Design and synthesis of a combinatorial chemistry library of 7-acyl, 10-acyl, and 7,10-diacyl analogues of paclitaxel (taxol) using solid phase synthesis

Article abstract of DOI:10.1021/np010552a

A series of 10-acyl and 7,10-diacyl paclitaxel analogues (7a-7e and 9a-9u) have been synthesized using a solid phase combinatorial chemistry approach, and a second series of 7-acyl-10-deacetylpaclitaxel analogues have been prepared by conventional chemist

Full text of DOI:10.1021/np010552a

1136
J . Nat. Prod. 2002, 65, 1136-1142
Design a n d Syn th esis of a Com bin a tor ia l Ch em istr y Libr a r y of 7-Acyl, 10-Acyl,
a n d 7,10-Dia cyl An a logu es of P a clita xel (Ta xol) Usin g Solid P h a se Syn th esis
Prakash G. J agtap,†,§ Erkan Baloglu,†, Donna M. Barron,‡,| Susan Bane,‡ and David G. I. Kingston*,†
Department of Chemistry, M/ C 0212, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, and
Department of Chemistry, State University of New York at Binghamton, Binghamton, New York 13902-6016
Received November 2, 2001
A series of 10-acyl and 7,10-diacyl paclitaxel analogues (7a -7e and 9a -9u ) have been synthesized using
a solid phase combinatorial chemistry approach, and a second series of 7-acyl-10-deacetylpaclitaxel
analogues have been prepared by conventional chemistry. In the first series, 10-deacetylpaclitaxel (4)
was linked through its 2′-hydroxyl group using 1% polystyrene-divinyl benzene resin functionalized with
butyldiethylsilane linker (PS-DES) and then acylated at the C-10 hydroxyl group with various anhydrides
and dialkyl dicarbonates in the presence of CeCl3. The resin-bound C-10 acylated paclitaxel derivatives
(6a -6e) were then treated with various carboxylic acids in the presence of 1,3-diisopropylcarbodiimide
in toluene to provide polymer-supported 7,10-diacylpaclitaxels (8a -8u ). These 7-acyl- and 7,10-
diacylpaclitaxels (6a -6e and 8a -8u ) were cleaved from the resin to give the 24 paclitaxel analogues
7a -7e and 9a -9u . Nine 7-acyl-10-deacetylpaclitaxel analogues were also prepared by conventional
chemistry. Methodology to determine the tubulin-assembly activity of compounds prepared in small
quantities by a combinatorial approach has been developed, and four analogues with improved tubulin-
assembly activity as compared with paclitaxel were found, together with two analogues with improved
cytotoxicity.
The natural diterpenoid paclitaxel (Taxol) (1) has become
a major anticancer drug, with U.S. sales in 2000 estimated
at over $1.5 billion.1 Its interesting mechanism of action
as a promoter of tubulin polymerization2 and its com-
mercial success have combined to maintain a high level of
interest in the preparation of paclitaxel analogues with
improved bioactivity, and large numbers of analogues have
been prepared.3,4 Among the compounds that have been
prepared are many with modified acyl groups at the C-105-7
and C-78,9 positions, and one of the compounds in a clinical
trial conducted by Bristol-Myers Squibb as a second-
generation paclitaxel analogue is a C-7 derivative.10
Resu lts a n d Discu ssion
Since combinatorial chemistry can be carried out ef-
ficiently by the “split and pool” technique in a resin-based
methodology,18 this approach was used in our synthetic
design. The key question in the design of such an approach
then becomes the selection of the attachment of the
paclitaxel substrate to the resin. On the basis of the known
SAR of paclitaxel3,4,19 an attachment through the 2′-
hydroxyl group appeared to be the most desirable, since
modifications at this position are usually deleterious to
activity. The previous resin-based approach15 had at-
tempted to link at this position, but had found that the
THP ether linker or related alkoxy linkers were unsatisfac-
tory due to steric hindrance. These workers thus developed
an approach through a glutamic acid “handle” (2), but this
Most of the studies to date have focused on paclitaxel
analogues modified at one site only, although recently work
has begun to appear where modifications are carried out
at two or more sites simultaneously.11-14 The preparation
of analogues modified at more than one site can most
efficiently be carried out by the methods of combinatorial
chemistry, and thus the development of some general
methods that could be applied to the synthesis of paclitaxel
analogues was sought. To date, only one publication on the
combinatorial synthesis of paclitaxel analogues has ap-
peared. Xiao et al.15 described the use of radio frequency
encoded tags to do combinatorial chemistry on a resin, but,
as discussed below, they were restricted to the preparation
of analogues of the general structure 2. In some related
work Georg and co-workers have prepared a number of
C-716 and C-1017 analogues by a parallel synthesis ap-
proach, but this work has not yet been extended to the
combinatorial synthesis of C-7, C-10 analogues.
* To whom inquiries should be addressed. Tel: (540) 231-6570. Fax: (540)
231-7702. E-mail: dkingston@vt.edu.
† Virginia Polytechnic Institute and State University.
‡ State University of New York at Binghamton.
§ Current address: Laboratory for Drug Discovery in Neurodegeneration,
65 Landsdowne St., Cambridge, MA 02139.
limited them to preparing N-glutamyl analogues and
precluded the synthesis of analogues with a normal N-
benzoyl function. Since it was desired to develop a combi-
natorial approach to paclitaxel analogues that would allow
the preparation of N-benzoyl analogues, the use of alter-
Current address: ImmunoGen Inc., 128 Sidney St., Cambridge, MA
02139.
| Current address: Regeneron Pharmaceuticals, Inc., 81 Columbia
Turnpike, Rensselaer, NY 12144.
