found
to be highly cytotoxic. Especially, the analogues 1b and
1d bearing N-cycloalkenoyl group were more potent up
to 20 times than paclitaxel. The most cytotoxic com-
pound 1b in vitro was further evaluated in an in vivo
experiment against ip implanted B16 melanoma. As
shown in Table 1, the compound 1b caused tumor
growth inhibition (T/C=212%) more than paclitaxel
(T/C=200%). The induction of apoptosis was also
studied by DNA fragmentation after treatment with
paclitaxel or its N-acyl analogues 1a±d, and analyzed by
sub-G1% resulting from DNA fragmentation after 72 h
from the time of initial exposure. All of the analogues
1a±d exhibited stronger ability to induce apoptosis than
paclitaxel. Especially, the most cytotoxic compound 1b
displayed the strongest ability for the induction of
apoptosis (66.86%). It can be concluded from this study
that modi®cations at the 30-N-acyl group of paclitaxel
are tolerated well in many cases.
The synthetic route employed for the preparation of
analogues 1a±d is shown in Scheme 1. The coupling
reaction of 7-TCA-baccatin III 2 with oxazolidine-pro-
tected side chain precursor 3 was carried out in the pre-
sence of DCC at ambient temperature (35ꢀC) to a€ord 4
in 84% yield. Acid-mediated oxazolidine cleavage of the
compound 4, followed by N-acylation of the resultant
free amine 5 with an appropriate acid chloride (cyclo-
pentanoyl chloride, 1-cyclopentenoyl chloride, cyclo-
hexanoyl chloride or 1-cyclohexenoyl chloride) gave the
corresponding 30-acyl-30-debenzoyl-7-TCA-paclitaxels
6a±d. Finally, the 7-trichloroacetyl group of 6a±d was
easily removed with excess of ammonium acetate (ca. 5
equiv) to give the desired 30-acyl-30-debenzoylpaclitaxel
analogues 1a±d in satisfactory yields. Spectroscopic data
(NMR and FAB-HRMS) of 1a±d were consistent with
their assigned structures.
In summary, we have prepared N-acyl-N-debenzoyl-
paclitaxel derivatives 1a±d and evaluated them in dif-
ferent biological methods. Hydrophobic cycloalkyl and
cycloalkenyl substituted 30-N-acyl analogues 1a±d
showed cytotoxicity and the strong ability to induce
apoptosis.
Results and Discussion
The biological activities of 30-N-acyl-N-debenzoylpacli-
taxel analogues 1a±d were evaluated for their cytotoxi-
cities against human cancer cell lines (A 549 and SK-OV
3) and their abilities to induce apoptosis against HL-60

E. J. Roh et al. / Bioorg. Med. Chem. 7 (1999) 2115±2119
2117
Scheme 1. Reagents and conditions: (i) DCC, toluene, 35ꢀC, 2 h; (ii) c-HCl, then aq NaHCO3, EtOAc; (iii) RCOCl, pyridine; (iv) NH4OAc, MeOH-
THF.
Table 1. Biological evaluation of 30-N-acyl-30-N-debenzoylpaclitaxel analogues 1a±d
Compound
Tumor cell cytotoxicity ED50/ED50 (paclitaxel)a
Apoptosis against
HL 60 (%)b
In vivo antitumor activity in
B16 melanoma tumor modelc
% T/Cd (mg/kg/inj.)e
A549
SK-OV 3
Paclitaxel
1
0.4
<0.05
4.44
0.56
1
59.70
62.68
66.86
61.96
60.41
200 (20)
212 (20)
1a
1b
1c
1d
1.67
0.13
5.68
0.83
a
ED50=concentration which produces 50% inhibition of proliferation after 72 h of incubation. Relative to paclitaxel=1. A 549: non-small cell
lung carcinoma, SK-OV 3: ovarian carcinoma.
b
% of sub-G1 by DNA fragmentation. The data represent the mean values of at least three separate experiments. For details of the assay, see
Experimental.
c
B16 melanoma, ip (intraperitoneal) implant model.
T/C refers to the percentage of the median survival time of drug-treated mice (seven per dose) to saline-treated controls.
