Design, Synthesis, and Bioactivities of Steroid-Linked Taxol Analogues as Potential Targeted Drugs for Prostate and Breast Cancer

Article abstract of DOI:10.1021/np030296x

The female steroid hormone 3,17β-estradiol (2) was selected as an agent to target taxol (1) to estrogen receptor (ER) positive breast cancer cells. Estradiol-taxol conjugates (ETC) were synthesized through linkages from the 11- or 16-position of estradiol

Full text of DOI:10.1021/np030296x

152
J . Nat. Prod. 2004, 67, 152-159
Design , Syn th esis, a n d Bioa ctivities of Ster oid -Lin k ed Ta xol An a logu es a s
P oten tia l Ta r geted Dr u gs for P r osta te a n d Br ea st Ca n cer
Changhui Liu,† J eannine S. Strobl,‡ Susan Bane,§ J ennifer K. Schilling,† Meredith McCracken,‡
Sabarni K. Chatterjee,§ Rayhana Rahim-Bata,‡ and David G. I. Kingston*,†
Department of Chemistry, M/ C 0212, Virginia Polytechnic Institute & State University, Blacksburg, Virginia 24061,
Department of Biochemistry & Molecular Pharmacology, West Virginia University, Morgantown, West Virginia 26506, and
Department of Chemistry, State University of New York, Binghamton, New York 13902
Received J une 26, 2003
The female steroid hormone 3,17â-estradiol (2) was selected as an agent to target taxol (1) to estrogen
receptor (ER) positive breast cancer cells. Estradiol-taxol conjugates (ETC) were synthesized through
linkages from the 11- or 16-position of estradiol to the 2′-, 7-, or 10-position of taxol. All conjugates were
cytotoxic to the A2870 ovarian cancer cell line, although less so than taxol. The MCF-7 breast cancer cell
line (ER-R positive) and MDA-MB-231 breast cancer cell line (ER-R negative) were also used to evaluate
the selectivity and cytotoxicity of these conjugates. One conjugate showed some selectivity for ER positive
cells, but it was less potent than taxol. Two ETC hemisuccinates were also prepared to improve the
solubility of the conjugates. The corresponding Na and triethanolammonium salts were slightly more
cytotoxic than the acid form but were much less cytotoxic than the corresponding ETC.
Taxol1 (1) was first isolated from the bark of the Pacific
yew about 35 years ago by Drs. Wall and Wani.2 Although
its development as an anticancer agent was delayed by
numerous reasons, including its scarcity and insolubility,3
the discovery of its tubulin-assembly activity4 and other
factors motivated oncologists to overcome these problems.
It has since become one of the most important current
drugs for the treatment of several cancers, including breast
hormone conjugates. The female hormone estradiol (2)
and ovarian cancers;5 its importance in the treatment of
plays an important role in breast cancer, and the hormone
breast cancer has been reviewed,6 as has its chemistry.7
dependence of breast cancer was first reported by Beatson
Like almost all anticancer drugs taxol does have some
in the late 1800s.11 Further studies revealed the interaction
toxic side effects, such as bone marrow suppression and
between steroid hormones and their receptors12 and, thus,
neutropenia,8 and many tumors also show significant
led to a better understanding of the hormone in controlling
resistance to therapy with taxol.9 One approach to improv-
the growth of breast cancer.13 The hormone dependence of
ing its selectivity and efficacy is by targeting it to selected
breast cancer can also be used as a drug delivery target
tumors through the use of various conjugates, and several
through the recognition and binding of estrogen to its
taxol conjugates have been synthesized recently with
receptor, and several studies have investigated the target-
improved selectivity and solubility.10 Thus Safavy reported
ing of drug molecules into breast cancer cells by linking
a water-soluble and tumor-recognizing conjugate of taxol
them to estradiol or other estrogens.14 The potential
and BBN[7-13], which retained binding ability to the BBN/
benefits of this approach include the improvement of a
GRP receptor compared to the free BBN[7-13] molecule.10a
drug’s therapeutic effectiveness and bioavailability, coupled
Huang used the binding ability of somatostatin (SST) to
with a reduction in multidrug resistance (MDR) and toxic
its receptors (SSTRs) to specifically target taxol to tumor
side-effects.