10.1021/np010552a CCC: $22.00
© 2002 American Chemical Society and American Society of Pharmacognosy
Published on Web 07/11/2002

Analogues of Paclitaxel
J ournal of Natural Products, 2002, Vol. 65, No. 8 1137
Ta ble 1. Tubulin Polymerization Data of 10-Acyl and 7,10-Diacyl Paclitaxels (7a -7e and 9a -9u )
% tubulin polymerization at the indicated dose (µM)
R1
C-10
R2
C-7
cmpd
% yield
0.1
1.0
10
activity (rel. to PTX)a
1
COCH3
COC6H5
H
H
H
H
H
H
NA
60
56
60
54
69
62
59
61
58
57
55
59
64
56
66
59
56
66
69
58
52
62
54
59
58
71
2.3
46
26
34
13
NT
22
24
29
30
33
29
27
10
10
0
0
10
0
20
6
5
10
20
5
4
NT
66
78
80
83
54
NT
52
53
56
61
66
66
41
32
39
20
3
26
33
72
62
44
51
51
37
52
NT
100
113
117
115
114
NT
78
67
92
91
81
116
109
33
43
48
24
53
97
114
113
111
102
120
111
123
NT
NA
+++
+++
+++
++
NA
+
7a
7b
7c
7d
7e
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
9s
9t
9u
COCHdCHCH3
COOCH2C6H5
COCH2CH3
COCH2CH2CH3
COC6H5
COC6H5
COC6H5
COC6H5
COC6H4OCH3 (m)
COCHdC(CH3)2
COCH2Cl
+
+
COC3H5
+
COCHdCHCH3 COC6H5
COCHdCHCH3 COCH2Cl
COCHdCHCH3 COC3H5
+
++
++
+
COOCH2C6H5
COOCH2C6H5
COOCH2C6H5
COOCH2C6H5
COOCH2C6H5
COCH2CH3
COCH2CH3
COCH2CH3
COCH2CH3
COCH2CH3
COCH2CH3
COCH2CH3
COCH2CH3
COC6H5
COCHdC(CH3)2
COCH2Cl
COCH2CH3
COC3H5
COC6H5
COCH2Cl
COC3H5
COCH3
COCH2CH2CH2CH3
COCHdC(CH3)2
COCH2CH3
COCH2CH2CH3
+
-
-
+
-
+++
++
++
++
++
++
++
NA
COCH2CH2CH3 COCH2CH3
a
Activity relative to paclitaxel (PTX). +++ More active than PTX at all three doses. ++ More active than PTX at two doses. + More
active than PTX at one dose. - Less active than PTX. NT ) Not tested. NA ) Not applicable.
nate linkers was investigated. After some experimentation,
the PS-DES resin was selected as being the most suitable
for this purpose. The PS-DES resin is a 1% cross-linked
polystyrene-divinyl benzene resin functionalized with a
butyldiethylsilane linker, and it has the advantage of being
stable under normal conditions. Although hydrosilanes can
be reacted directly with alcohols,20,21 it was found to be
expedient to convert the resin to its chloro derivative 3 by
treatment with 1,3-dichloro-5,5-dimethylhydantoin.22,23
Treatment of the PS silyl chloride resin 3 with excess 10-
deacetylpaclitaxel (4)24 in CH2Cl2 in the presence of imi-
dazole provided resin-bound 10-deacetylpaclitaxel (5), with
a loading of 265 mg of 5 per gram of initial resin. Unreacted
10-deacetylpaclitaxel was recovered and was recycled after
purification.
cleaved from the resin using HF/pyridine in THF to give
the 10-acyl derivatives 7a -7e.
Acylation of the resin-bound intermediates 6a -6e at the
C-7 position was achieved by the well-established carbo-
diimide route26 using 1,3-diisopropylcarbodiimide (DIPC)
and acid. This gave derivatives 8a -8u , which were again
treated to remove excess reagents by washing the resin
with MeOH, EtOAc, DMF, and CH2Cl2. The 7,10-diacylpa-
clitaxel analogues 9a -9u were isolated from the resin after
the final cleavage with HF/pyridine in THF followed by
quenching the reaction mixture with methoxytrimethyl-
silane. The percentage yields of compounds 7a -7e and 9a -
9u are shown in Table 1.
The conversion of the resin-bound paclitaxel derivatives
to 7-acyl and 7,10-diacyl analogues of paclitaxel was
investigated next as a test of the chemistry involved. A
variety of acyl groups were thus selected, with the selection
based in part on those groups that have given improved
activity as single modifiers and in part on a desire to test
a wide range of acyl groups. The actual conversions were
accomplished by standard paclitaxel chemistry. The forma-
tion of 10-acyl derivatives was achieved using Holton’s
method.25 Thus, the derivatized resin 5 was treated with
excess of a carboxylic acid anhydride or an alkyl carbonate
in THF, using a catalytic amount of CeCl3, to give the 10-
acyl derivatives 6a -6e. Acylation at C-10 proceeded as
selectively on the resin as in solution, and after washing
to remove excess reagent and catalyst the product was
The purities of all final compounds were determined on
the basis of their H NMR spectra and TLC analysis. After
1
the final cleavage with HF/pyridine compounds 7a -7b and
9a -9g, 9i, 9j, 9n , and 9r were observed to be contaminated
1
with urea that had not been completely washed away; H
NMR analysis showed purities of less than 80%. These

1138 J ournal of Natural Products, 2002, Vol. 65, No. 8
J agtap et al.
Sch em e 1
compounds were thus purified by preparative TLC on silica
gel and had purities of 95% or higher (as judged by 1H NMR
and TLC) after purification. The analogues 7c, 7d , 9h , 9k ,
9l, 9m , 9o, 9p , 9q, 9s, and 9t were less contaminated; their
of the good activity of the 7-chloroacetylpaclitaxel analogue
9n . A variety of mono-, di-, and tribasic amines were
selected for reaction with this substrate, with the concept
that these could be converted into salts with increased
water solubility as compared with paclitaxel.
1
analyses by H NMR spectroscopy showed purities in the
range of 80-90%.
7-Chloroacetyl-10-deacetylpaclitaxel (10a ) was prepared
by reaction of 2′-(tert-butyldimethylsilyl)-10-deacetylpacli-
taxel28 with chloroacetic anhydride, followed by desilyla-
tion. Reaction of 10a with the appropriate amines gave the
analogues 10b-10j in good to excellent yields.