Dose administered ip on days 1, 4, 7, and 10; vehicle used: cremophor, ethanol and saline.
d
e
Experimental
on a Varian Gemini 300 spectrometer using TMS as
an internal standard. IR spectra were recorded on a
MIDAC 101025 FT±IR spectrometer and main
absorption frequencies were given in cm 1. HRMS
(FAB) analysis was carried out by the Mass Spectro-
metry Analysis Group at Korea Basic Science Institute.
The 7-TCA-baccatin III (2) and oxazolidine-protected
side chain precursor 3 were prepared according to the
reported procedure.23
Chromatographic puri®cation of products was carried
out by ¯ash chromatography using Merck silica gel 60
(230±400 mesh). Thin layer chromatography was car-
ried out on Merck silica gel 60F plates. Melting points
were measured with a Thomas Hoover capillary melting
1
point apparatus and were uncorrected. H NMR (300
MHz) and 13C NMR (75.0 Hz) spectra were recorded

2118
E. J. Roh et al. / Bioorg. Med. Chem. 7 (1999) 2115±2119
General procedure for the synthesis of
30-acyl-30-debenzoylpaclitaxel 1a-d
by ¯ash column chromatography on silica gel (EtOAc:
n-hexane=1:1) to give the corresponding N-acyl-N-
debenzoylpaclitaxel 1a±d as a white solid.
Synthesis of the compound 4. To the mixture of 7-tri-
chloroacetylbaccatin III (2) (630 mg, 0.89 mmol), DCC
(530 g, 2.57 mmol) and DMAP (6 mg, 0.05 mmol) in
toluene (15 mL), was added a solution of (4S,5R)-2,2-
di(chloromethyl)-4-phenyl-1,3-oxazolidine-5-carboxylic
acid triethylamine salt (3) (1 g, 2.55 mmol) in toluene
(10 mL) at room temperature and the reaction mixture
was warmed to 35ꢀC. After stirring at this temperature
for 2 h, the reaction mixture was diluted with ethyl ace-
tate and washed with brine. After concentration in
vacuo, the crude product was puri®ed by ¯ash column
chromatography on silica gel (EtOAc:hexane=1:2) to
give 4 (740 mg, 84%) as a white solid: 1H NMR
(CDCl3, selected diagnostic peaks) d 1.15 (s, 3H), 1.24
(s, 3H), 1.79 (s, 3H), 1.84 (s, 3H), 1.99 (s, 3H), 2.16 (s,
3H), 2.60±2.71 (m, 1H), 3.78 (d, J=12.0 Hz, 1H), 3.86
(d, J=12.0 Hz, 1H), 3.91 (d, J=7.0 Hz, 1H), 4.04 (s, 2H),
4.12 (d, J=8.5 Hz, 1H), 4.27 (d, J=8.3 Hz, 1H), 4.43 (d,
J=8.3 Hz, 1H), 4.65 (d, J=8.1 Hz, 1H), 4.89 (d, J=9.3
Hz, 1H), 5.63 (d, J=7.7 Hz, 1H), 5.66 (d, J=7.1 Hz, 1H),
6.25 (t, J=8.9 Hz, 1H), 6.39 (s, 1H), 7.44±7.70 (m, 8H),
8.03 (d, J=7.0 Hz, 2H). 13C NMR (CDCl3) d 11.06,
14.96, 21.00, 21.58, 21.74, 26.78, 32.50, 35.78, 43.57,
46.51, 46.81, 48.09, 56.14, 66.49, 71.53, 74.79, 74.93,
76.55, 79.43, 80.59, 83.79, 98.87, 127.57, 129.07, 129.31,
129.43, 129.66, 130.50, 133.29, 134.35, 137.35, 141.77,
160.87, 167.32, 169.23, 170.48, 170.87, 190.31, 201.55.