cells.10b A report from Luo revealed that a conjugate of
The goal of the present research was to target taxol to
hyaluronic acid and taxol was selectively toxic toward the
estrogen receptor (ER) positive breast cancer cells through
human cancer cell lines that are known to overexpress HA
receptors.10c Fuchs and co-workers have reported the
preparation and evaluation of taxol-folic acid conjugates.10d
Finally, Ojima has reported a C-10 methyldisulfanylpro-
panoyl taxoid conjugated to monoclonal antibodies; these
conjugates were shown to possess selective in vivo anti-
tumor activity against EGFR-expressing A431 tumor xeno-
grafts.10e
the interaction between estradiol and its corresponding
receptor, with the goal of developing new drug candidates
against breast cancer, responsible for the second largest
number of cancer deaths in women.15 From previous
studies of the structure-activity relationships (SAR) of
estradiol, it is known that estradiol can be modified at the
16- and 11-positions without losing its ability to bind to
the ER.14 As for taxol, SAR studies have shown that the
10- and 7-positions can be acylated with only relatively
minor effects on the drug’s activity.7a,16 Another position
that can be used for targeting is the 2′-position, because
ester linkages at this position can be hydrolyzed in vivo,17
and hence an estradiol-taxol conjugate at the 2′-position
could serve as a “targeted pro-drug” if the targeting
occurred before hydrolysis. In this paper, we describe the
synthesis and biological evaluation of estradiol-taxol
One approach that has not yet been explored is that of
targeting taxol to breast cancer by means of selected steroid
Dedicated to the late Dr. Monroe E. Wall and to Dr. Mansukh C. Wani
of Research Triangle Institute for their pioneering work on bioactive natural
products.
* To whom correspondence should be addressed. Tel: (540) 231-6570.
Fax: (540) 231-3255. E-mail: dkingston@vt.edu.
† Virginia Polytechnic Institute & State University.
‡ West Virginia University.
§
State University of New York, Binghamton.
10.1021/np030296x CCC: $27.50
© 2004 American Chemical Society and American Society of Pharmacognosy
Published on Web 11/21/2003

Steroid-Linked Taxol Analogues
J ournal of Natural Products, 2004, Vol. 67, No. 2 153
Sch em e 1a
to SAR studies, the most reactive hydroxyl group in taxol
is the 2′-OH, followed by the 7- and 10-OH groups; the
1-OH group is inert to ester formation under normal
conditions.19 Direct acylation of taxol with compounds 5
and 7 thus yielded the 2′-acyl derivatives 8 and 10 (Scheme
2), respectively. Protection of the 2′-hydroxyl group as its
tert-butyldimethylsilyl ether 12, followed by acylation with
compounds 5 and 7, gave the 7-acyl analogues 13 and 15.
In general, conjugate formation occurred in low yield, with
conversion percentages of 25-35%, and with significant
amounts of unreacted taxol; the yields based on unrecov-
ered taxol were in the range 60-70%. Deprotection of the
silyl groups with HF-pyridine proceeded in good yields to
give the estradiol-taxol complexes 9, 11, 14, and 15.
The synthesis of estradiol-taxol conjugates at the 10-
position was achieved by converting 2′-(tert-butyldimeth-
ylsilyl)taxol (12) to 2′-(tert-butyldimethylsilyl)-10-deacetyl-
taxol (17) and hence to 2′-(tert-butyldimethylsilyl)-10-
deacetyl-7-(triethylsilyl)taxol (19) through a known pro-
cedure.20 During the deacetylation of 12 using hydrazine
monohydrate in ethanol, a byproduct of 30% of 2′-(tert-
butyldimethylsilyl)-7-epi-taxol (18) was observed (Scheme
3). Unfortunately, compound 19 did not undergo ester
formation using standard EDC/DMAP conditions. One
possibility is that the 10-position was too sterically hin-
dered to accept the relatively short linkage to estradiol
because the bulky 7-TES group might somehow block this
position. To test this hypothesis, 2′-(tert-butyldimethyl-
silyl)-7-epi-taxol was used as a substrate, since this not only
lacked the bulky 7-TES group but also had an unreactive
7-epi-hydroxyl group.21 Compound 18 reacted with estradiol
7 smoothly under EDC/DMAP conditions in CH2Cl2 to give
product 20 in 79% yield. Deprotection of 20 by HF-
pyridine gave 21 in good yield. Coupling of linker 5 with
18 was also attempted under the same conditions, but two
a
Reagents and conditions: (a) LiOH, THF/H2O, RT, 36 h, 72%; (b)
LHMDS, THF, then succinic anhydride, RT, overnight, 70%.
conjugates through ester linkers from the 11- and 16-
positions of estradiol to the 2′-, 7-, and 10-positions of taxol.