The tubulin-assembly activities of the 10-acyl analogues
7a -7d and the 7,10-diacyl paclitaxel analogues 9a -9t
were determined by a new method that has been adapted
to the measurement of activity on microtiter plates. In
brief, tubulin assembly was assessed by monitoring the
emission intensity of solutions containing tubulin (5 µM),
4′,6-diamidino-2-phenylindole (DAPI, 10 µM), and the drug
to be tested as a function of time. The extent of microtubule
assembly is directly proportional to the change in the
intensity of DAPI fluorescence under these assay condi-
tions.29 Concentrations over 2 orders of magnitude of
The initial method development was done on a medium
scale, using 450 mg of resin-bound paclitaxel for the initial
derivatization and 50-60 mg for subsequent reactions.
When the appropriate conditions had been developed, small
MikroKan reactors were used, which allowed the reactions
to be carried out using 30 mg of resin, corresponding to
about 6 mg of paclitaxel. A test run with these reactors
indicated that the syntheses could be carried out success-
fully on this scale.
A final set of analogues was prepared from 7-chloro-
acetyl-10-deacetylpaclitaxel. Preliminary studies with 7-chlo-
roacetyl-10-deacetylbaccatin III27 indicated that the chlo-
rine could readily be replaced with amines by a nucleophilic
displacement reaction, and the substrate 7-chloroacetyl-
10-deacetylpaclitaxel was then selected in part on the basis

Analogues of Paclitaxel
J ournal of Natural Products, 2002, Vol. 65, No. 8 1139
Ta ble 2. Biological Evaluation of 7-Acyl-10-deacetylpaclitaxel
Analogues
cytotoxicity to A2780
ovarian cancer cells
microtubule assembly
structure
(IC50, µg/mL)
I50 (µM)
10b
10c
10d
10e
10f
10g
10h
10i
10j
1
( 0.07 (5)
2.04 ( 0.94
1.02 ( 0.15
1.30 ( 0.32
0.59 ( 0.22
7.80 ( 2.33
N/A
0.85 ( 0.37
1.65 ( 0.75
4.34 ( 0.62
0.55 ( 0.1
0.18, 0.25
0.25, 0.2
0.67 ( 0.35 (3)
0.03, 0.02
0.86 ( 0.1 (3)
0.96
0.014, 0.11
0.9 ( 0.04 (3)
0.136 ( 0.08 (7)
in both a cytotoxicity assay and a tubulin-assembly assay.
The results of these assays are given in Table 2. All the
analogues were comparable to or less active than paclitaxel
in the tubulin polymerization assay, but compound 10i was
almost 10-fold more cytotoxic than paclitaxel, while com-
pound 10f was approximately 5-fold more cytotoxic. These
results indicate that 7-acylpaclitaxel analogues with basic
substituents have the potential to be more potent drugs
than paclitaxel and would have the benefit of combining
improved water solubility with improved activity.
Due to its promising cytotoxic activity, a comparison of
the water solubility of analogue 10i (as its hydrochloride
salt) and paclitaxel was made, using a water-butanol
partition method. The results indicated that the hydro-
chloride salt of 10i is approximately 9 times more soluble
in 0.1 N aqueous HCl than paclitaxel, again suggesting that
it is a promising lead compound.
In summary, the methodology has been developed for an
efficient resin-based combinatorial synthesis of 7-acyl- and
7,10-diacylpaclitaxel analogues and was applied to the
synthesis of 24 analogues. In addition, nine 7-acyl-10-
deacetylpaclitaxel analogues were prepared by conven-
tional chemistry. Methodology was also developed to
determine the tubulin-assembly activity of compounds
prepared in small quantities by a combinatorial approach,
and four analogues with improved tubulin-assembly activ-
ity as compared with paclitaxel and two analogues with
improved cytotoxicity have been discovered; one of these
also has improved water solubility as compared with
paclitaxel.
paclitaxel (control) and each drug candidate were tested.
The results of these assays are shown in Table 1. The
activities of the analogues were scored in comparison with
paclitaxel, with analogues showing a higher percent po-
lymerization than paclitaxel at a single dose being scored
as +, those with higher activity at two doses being scored
++, and the four analogues that were more active at all
three doses being scored +++. The most active analogues
were the three 10-acyl derivatives 7a , 7b, and 7c and the
7,10-diacyl derivative 9n . The derivatives 7a and 7b have
previously been prepared by conventional chemistry,30-32
and both derivatives were reported to have cytotoxicities
comparable to that of paclitaxel. Surprisingly, compound
7a was reported to have significantly poorer tubulin-
assembly activity than paclitaxel, but this different result
may be explained by the different way the assay was run.
The enhanced activity of the 7,10-diacyl compound 9n is
of interest because this is one of the few 7-acylpaclitaxels
to show enhanced bioactivity. Although the chloroacetyl
group is more labile than the acetyl group, the enhanced
activity is unlikely to be due to hydrolysis of 9n to 7c,
because acyl groups at the 7-position are relatively resis-
tant to hydrolysis.33
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. PS-DES resin was
purchased from Argonaut Technologies, Inc, CA. Other chemi-
cals were obtained from Aldrich Chemical Co. and were used
without further purification; the HF/pyridine used was ap-
proximately 70% HF, 30% pyridine. All anhydrous reactions
were performed under argon. THF was dried over sodium/
benzophenone. 1H NMR spectra were obtained in CDCl3 at 400
MHz and were assigned by comparison of chemical shifts and
coupling constants with those of related compounds. Some of
1
the H NMR spectra showed the presence of traces of EtOAc;
paclitaxel and its derivative retain EtOAc very tightly, and it
cannot be removed completely even on prolonged treatment
in vacuo at 38 °C. MicroKan reactors were purchased from
IRORI, Inc., CA. The Cytofluor 4000 was obtained from
PerSeptive Biosystems, Framingham, MA.