30-Cyclopentanoyl-30-debenzoylpaclitaxel (1a). H NMR
1
(CDCl3, selected diagnostic peaks) d 1.08 (s, 3H), 1.20
(s, 3H), 1.61 (s, 3H), 1.75 (s, 3H), 2.10 (s, 3H), 2.18 (s,
3H), 2.29 (s, 3H), 2.40±2.60 (m, 2H), 3.71 (d, J=7.0 Hz,
1H), 4.11 (d, J=8.4 Hz, 1H), 4.23 (d, J=8.4 Hz, 1H),
4.33 (dd, J=6.8, 10.6 Hz, 1H), 4.61 (d, J=2.5 Hz, 1H),
4.87 (d, J=8.3 Hz, 1H), 5.50 (dd, J=2.4, 8.9 Hz, 1H),
5.60 (d, J=7.0 Hz, 1H), 6.13 (t, J=9.4 Hz, 1H), 6.21 (s,
1H), 7.20±7.60 (m, 8H), 8.05 (d, J=7.1 Hz, 2H); 13C
NMR (CDCl3) d 9.97, 15.20, 21.25, 22.33, 23.00, 26.21,
27.20, 30.66, 31.05, 43.64, 46.00, 54.84, 59.00, 72.57,
72.84, 73.61, 75.38, 75.98, 79.39, 81.52, 84.81, 127.30,
128.61, 129.10, 129.36, 129.56, 130.62, 133.53, 134.08,
138.47, 142.50, 167.39, 170.68, 171.66, 173.31, 176.61,
204.08; HRMS (FAB) calcd for C46H56NO14 (M+H+)
846.3701, found 846.3698.
30 -(1-Cyclopentenoyl)-30 -debenzoylpaclitaxel (1b). 1H
NMR (CDCl3, selected diagnostic peaks) d 1.08 (s, 3H),
1.19 (t, 3H), 1.61 (s, 3H), 1.73 (s, 3H), 2.18 (s, 3H), 2.28
(s, 3H), 2.46 (m, 3H), 3.71 (d, J=7.0 Hz, 1H), 4.11 (d,
J=8.4 Hz, 1H), 4.22 (d, J=8.4 Hz, 1H), 4.33 (dd,
J=6.6, 10.7 Hz, 1H), 4.65 (d, J=2.8 Hz, 1H), 4.87 (d,
J=7.8 Hz, 1H), 5.55 (dd, J=2.7, 8.7 Hz, 1H), 5.60 (d,
J=7.0 Hz, 1H), 6.14 (t, J=8.6 Hz, 1H), 6.20 (s, 1H),
6.37 (d, J=8.8 Hz, 1H), 6.47 (m, 1H), 7.30±7.55 (m,
8H), 8.04 (d, J=7.1 Hz, 2H); 13C NMR (CDCl3) d 9.96,
15.22, 21.26, 22.26, 22.98, 23.62, 27.27, 31.89, 33.61,
36.02, 43.60, 46.01, 55.03, 59.01, 72.57, 72.69, 73.69,
75.37, 75.99, 79.38, 81.53, 84.80, 127.40, 128.68, 129.10,
129.37, 129.58, 130.60, 133.57, 134.09, 138.49, 138.90,
139.99, 142.45, 165.58, 167.36, 170.73, 171.65, 173.11,
204.06; HRMS (FAB) calcd for C46H54NO14 (M+H+)
844.3544, found 844.3577.
7-Trichloroacetyl-30-debenzoylpaclitaxel 5. To a solution
of oxazolidine-protected 7-trichloroacetylpaclitaxel (4)
(0.2 g, 0.20 mmol) in ethyl acetate (5 mL) was added
concd -HCl (0.05 mL) at 0ꢀC. After stirring for 30 min,
the reaction mixture was neutralized by addition of
aqueous NaHCO3 and the organic phase was washed
with brine. The organic layer was dried over anhydrous
MgSO4 and concentrated in vacuo to a€ord the crude
product of 7-trichloroacetyl-30-debenzoylpaclitaxel 5,
which was used for the next reaction without puri®cation.