Resu lts a n d Discu ssion
Syn th esis. The synthesis of estradiol linkers 5 and 7 is
outlined in Scheme 1. The commercially available estrone
(3) was converted to compounds 414d and 618 through
reported procedures. Compound 4 was hydrolyzed to
generate compound 5 with a free carboxyl group for
coupling. The linker 7 was obtained by reacting 6 with
succinic anhydride. The use of pyridine as solvent only gave
a 30% yield, but deprotonation of 6 with LHMDS in THF
followed by addition of succinic anhydride gave 7 in 70%
yield based on unrecovered starting materials.
With the two estradiol linkers 5 and 7 in hand, the
estradiol-taxol conjugates could be assembled. According
Sch em e 2a
a
Reagents and conditions: (a) 5, EDC/DMAP, toluene, 60 °C, 24 h, 73%; (b) HF-pyridine, THF, RT, overnight, 97%; (c) 7, EDC/DMAP, toluene, 60 °C,
24 h, 78%; (d) HF-pyridine, THF, RT, overnight, 92%; (e) TBSCl, imidazole, DMF, 65 °C, 3 h, 95%; (f) 5, EDC/DMAP, toluene, 60 °C, 48 h, 65%; (g) HF-
pyridine, THF, RT, overnight, 82%; (h) 7, EDC/DMAP, toluene, 60 °C, 48 h, 65%; (i) HF-pyridine, THF, RT, overnight, 91%.

154 J ournal of Natural Products, 2004, Vol. 67, No. 2
Liu et al.
Sch em e 3a
monobenzyl succinate using EDC/DMAP conditions to
protect the 2′-position. This was followed by introduction
of the estradiol linker 7 at the 7-position using the
conditions described previously. The desired compound 25
was obtained after desilylation and hydrogenolysis; its
sodium and triethanolamine salts (26 and 27) were also
prepared. The 7-hemisuccinate 30 was obtained using the
reverse order of steps, with initial acylation of taxol with
estradiol 7 followed by acylation with monobenzyl succinate
at C-7 and deprotection; its sodium and triethanolamine
salts (31 and 32) were also prepared by a previously
reported procedure.19a
Biologica l Resu lts. The biological activities of taxol and
of the estrogen conjugates 9, 11, 14, 16, and 21 were
compared in a tubulin-assembly assay, for cytotoxicity to
estrogen receptor (ER) negative A2780 ovarian cancer cells,
ER (beta) positive PC-3 prostate cancer cells, and two lines
of human breast tumor cells (Table 1). The taxol IC50 value
estimated by nonlinear regression analysis was similar in
the ER-R positive MCF-7 and ER-R negative MDA-231
lines, 4.9 and 4.5 nM, respectively, and both these values
were lower by over an order of magnitude than the IC50
value in the PC-3 prostate cancer cell line. The 2′-
substituted taxol conjugates 9 and 11 were both about as
active as taxol in the PC-3 cell line, but were less active
than taxol in the breast cancer lines. They were also less
active than taxol in the tubulin-assembly assay. These
results are explicable by postulating that the 2′-derivatives
undergo slow conversion to taxol under the conditions of
the cell culture, with the conversion being more rapid in
the PC-3 assay than in the two breast cancer cell lines;
the lower activity of both compounds in the tubulin-
assembly assay is consistent with this hypothesis. Similar
results were obtained for the activity of 2′-acetyltaxol.22
Neither compound 9 nor 11 showed any significant selec-
tivity for the ER-R positive cell line MCF-7 as compared
with the ER-R negative line MDA-MB-231; this result is
also consistent with hydrolysis under cell culture condi-
tions. Interestingly, the MDA-MB-231 breast tumor cell
line which expresses ER-â receptors was more sensitive to
compounds 9 and 11 than the ER-R positive MCF-7 breast
tumor line. In addition, the steroid conjugate 11 may show
improved activity compared with taxol against the PC-3
line. Recently, clinical samples of prostate cancer as well
as certain prostate cell lines (PC-3) have been found to
express ER-â receptors, and expression is correlated with
tumor aggressiveness on the Gleason scale.23 These data
raise the possibility that these derivatives target the beta
form of the estrogen receptor.