10-Dea cetyl-2′-(P S-DES)-p a clita xel (5). To PS-DES resin
(750 mg, 0.83 mmol/g, 0.62 mmol) under argon was added a
solution of 1,3-dichloro-5,5-dimethylhydantoin (365 mg, 1.86
mmol) in CH2Cl2 (6 mL), and the mixture was stirred at room
temperature for 2 h. The chlorinated resin (3) was washed with
CH2Cl2 (4 × 5 mL) using a cannula under an argon atmo-
sphere. A solution of 10-deacetylpaclitaxel24 (4, 485 mg, 0.59
In addition to the four analogues mentioned above, nine
additional analogues (7d , 9f, 9g, 9o-9t) were more potent
than paclitaxel at two concentrations. These compounds
have varying groups at the 7-position, but all had either
an ethanoyl or a 2-butenoyl group at the 10-position. It thus
appears that these groups are favorable to the activity of
7-acyl analogues, and further study of additional analogues
of this type is warranted.
The analogues 10b-10h were prepared in larger amounts
than those described earlier, and they were thus assayed

1140 J ournal of Natural Products, 2002, Vol. 65, No. 8
J agtap et al.
mmol) and imidazole (385 mg, 6.0 mmol) in CH2Cl2 (6 mL)
was immediately added to the washed resin, and the reaction
mixture was further stirred at room temperature. After 24 h
CH3OH (1 mL) was added, and the resin was washed with
CH2Cl2 (2 × 5 mL), water (5 mL), EtOAc (2 × 5 mL), and
finally CH2Cl2 (2 × 5 mL) and dried under vacuum for 12 h to
give resin 5 loaded with 10-deacetylpaclitaxel (950 mg). The
filtrate was transferred to a separatory funnel and washed
with H2O (10 mL) and brine (10 mL) and dried over Na2SO4.
The organic layer was filtered and concentrated, and the
residue obtained was purified by column chromatography on
silica gel using 60% EtOAc/hexane to give unreacted 10-
deacetylpaclitaxel (270 mg).
10-deacetylpaclitaxel, which was used directly in the next step.
To a stirred solution of a portion of 2′-O-(tert-butyldimethyl-
silyl)-7-chloroacetyl-10-deacetylpaclitaxel (0.204 g, 0.203 mmol)
in THF (12 mL) was added pyridine (3.2 mL) at 0 °C, the
mixture was stirred for 5 min, and HF-pyridine (3.2 mL) was
introduced. The reaction mixture was allowed to come to room
temperature and stirred overnight. The reaction mixture was
then diluted with EtOAc, washed with saturated aqueous
NaHCO3 solution, and worked up in the usual way. The crude
product was purified by preparative TLC (Si gel, 60% EtOAc/
hexane) to give 7-chloroacetyl-10-deacetylpaclitaxel (95%). 1H
NMR (CDCl3, 399.951 MHz): δ 8.1 (d, 2H), 7.30 (d, 2H), 7.61
(tt, 1H), 7.52-7.32 (m, 10H), 7.16 (d, J ) 8.8, 1H, NH), 6.17
(t, 1H, C-13), 5.76 (d, J ) 9.2, 1H, C-3′), 5.67 (d, J ) 6.8, 1H,
C-2), 5.49 (m, 1H, C-7), 5.26 (s, 1H, C-10), 4.92 (d, J ) 8.8,
1H, C-5), 4.77 (s, 1H, C-2′), 4.32 (d, J ) 8.8, 1H, C-20), 4.22
(d, J ) 8.8, 1H, C-20), 3.97 (m, 4H, CH2-Cl, C-3 and C-2′-
OH), 2.56 (m, 1H, C-6), 2.39 (s, 3H, C-4 Ac), 2.29 (m, 2H, C-6,
C-14), 1.96 (m, 1H, C-14), 1.92 (s, 1H, C-1-OH), 1.85 (s, 3H,
C-18 Me), 1.8 (s, 3H, C-19 Me), 1.17 (s, 3H, C-17 Me), 1.06 (s,
3H, C-16 Me). 13C NMR (CDCl3, 100.578 MHz): δ 210.6 (C-9),
172.5 (C-1′), 170.5 (C-7 CdO), 167.1 (C-4 Ac CdO), 166.8 (NH
CdO), 166.4 (C-2 Bz CdO), 138.6, 137.9, 135.6, 133.7, 133.6,
131.9, 130.1, 129.0, 128.9, 128.7, 128.6, 128.3, 127.0, 126.9,
83.4 (C-5), 80.5 (C-4), 78.6 (C-1), 76.5 (C-20), 74.5 (C-10), 74.5
(C-2), 73.7 (C-2′), 73.2 (C-13), 72.2 (C-7), 60.4 (C-6), 56.3 (C-
8), 55.0 (C-3′), 45.9 (C-3), 42.8 (C-17 Me), 40.5 (CH2Cl), 35.9
(C-14), 33.1 (C-6), 26.2 (C-15), 22.4 (C-4 Me), 20.5, 14.13 (C-
18), 14.1, 10.9 (C-19 Me).
10-Acyl-10-d ea cetyl-2′-(P S-DES)-p a clita xels 6a -6e a n d
7,10-Dia cyl-10-d ea cet yl-2′-(P S-DE S)-p a clit a xels 8a -8u .
To resin 5 (450 mg) under argon was added a solution of the
corresponding carboxylic acid anhydride or carbonate (10
equiv) in THF (6 mL), followed by addition of CeCl3 (2 mg).
The reaction mixture was stirred under argon at room tem-
perature for 24 h. The resin was washed and dried under
vacuum overnight to give resins 6a -6e. These resins (50-60
mg each) were subjected to coupling with the appropriate acid
(10 equiv), diisopropylcarbodiimide (DIPC,10 equiv), and pyr-
rolidinopyridine (PP, 2.0 mg) in toluene (2.0 mL) at room
temperature. After 24 h, MeOH (0.5 mL) was added, and the
resin was washed thoroughly and dried under vacuum to yield
the resin-bound 7,10-diacylpaclitaxel derivatives 8a -8u .