30-Cyclohexanoyl-30-debenzoylpaclitaxel (1c). H NMR
1
(CDCl3, selected diagnostic peaks) d 1.09 (s, 3H), 1.20
(s, 3H), 1.61 (s, 3H), 2.10 (s, 3H), 2.18 (s, 3H), 2.28 (s,
3H), 2.21±2.26 (m, 2H), 2.28 (s, 3H), 2.42±2.51 (m, 2H),
3.71 (d, J=7.0 Hz, 1H), 4.12 (d, J=8.4 Hz, 1H), 4.23
(d, J=8.4 Hz, 1H), 4.33 (dd, J=6.9, 10.8 Hz, 1H), 4.61
(d, J=2.4 Hz, 1H), 4.87 (d, J=7.7 Hz, 1H), 5.49 (dd,
J=2.6, 8.9 Hz, 1H), 5.61 (d, J=7.0 Hz, 1H), 6.13 (t,
J=9.0 Hz, 2H), 6.21 (s, 1H), 7.25±7.55 (m, 8H), 8.05 (d,
J=7.2 Hz, 2H); 13C NMR (CDCl3) d 9.97, 15.19, 21.26,
22.33, 22.99, 25.95, 27.21, 29.96, 30.10, 36.00, 43.64,
45.83, 45.98, 54.54, 59.00, 72.57, 72.91, 73.47, 75.39,
75.99, 79.33, 81.53, 84.81, 127.29, 128.62, 129.11,
129.37, 129.59, 130.63, 133.57, 134.07, 138.42, 142.47,
167.35, 170.64, 171.67, 173.36, 176.43, 204.09; HRMS
(FAB) calcd for C47H58NO14 (M+H+) 860.3857, found
860.3867.
7-Trichloroacetyl-30-acyl-30-debenzoylpaclitaxel 6a±d. To
a stirred solution of the crude product of free amine 5
(50 mg) in pyridine (5 mL) was added dropwise an
appropriate acid chloride [cyclopentanoyl chloride,
1-cyclopentenoyl chloride, cyclohexanoyl chloride or
1-cyclohexenoyl chloride] (0.17 mmol) at 0ꢀC. After
stirring for 2 h at the same temperature, the reaction
mixture was diluted with ethyl acetate and washed with
brine. The organic layer was dried over anhydrous
MgSO4 and concentrated in vacuo to give the crude
residue of the corresponding 7-trichloroacetyl-30-acyl-30-
debenzoylpaclitaxel (6a±d), which was used for the next
reaction without puri®cation.
N-Acyl-N-debenzoylpaclitaxel 1a±d. To a stirred solu-
tion of the crude product of 6a±d in MeOH (5 mL) and
THF (5 mL) was added ammonium acetate (13 mg,
0.16 mmol) at room temperature. After completion of
the reaction (ca. 2 h), the reaction mixture was dilu-
ted with ethyl acetate and washed with brine. After
concentration in vacuo, the crude product was puri®ed
30 -(1-Cyclohexenoyl)-30 -debenzoylpaclitaxel (1d). 1H
NMR (CDCl3, selected diagnostic peaks) d 1.08 (s, 3H),
1.21 (s, 3H), 1.61 (s, 3H), 1.72 (s, 3H), 1.72 (s, 3H), 2.17
(s, 3H), 2.28 (s, 3H), 3.71 (d, J=7.0 Hz, 1H), 4.11 (d,
J=8.4 Hz, 1H), 4.22 (d, J=8.4 Hz, 1H), 4.32 (dd,
J=6.7, 10.8 Hz, 1H), 4.63 (d, J=2.9 Hz, 1H), 4.86 (d,

E. J. Roh et al. / Bioorg. Med. Chem. 7 (1999) 2115±2119
2119
J=7.7 Hz, 1H), 5.53 (dd, J=2.8, 8.7 Hz, 1H), 5.60 (d,
References
J=7.0 Hz, 1H), 6.13 (t, J=8.2 Hz, 1H), 6.20 (s, 1H),
6.45 (d, J=8.7 Hz, 1H), 6.57 (m, 1H), 7.20±7.55 (m,
8H), 8.04 (d, J=7.2 Hz, 2H); 13C NMR (CDCl3) d 8.55,
13.80, 19.84, 20.36, 20.97, 21.57, 23.23, 24.37, 25.87,
34.61, 42.19, 44.60, 53.79, 57.61, 71.17, 71.29, 72.35,
73.97, 74.58, 78.02, 80.11, 83.40, 126.01, 127.25, 127.69,
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137.15, 141.11, 165.98, 167.28, 169.30, 170.24, 171.78,
202.68; HRMS (FAB) calcd for C47H56NO14 (M+H+)
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Acknowledgements
Financial support from the Ministry of Science and
Technology of Korea (2N 16490 to C.E.S.) is gratefully
acknowledged.