a
Reagents and conditions: (a) hydrazine monohydrate, EtOH, RT, 1.5
h; (b) TESCl, imidazole, DMF, RT, 10 min, 89%; (c) 7, EDC/DMAP, CH2Cl2,
RT, 24 h, 79%; (d) HF-pyridine, THF, RT, overnight, 90%; (e) 5, EDC/
DMAP, toluene or CH2Cl2, RT, 24 h; (f) 5, EDC/DMAP, toluene, or CH2Cl2,
RT, 72 h; (g) 7, EDC/DMAP, toluene, or CH2Cl2, RT, 72 h.
inseparable products were obtained as determined by NMR
spectroscopy.
It is well known that taxol has very low solubility in
water, and the estradiol-taxol conjugates would be ex-
pected to be even less soluble, since estradiol is hydropho-
bic. We thus synthesized two estradiol-taxol conjugates
with improved water solubility. It is been reported that a
hemisuccinate at the 2′-position of taxol can improve the
drug’s solubility when the free carboxyl group was neutral-
ized as its sodium or (triethanol)ammonium salts.19a Scheme
4 shows the synthesis of two estradiol-taxol conjugates
with either a 2′-hemisuccinate or a 7-hemisuccinate ester
group. Compound 22 was prepared by reaction of taxol with
Ta ble 1. Cytotoxicity and Tubulin-Assembly Activity of Steroid-Linked Taxol Derivatives
% assembly,
% assembly,
A2780
IC50 (nM)
PC-3
IC50 (nM)
MDA-MB-231
IC50 (nM)
MCF-7
IC50 (nM)
compound
0.2 µMa
1.0 µMa
taxol (1)
9
11
14
16
21
25
26
27
100
45
60
100
55
60
25
180
680
8300
2900
77 ( 3
73 ( 12
40 ( 10
120 ( 20
320 ( 80
68 ( 7
NT
NT
NT
NT
NT
4.5 ( 1.2
22 ( 4.5
51 ( 4.6
2200 ( 800
780 ( 100
304 ( 12b
NT
NT
NT
NT
NT
4.9 ( 1.8
39 ( 0.6
62 ( 12
1600 ( 90
557 ( 117
103 ( 3.4b
NT
NT
NT
NT
NT
100
100
100
NT
NT
NT
NT
NT
NT
100
100
100
NT
NT
NT
NT
NT
NT
1900
15 000
10 000
13 000
15 000
12 000
10 000
30
31
32
NT
NT
NT
a
The extent of tubulin assembly induced by 0.2 and 1.0 µM taxol and by each compound with 10 µM tubulin was determined. The
extent of tubulin assembly in the presence of taxol is defined as 100%, and the extent of tubulin assembly with each ligand was compared
with this value. n ) 3 experiments in quadruplicate, p < 0.001.
b

Steroid-Linked Taxol Analogues
J ournal of Natural Products, 2004, Vol. 67, No. 2 155
Sch em e 4a
a
Reagents and conditions: (a) BnOCOCH2CH2COOH, EDC/DMAP, CH2Cl2, RT, 24 h, 40%; (b) 7, EDC/DMAP, CH2Cl2, RT, 48 h, 70%; (c) HF-pyridine,
THF, RT, overnight, 98%; (d) H2, Pd-C, EtOAc, 30 psi, 24 h, 80%; (e) BnOCOCH2CH2COOH, EDC/DMAP, CH2Cl2, RT, 48 h, 90%; (f) HF-pyridine, THF, RT,
overnight, 99%; (g) H2, Pd-C, EtOAc, 50 psi, 24 h, 50%.