10-Acyl-10-d ea cetylp a clita xels 7a -7e a n d 7,10-Dia cyl-
10-d ea cetylp a clita xels 9a -9u . The resins 6a -6e and 8a -
8u were taken individually and suspended in dry THF (1.5
mL). HF/pyridine (0.5 mL) was added to each and the resulting
mixture stirred at room temperature. After 2 h, the mixture
was treated with MeOSiMe3 and stirred at room temperature
for a further 30 min. The reaction mixture was diluted with
EtOAc (5 mL), and the resin was washed with EtOAc (2 × 5
mL). The combined organic layers were washed thoroughly
with dilute NaHCO3, HCl (1.0 N), water, and finally brine,
dried over Na2SO4, filtered, and evaporated to afford the
desired 10-acyl-10-deacetylpaclitaxel derivatives 7a -9e and
the 7,10-diacyl-10-deacetylpaclitaxel derivatives 9a -9u (Table
1). Samples that were contaminated with impurities, as judged
Gen er a l P r oced u r e for th e Su bstitu tion of Ch lor in e
w ith Nu cleop h ilic Am in es. Syn th esis of th e P a clita xel
Der iva tives 10b-10j. To a stirred solution of 7-chloroacetyl-
10-deacetylpaclitaxel (10a , 0.033 mmol) in DMF (0.3 mL) at
room temperature was added the selected amine (0.099 mmol),
and the mixture was stirred for 3-4 h. The reaction mixture
was then diluted with EtOAc and worked up in the usual way.
The crude product was purified by preparative TLC (Si gel,
60-70% EtOAc/hexane), and the desired product was isolated
in 85-95% yield.
1
P a clita xel d er iva tive 10b: H NMR δ 8.11 (d, 2H), 7.75
(d, 2H), 7.61 (tt, 1H), 7.52-7.33 (m, 10H), 7.20 (s, 4H), 7.13
(d, J ) 8.8, 1H, NH), 6.18 (t, 1H, C-13), 5.78 (d, J ) 8.8, 1H,
C-3′), 5.67 (d, J ) 6.8, 1H, C-2), 5.49 (m, 1H, C-7), 5.35 (s, 1H,
C-10), 4.92 (d, J ) 8.8, 1H, C-5), 4.77 (s, 1H, C-2′), 4.34 (d, J
) 8.8, 1H, C-20), 4.22 (d, J ) 8.8, 1H, C-20), 4.15 (s, 4H), 4.05
(s, 1H), 3.97 (d, J ) 6.8, 1H, C-3), 3.67 (bs, 1H, C-2′-OH), 3.59
(s, 2H), 2.54 (m, 1H, C-6), 2.39 (s, 3H, C-4 Ac), 2.29 (m, 2H,
C-6, C-14), 1.95 (m, 1H, C-1-OH), 1.83 (s, 3H, C-18 Me), 1.81
(s, 3H, C-19 Me), 1.69 (s, 1H), 1.2 (s, 3H, C-17 Me), 1.07 (s,
3H, C-16 Me); 13C NMR (CDCl3, 100.578 MHz) δ 211.2 (C-9),
172.5 (C-1′), 170.4 (C-7 CdO), 166.9 (C-4 Ac CdO), 138.6,
137.9, 15.7, 133.8, 133.6, 131.9, 130.2, 129.1, 128.3, 127.2,
127.05, 127.00, 122.4, 85.5 (C-5), 80.6 (C-4), 78.7 (C-1), 74.5
(C-10), 73.2 (C-2), 72.3 (C-7), 58.6, 56.5, 55.3 (C-8), 55.0 (C-
3′), 46.0 (C-3), 42.9 (C-17 Me), 36.0 (C-14), 33.4 (C-6), 26.3 (C-
15), 22.5 (C-4 Me), 20.5, 14.2 (C-18 Me), 11.0 (C-19 Me);
HRFABMS m/z 971.4000 (calc for C55H59N2O14, MH+, 971.3966).
1
by TLC and H NMR spectroscopy, were purified by PTLC on
Si gel (500 µM, 40% EtOAc/hexane).
Syn th esis of 7e a n d 9u Usin g Micr or ea ctor Via ls. Resin
5 was distributed into two MicroKan vials (30 mg each) and
then immersed in dry THF (6 mL). A solution of butyric
anhydride (10 equiv) and CeCl3 (2 mg) was added, and the
reaction mixture was stirred under argon at room temperature
for 24 h. The vials were washed and dried under vacuum
overnight to give the resin-bound 10-butanoyl-10-deacetylpa-
clitaxel derivative 7e. One vial was placed in dry toluene (2
mL) and reacted with propionic acid (10 equiv), DIPC (10
equiv), and PP (2.0 mg). After 24 h, MeOH (0.5 mL) was added,
and the vial was washed thoroughly and dried under vacuum
to yield the resin-bound 10-butanoyl-10-deacetyl-7-propanoylpa-
clitaxel derivative 9u . The two microreactor vials containing
resins 7e and 9u were placed in separate 5 mL Teflon vials
and then immersed in dry THF (1.5 mL) and treated with HF-
pyridine (0.5 mL). The reaction mixtures were stirred at room
temperature for 2 h. After 2 h, they were treated with
MeOSiMe3 and stirred at room temperature for 30 min. The
reaction mixtures were diluted with EtOAc (5 mL), and the
resin was washed with EtOAc (2 × 5 mL). The combined
organic layers were washed thoroughly with dilute NaHCO3,
HCl (1.0 N), H2O, and finally brine, dried over Na2SO4, and
evaporated to afford the paclitaxel derivatives 10-butanoyl-
10-deacetylpaclitaxel (7e, 69%) and 10-butanoyl-10-deacetyl-
7-propanoylpaclitaxel derivative (9u , 71%), each in a purity
of 90% or better as judged by TLC.
1
P a clita xel d er iva tive 10c: H NMR δ 8.11 (d, 2H), 7.75
(d, 2H), 7.60 (tt, 1H), 7.52-7.33 (m, 10H), 7.07 (d, J ) 8.8,
1H, NH), 6.18 (t, 1H, C-13), 5.79 (d, J ) 8.8, 1H, C-3′), 5.66
(d, J ) 6.8, 1H, C-2), 5.53 (m, 1H, C-7), 5.30 (s, 1H, C-10),
4.90 (d, J ) 8.8, 1H, C-5), 4.77 (s, 1H, C-2′), 4.32 (d, J ) 8.4,
1H, C-20), 4.21 (d, J ) 8.4, 1H, C-20), 3.96 (d, J ) 6.8, 1H,
C-3), 3.69 (bs, 1H, C-2′-OH), 3.1 (s, 2H), 2.52 (m, 2H), 2.45 (m,
2H), 2.39 (s, 3H), 2.29 (m, 2H), 1.94 (m, 2H), 1.84 (s, 3H, C-18
Me), 1.80 (s, 3H, C-19 Me), 1.62-1.54 (m, 8), 1.25 (s, 3H, C-17
Me), 1.19 (s, 3H, C-16 Me).