F igu r e 1. Inhibition of breast tumor cell survival in vitro by taxol and compound 16. Human breast tumor cell lines were incubated for 48 h with
the indicated drug concentrations. The cell survival response in estrogen-receptor negative MDA-MB-231 cells and estrogen-receptor positive
MCF-7 cells was determined using the MTS assay. Response (A490 nm) is plotted as a fraction of control cells, which was set to 100%. A nonlinear
regression fit to a sigmoidal dose-response equation is shown. Data are representative of n ) 2 independent experiments performed in quintuplicate.
The two C-7-substituted derivatives 14 and 16 were both
significantly less potent cytotoxic agents than taxol in the
two breast cancer cell lines, although both compounds were
comparable to taxol in their tubulin-assembly activity and
were only less active in the PC-3 cell line by factors of 1.6
and 4.2, respectively. Although both compounds showed
modest selectivities toward the ER-R positive cell line MCF-
7, the observed differences were not statistically significant.
The dose-response curves for taxol and compound 16
are shown in Figure 1. The maximal antiproliferative
response to either taxol or 16 was 85-90% inhibition of
cell survival by 48 h; thus the efficacy of both compounds
was equivalent. In MCF-7 cells, the maximal reduction in
cell survival elicited by either taxol or 16 in a 48 h
incubation was 20-30%. When MCF-7 cells were incubated
with taxol or 16 for 7 days, the maximal decrease in cell
survival was approximately 70%. The difference in the
efficacy of taxol and the steroid-conjugated derivative
between MDA-MB-231 cells and MCF-7 cells is most likely
the differences in the cell doubling time. For MDA-MB-
231 cells with a cell doubling time of approximately 22 h,
nearly all cells are exposed to taxol or 16 during a sensitive
stage of the cell cycle during the 48 h incubation period.
However, MCF-7 cells, with a doubling time of nearly 60
h, require a much longer period of drug exposure before a
similar fraction of the cells enter or transit the taxol-
sensitive phase of the cell cycle.
The 10-substituted derivative 21 gave the most interest-
ing results. It had comparable activity to taxol in both the
tubulin-assembly and PC-3 assays, and it also showed a
3-fold greater activity (p < 0.001) toward the ER-R positive
MCF-7 cell line than the ER-R negative MDA-MB-231 cell

156 J ournal of Natural Products, 2004, Vol. 67, No. 2
Liu et al.
procedure was applied to estradiol derivative 7 to give 10 and
to the reaction of 2′-tert-butyldimethylsilyltaxol (12) with
estradiols 5 and 7 to give the 7-acyl analogues 13 and 14,
respectively.
line. It was however significantly less potent than taxol to
both these cell lines. Our results do, however, suggest that
future efforts at targeting taxol to ER-R positive breast
cancer cells would be most fruitful if centered around
modifications at the C-10 position.
The hemisuccinates 25-27 and 30-32 were tested only
in the A2780 ovarian cancer cell line; they were all found
to be significantly less active that taxol, and so were not
subjected to further testing.