1
P a clita xel d er iva tive 10d : H NMR δ 8.11 (d, 2H), 7.75
(d, 2H), 7.60 (tt, 1H), 7.52-7.33 (m, 10H), 7.09 (d, J ) 9.2,
1H, NH), 6.18 (t, 1H, C-13), 5.79 (d, J ) 8.8, 1H, C-3′), 5.66
(d, J ) 6.8, 1H, C-2), 5.53 (m, 1H, C-7), 5.30 (s, 1H, C-10),
4.90 (d, J ) 8.8, 1H, C-5), 4.77 (s, 1H, C-2′), 4.32 (d, J ) 8.4,
1H, C-20), 4.21 (d, J ) 8.4, 1H, C-20), 3.98 (s, 1H), 3.96 (s,
1H), 3.73 (t, 4H), 3.58 (bs, 1H), 3.13 (s, 2H), 2.53 (m, 5H), 2.39
(s, 3H, C-4-Ac), 2.29 (m, 2H, C-6, C-14), 1.94 (m, 1H, C-1-OH),
7-Ch lor oa cetyl-10-d ea cetylp a clita xel (10a ). To a stirred
solution of 2′-O-(tert-butyldimethylsilyl)-10-deacetylpaclitaxel28
(0.725 mg, 0.78 mmol) in THF at room temperature was added
chloroacetic anhydride (1.34 g, 7.8 mmol), the mixture was
stirred for 2 h, and the product was worked up by standard
methods to give 2′-O-(tert-butyldimethylsilyl)-7-chloroacetyl-

Analogues of Paclitaxel
J ournal of Natural Products, 2002, Vol. 65, No. 8 1141
1.84 (s, 3H, C-18 Me), 1.81 (s, 3H, C-19 Me), 1.73 (s, 1H), 1.18
(s, 3H, C-17 Me), 1.07 (s, 3H, C-16 Me); 13C NMR (CDCl3,
100.578 MHz) δ 211.0 (C-9), 172.5 (C-1′), 170.4 (C-7 CdO),
169.0, 167.0 (C-4-Ac CdO), 166.9 (NH CdO), 138.6, 137.9,
135.7, 133.8, 133.6, 131.9, 130.2, 129.1, 129.0, 128.3, 127.0,
83.6 (C-5), 80.6 (C-4), 78.7 (C-1), 76.6, 74.6 (C-10), 74.5, 73.2
(C-2), 72.3 (C-7), 72.0, 66.7, 59.2, 56.5, 54.9 (C-3′), 53.0, 46.0
(C-3), 42.9 (C-17 Me), 35.9 (C-14), 33.5 (C-6), 26.3 (C-15), 22.5
(C-4 Me), 20.4, 14.2 (C-18 Me), 10.9 (C-19 Me); HRFABMS m/z
939.3914 (calc for C51H59N2O15, MH+, 939.3915).
P a clita xel d er iva tive 10i: 1H NMR δ 8.18 (d, 1H), 8.11
(d, 2H), 7.74 (d, 2H), 7.61 (tt, 1H), 7.52-7.34 (m, 13H), 7.1 (d,
J ) 8.8, 1H, NH), 6.6 (m, 2H), 6.18 (t, 1H, C-13), 5.78 (d, J )
6.8, 1H, C-3′), 5.66 (s, 1H, C-2), 5.5 (m, 1H, C-7), 5.29 (s, 1H,
C-10), 4.91 (d, J ) 8.4, 1H, C-5), 4.77 (s, 1H, C-2′), 4.32 (d, J
) 8.8, 1H, C-20), 4.21 (d, J ) 8.8, 1H, C-20), 3.99 (bs, 1H),
3.97 (bs, 1H), 3.59 (m, 5H), 3.19 (s, 2H), 2.64 (t, 5H), 2.53 (m,
1H), 2.39 (s, 3H, C-4 Ac), 2.32 (m, 2H, C-6, C-14), 1.94 (m, 1H,
C-14), 1.84 (s, 3H, C-18 Me), 1.81 (s, 3H, C-19 Me), 1.69 (s,
2H), 1.19 (s, 3H, C-17 Me), 1.07 (s, 3H, C-16 Me); 13C NMR
(CDCl3, 100.578 MHz) δ 211.0 (C-9), 172.5 (C-1′), 170.4 (C-7
CdO), 169.1, 166.9 (C-4 Ac), 159.4, 147.9, 138.6, 137.9, 137.5,
135.7, 133.8, 131.9, 130.2, 129.0, 128.7, 127.0, 127.0, 113.4,
107.1, 83.6 (C-5), 80.6 (C-4), 78.7 (C-1), 74.6 (C-10), 74.5 (C-
2), 73.2, 72.3 (C-7), 72.0, 59.0, 56.4 (C-8), 54.9 (C-3′), 52.5, 46.1
(C-3), 45.0, 42.9 (C-17 Me), 35.9 (C-14 Me), 33.5 (C-6), 26.3
(C-15), 22.5 (C-4 Me), 20.4, 14.2 (C-18 Me), 10.9 (C-19 Me);
P a clita xel d er iva tive 10e: 1H NMR δ 8.12 (d, 2H), 7.77
(d, 2H), 7.61 (tt, 1H), 7.53-7.26 (m, 10H), 7.15 (bs, 1H), 6.18
(t, 1H, C-13), 5.79 (d, J ) 8.8, 1H, C-3′), 5.66 (d, J ) 6.8, 1H,
C-2), 5.53 (m, 1H, C-7), 5.30 (s, 1H, C-10), 4.90 (d, J ) 8.8,
1H, C-5), 4.77 (s, 1H, C-2′), 4.32 (d, J ) 8.4, 1H, C-20), 4.21
(d, J ) 8.4, 1H, C-20), 3.96 (d, J ) 6.8, 1H, C-3), 3.69 (bs, 1H,
C-2′-OH), 3.42 (d, 2H), 3.25 (bs, 1H), 3.00 (bs, 5H), 2.76 (s,
2H), 2.58 (m, 2H), 2.4 (s, 3H, C-4-Ac), 2.28 (m, 2H, C-6, C-14),
2.03 (m, 2H), 1.83 (s, 3H, C-18 Me), 1.81 (s, 3H, C-19 Me),
1.62 (s, 1H), 1.21 (s, 3H, C-17 Me), 1.16 (s, 3H), 1.06 (s, 3H,
C-16 Me); 13C NMR (CDCl3, 100.578 MHz) δ 210.9 (C-9), 172.5
(C-1′), 170.3 (C-7 CdO), 169.1, 167.1 (C-4 Ac), 166.8 (NH
CdO), 138.5, 138.0, 135.7, 133.7, 131.9, 130.1, 129.1, 128.9,
128.7, 128.6, 128.2, 127.0, 126.9, 83.6 (C-5), 80.6 (C-4), 78.5
(C-1), 76.5, 74.6 (C-10), 74.4, 73.1 (C-2), 72.2 (C-7), 72.0, 58.7,
56.4, 55.0, 54.5, 55.3, 46.0, 45.7, 42.9 (C-17 Me), 35.2 (C-14),
33.4 (C-6), 26.3 (C-15), 22.4 (C-4 Me), 20.5, 14.1 (C-18 Me),
HRFABMS m/z 1015.4310 (calc for
1015.4341).
C56H63N4O14,
MH+,
P a clita xel d er iva tive 10j: 1H NMR δ 8.11 (d, 2H), 7.85
(d, 2H), 7.74 (d, 2H), 7.62 (t, 1H), 7.53-7.34 (m, 12H), 7.05 (d,
J ) 8.8, 1H, NH), 6.86 (d, J ) 8.8, 2H), 6.19 (t, 1H, C-13),
5.79 (d, J ) 8.8, 1H, C-3′), 5.66 (d, J ) 6.8, 1H, C-2), 5.53 (m,
1H, C-7), 5.31 (s, 1H, C-10), 4.92 (d, J ) 8.8, 1H, C-5), 4.77 (s,
1H, C-2′), 4.32 (d, J ) 8.4, 1H, C-20), 4.21 (d, J ) 8.4, 1H,
C-20), 3.96 (d, 1H, C-3), 3.95 (s, 1H, C-2′-OH), 3.5 (d, 1H), 3.39
(t, 4H), 3.21 (s, 2H), 2.69 (t, 4H), 2.55 (m, 2H), 2.52 (s, 3H),
2.4 (s, 3H, C-4 Ac), 2.3 (s, 2H, C-6, C-14), 1.95 (m, 1H, C-14),
1.85 (s, 3H, C-18 Me), 1.82 (s, 3H, C-19 Me), 1.2 (s, 3H, C-17
Me), 1.09 (s, 3H, C-16 Me); 13C NMR (CDCl3, 100.578 MHz) δ
211.1 (C-9), 195.7, 175.3, 172.5 (C-13), 170.4 (C-7 CdO), 166.9
(NH CdO), 154.1, 138.7, 135.7, 133.8, 131.9, 130.4, 129.2,
128.8, 128.7, 127.0, 131.9, 130.4, 130.2, 129.2, 128.7, 127.0,
113.5, 83.6 (C-5), 80.6 (C-4), 78.7 (C-1), 74.6 (C-10), 73.2 (C-
13), 72.3, 72.1 (C-7), 58.8, 56.5 (C-8), 54.9 (C-3′), 52.2, 47.23,
42.9 (C-17 Me), 33.5 (C-14), 26.3 (C-15), 26.1, 22.5 (C-4 Me),
20.4, 14.2 (C-18 Me), 10.9 (C-19 Me); HRFABMS m/z 1056.4519
(calc for C59H66N3O15, MH+, 1056.4494).
Micr otiter -Ba sed Tu bu lin P olym er iza tion Bioa ssa y.
Microtubule assembly assays were carried out in 96-well plates
and read by a fluorescence plate reader. Samples were
prepared as follows: PMEG buffer, consisting of 100 mM
PIPES, 1 mM MgSO4, 2 mM EGTA, 0.1 mM GTP, at pH 6.9,
and also containing the ligand to be tested, was pipetted into
each well in the plate. DAPI (4′,6-diamidino-2-phenylindole)
was added to yield a final concentration of 10 µM. Tubulin in
PMEG buffer was added using a multichannel pipettor to a
final concentration of 5 µM. The solutions in the wells were
mixed using the pipettor, and care was taken to avoid
introduction of bubbles into the well. Each sample was
prepared in duplicate, triplicate, or quadruplicate, depending
on sample size. Polymerization was monitored using a Cyto-
Fluor 4000; the excitation filter was set at 360/40 nm and the
emission filter at 460/40 nm. The temperature of the instru-
ment was set at 37 °C. The change in fluorescence of each
solution was determined and was normalized with respect to
the polymerization curve for the standard, 10 µM paclitaxel.
All polymerizations were run in triplicate or quadruplicate.
10.9 (C-19 Me); HRFABMS m/z 952.4241 (calc for C52H62N3O14
,
MH+, 952.4232).