2′-{4-[3-ter t-Bu tyldim eth ylsilyloxy-17â-tr ieth ylsilyloxy-
estr a -1,3,5(10)-tr ien e-16r-yl]-2E-bu t-2-en oyl}ta xol (8): 1H
NMR (CDCl3) δ 0.19 (6H, s), 0.61 (6H, q, J ) 7.9 Hz), 0.79
(3H, s), 0.97 (9H, t, J ) 7.9 Hz), 0.98 (9H, s), 1.13 (3H, s), 1.24
(3H, s), 1.68 (3H, s), 1.95 (3H, brs), 2.23 (3H, s), 2.44 (3H, s),
1.20-2.90 (20H, taxol and steroid skeletons), 3.29 (1H, d, J )
7.4 Hz), 3.82 (1H, d, J ) 7.4 Hz), 4.20 (1H, d, J ) 8.4 Hz),
4.32 (1H, d, J ) 8.4 Hz), 4.46 (1H, m), 4.98 (1H, dd, J ) 9.6,
2.0 Hz), 5.56 (1H, d, J ) 3.6 Hz), 5.58 (1H, d, J ) 7.2 Hz),
5.93 (1H, d, J ) 15.6 Hz), 5.96 (1H, dd, J ) 9.3, 3.6 Hz), 6.26
(1H, t, J ) 9.1 Hz), 6.30 (1H, s), 6.55 (1H, d, J ) 2.6 Hz, Ar),
6.61 (1H, dd, J ) 8.5, 2.6 Hz, Ar), 6.93 (1H, d, J ) 9.3 Hz),
7.10 (1H, d, J ) 8.5 Hz, Ar), 7.30-7.70 (11H, m, Ar), 7.75 (2H,
m, Ar), 8.13 (2H, m, Ar); 13C NMR (CDCl3) δ -4.2, 5.6, 7.3,
9.8, 12.3, 15.1, 18.4, 21.1, 22.9, 25.9, 26.4, 26.5, 27.1, 29.3, 29.8,
35.7, 35.8, 37.4, 37.9, 38.8, 43.1, 43.4, 44.2, 44.5, 45.8, 48.4,
53.2, 58.7, 72.0, 72.4, 74.0, 75.3, 75.8, 76.6, 79.5, 81.2, 84.7,
87.8, 117.4, 120.1, 126.3, 126.9, 127.3, 128.7, 128.9, 129.0,
129.3, 129.4, 130.4, 132.2, 132.9, 133.1, 133.92, 133.95, 137.3,
138.0, 143.2, 152.3, 153.5, 165.6, 167.25, 167.29, 168.5, 170.0,
171.5, 204.1; HRFABMS m/z 1442.6644 [M + Na+] (calcd for
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Chemicals were
obtained from Aldrich Chemical Co. and were used without
further purification. All solvents were of reagent grade or
HPLC grade. THF was distilled over sodium/benzophenone,
and CH2Cl2 was distilled over calcium hydride. All 1H NMR
spectral data were obtained in CDCl3 or CD3OD on a Varian
1
Unity 400 spectrometer (operating at 399.951 MHz for H and
100.578 MHz for 13C). Mass spectra were obtained at Analyti-
cal Service in the Department of Chemistry (HRFABMS) or
the Department of Biochemistry (MALDI-TOFMS) at Virginia
Tech.
7-{4-[3-ter t-Bu tyld im eth ylsilyloxy-17â-tr ieth ylsilyloxy-
estr a -1,3,5(10)-tr ien e-16r-yl]-2E-bu t-2-en oic Acid (5). To
a solution of 4 (836 mg, 1.36 mmol) in THF (8 mL) was added
LiOH (131 mg, 5.44 mmol) in water (8 mL). After stirring at
room temperature for 36 h, the reaction mixture was quenched
with saturated ammonium chloride and extracted three times
with ethyl acetate (50 mL). The combined organic phase was
washed through water and brine, dried over sodium sulfate,
and concentrated in a vacuum. The residue was purified by
column chromatography (10% EtOAc/hexane) to give 5 (560
mg, 72%): 1H NMR (CDCl3) δ 0.21 (6H, s), 0.64 (6H, q, J )
7.9 Hz), 0.82 (3H, s), 1.00 (9H, s), 1.01 (9H, t, J ) 7.9 Hz),
1.20-2.90 (16H, steroid skeleton), 3.33 (1H, d, J ) 7.3 Hz),
5.88 (1H, d, J ) 15.6 Hz), 6.56 (1H, d, J ) 2.7 Hz, Ar), 6.63
C
81H105NO17Si2Na, 1442.6819).