P a clita xel d er iva tive 10f: 1H NMR δ 8.11 (d, 2H), 7.74
(d, 2H), 7.60 (tt, 1H), 7.52-7.34 (m, 12H), 7.08 (d, J ) 8.8,
1H, NH), 6.85 (s, 1H), 6.73 (s, 2H), 6.17 (t, 1H, C-13), 5.9 (s,
2H), 5.78 (d, J ) 6.8, 1H, C-3′), 5.66 (s, 1H, C-2), 5.5 (m, 1H,
C-7), 5.27 (s, 1H, C-10), 4.91 (d, J ) 8.4, 1H, C-5), 4.77 (s, 1H,
C-2′), 4.32 (d, J ) 8.8, 1H, C-20), 4.21 (d, J ) 8.8, 1H, C-20),
4.02 (s, 1H), 3.96 (d, J ) 7.2, 1H, C-3), 3.52 (d, J ) 4.4, 1H),
3.41 (s, 2H), 3.13 (s, 2H), 2.61-2.49 (m, 11H), 2.39 (s, 3H, C-4
Ac), 2.29 (m, 2H), 1.94 (m, 1H), 1.84 (s, 3H, C-18 Me), 1.79 (s,
3H, C-19 Me), 1.66 (s, 3H), 1.18 (s, 3H, C-17 Me), 1.07 (s, 3H,
C-16 Me); 13C NMR (CDCl3, 100.578 MHz) δ 210.9 (C-9), 172.4
(C-13), 170.4 (C-7 CdO), 169.2, 166.9 (C-4 Ac), 147.6, 146.6,
138.5, 137.9, 135.7, 133.7, 131.9, 130.2, 129.0, 128.7, 128.7,
128.3, 127.0, 122.2, 109.5, 107.8, 100.8, 83.6 (C-5), 80.7 (C-4),
79.5, 78.7 (C-1), 74.6 (C-10), 74.5, 73.2 (C-2), 72.3 (C-7), 72.1,
69.8, 62.6, 59.0, 56.4, 54.9, 52.7, 52.6, 46.1, 42.9, 38.5, 35.9
(C-14), 34.4, 33.5 (C-6), 26.3 (C-15), 22.5 (C-4 Me), 21.7, 20.4,
19.2, 17.8, 14.2 (C-18 Me), 10.9 (C-19 Me); HRFABMS m/z
1072.4497 (calc for C59H66N3O16, MH+, 1072.4443).
1
P a clita xel d er iva tive 10g: H NMR δ 8.11 (d, 2H), 7.75
(d, 2H), 7.60 (tt, 1H), 7.52-7.33 (m, 10H), 7.11 (d, J ) 8.8,
1H, NH), 6.18 (t, 1H, C-13), 5.79 (d, J ) 8.8, 1H, C-3′), 5.66
(d, J ) 6.8, 1H, C-2), 5.53 (m, 1H, C-7), 5.30 (s, 1H, C-10),
4.90 (d, J ) 8.8, 1H, C-5), 4.77 (s, 1H, C-2′), 4.32 (d, J ) 8.4,
1H, C-20), 4.21 (d, J ) 8.4, 1H, C-20), 3.96 (d, J ) 6.8, 1H,
C-3), 3.1 (d, 2H), 2.6 (m, 5H), 2.4 (s, 3H, C-4 Ac), 2.29 (m, 2H,
C-6, C-14), 1.93 (m, 1H, C-14), 1.84 (s, 3H, C-18 Me), 1.82 (s,
3H, C-19 Me), 1.67 (s, 1H), 1.2 (s, 3H, C-17 Me), 1.07 (s, 3H,
C-16 Me); 13C NMR (CDCl3, 100.578 MHz) δ 205.9 (C-9), 172.5
(C-1′), 170.4 (C-7 CdO), 169.1, 167.1 (C-4 Ac), 138.5, 135.7,
133.7, 131.9, 130.2, 129.0, 128.8, 128.7, 128.3, 127.0, 83.6 (C-
5), 80.7 (C-4), 78.8 (C-1), 74.6 (C-10), 73.2 (C-2′), 72.3 (C-7),
72.0, 58.9 (C-8), 56.4 (C-8), 54.9 (C-9), 52.3, 46.1 (C-3), 42.9
(C-17 Me), 33.4, 26.3 (C-15), 22.5 (C-4 Me), 20.5, 14.2 (C-18
Me), 10.9 (C-19 Me).
Sta n d a r d Tu bu lin P olym er iza tion Bioa ssa y. The stan-
dard tubulin polymerization bioassay was performed as previ-
ously described.34
Deter m in a tion of th e Octa n ol-Wa ter P a r tition of
P a clita xel a n d 10i. Paclitaxel and analogue 10i were each
partitioned between 1-octanol and 0.1 N aqueous HCl solution
with vigorous shaking for 1 h. After the layers were separated
the UV absorbance of each layer of paclitaxel and 10i was
determined at 229 nm. For paclitaxel, the absorbance ratio of
the aqueous layer to the 1-octanol layer was 0.017, and for
compound 10i it was 0.155.
1
P a clita xel d er iva tive 10h : H NMR δ 8.11 (d, 2H), 7.75
(d, 2H), 7.61 (tt, 1H), 7.52-7.34 (m, 10H), 7.08 (d, J ) 8.8,
1H, NH), 6.18 (t, 1H, C-13), 5.78 (d, J ) 6.8, 1H, C-3′), 5.66 (s,
1H, C-2), 5.5 (m, 1H, C-7), 5.29 (s, 1H, C-10), 4.91 (d, J ) 8.4,
1H, C-5), 4.77 (s, 1H, C-2′), 4.32 (d, J ) 8.8, 1H, C-20), 4.21
(d, J ) 8.8, 1H, C-20), 4.01 (bs, 1H, C-2′-OH), 3.96 (d, J ) 7.2,
1H, C-3), 3.15 (s, 2H), 2.84 (t, 2H), 2.55 (m, 5H), 2.39 (s, 3H,
C-4 Ac), 2.31-2.19 (m, 5H), 1.96 (m, 2H), 1.84 (s, 3H, C-18
Me), 1.81 (s, 3H, C-19 Me), 1.77 (m, 5H), 1.19 (s, 3H, C-17
Me), 1.08 (s, 3H, C-16 Me); HRFABMS m/z 1006.4735 (calc
for C56H68N3O14 MH+, 1006.4701).
Ack n ow led gm en t. This work was supported by a research
grant from the National Institutes of Health (CA-69571), and
this support is gratefully acknowledged.

1142 J ournal of Natural Products, 2002, Vol. 65, No. 8
J agtap et al.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectral data for
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