Su ccin ic acid, 3,17â-di-ter t-bu tyldim eth ylsilyloxyestr a-
1,3,5(10)-tr ien e-11â-yl ester 2′-ta xol ester (10): 1H NMR
(CDCl3) δ 0.02 (6H, brs), 0.17 (6H, s), 0.77 (3H, s), 0.88 (9H,
s), 0.96 (9H, s), 1.13 (3H, s), 1.23 (3H, s), 1.68 (3H, s), 1.94
(3H, brs), 2.22 (3H, s), 2.45 (3H, s), 1.15-2.90 (21H, taxol and
steroid skeletons), 3.66 (1H, t, J ) 8.4 Hz), 3.82 (1H, d, J )
7.2 Hz), 4.20 (1H, d, J ) 8.6 Hz), 4.32 (1H, d, J ) 8.6 Hz),
4.45 (1H, dd, J ) 9.7, 7.2 Hz), 4.97 (1H, dd, J ) 9.6, 1.7 Hz),
5.41 (1H, td, J ) 10.5, 5.2 Hz), 5.54 (1H, d, J ) 3.0 Hz), 5.68
(1H, d, J ) 7.0 Hz), 6.00 (1H, dd, J ) 9.2, 3.0 Hz), 6.24-6.31
(2H, overlapped), 6.54-6.61 (2H, overlapped, Ar), 6.85 (1H,
d, J ) 8.3 Hz, Ar), 6.99 (1H, d, J ) 9.2 Hz), 7.30-7.65 (11H,
Ar), 7.76 (2H, m, Ar), 8.15 (2H, m, Ar); 13C NMR (100 MHz,
CDCl3) δ -4.5, -4.3, -4.1, 9.8, 12.2, 15.1, 18.3, 18.4, 21.1, 22.4,
22.9, 23.4, 25.9, 26.1, 27.0, 27.1, 28.4, 29.1, 29.7, 31.2, 35.7,
35.8, 37.7, 42.6, 43.4, 44.6, 45.7, 46.6, 49.7, 53.0, 59.7, 72.0,
72.4, 74.3, 75.0, 75.3, 75.8, 76.6, 79.4, 81.2, 81.3, 84.7, 117.4,
120.2, 125.2, 126.8, 127.4, 128.7, 128.9, 129.0, 129.3, 129.4,
130.5, 132.2, 132.4, 132.9, 133.8, 133.9, 137.2, 139.4, 143.1,
153.9, 167.28, 167.30, 168.1, 170.0, 171.47, 171.54, 204.1;
(1H, dd, J ) 8.5, 2.7 Hz, Ar), 7.07-7.16 (2H, overlapped); 13
C
NMR (CDCl3) δ -4.1, 5.7, 7.3, 12.4, 18.4, 26.0, 26.5, 27.5, 29.4,
29.8, 37.5, 37.8, 38.8, 43.1,44.2, 44.6, 48.6, 87.8, 117.4, 120.2,
121.7, 126.3, 133.2, 138.1, 151.7, 153.5, 172.3; HRFABMS m/z
584.3707 [M+•] (calcd for C34H56O4Si2, 584.3717).
Su ccin ic Acid , Mon o-3,17â-d i-ter t-bu tyld im eth ylsilyl-
oxyestr a -1,3,5(10)-tr ien e-11â-yl Ester (7). To a solution of
6 (275 mg, 0.532 mmol) in 20 mL of dry THF was added
LHMDS (1 M, 0.80 mL, 0.798 mmol) at 0 °C. After stirring
for 1 h, succinic anhydride (1.06 g, 10.64 mmol) was added in
one portion. The reaction mixture was allowed to stir overnight
at room temperature. The reaction mixture was then poured
into 200 mL of water, and EtOAc (150 mL) was used to extract
the product. The extract was washed through water and brine,
dried over sodium sulfate, and concentrated in a vacuum. The
residue was purified by column chromatography (25% EtOAc/
hexane) to give 7 (164 mg, 50%) and recovered 6 (55 mg, 20%).
7: 1H NMR (CDCl3): δ 0.02 (3H, s), 0.03 (3H, s), 0.19 (6H, s),
0.79 (3H, s), 0.89 (9H, s), 0.98 (9H, s), 1.10-2.85 (17H, steroid
skeleton), 3.67 (1H, t, J ) 8.5 Hz), 5.45 (1H, td, J ) 10.6, 5.2
Hz), 6.58-6.63 (2H, m, Ar), 6.93 (1H, d, 8.1 Hz, Ar); 13C NMR
(CDCl3) δ -4.5, -4.3, -4.17, -4.15, 12.2, 18.3, 18.4, 23.4, 26.0,
26.1, 27.1, 28.4, 29.2, 29.6, 31.3, 37.7, 42.6, 44.5, 46.6, 49.7,
74.8, 81.2, 117.3, 120.0, 125.5, 132.4, 139.3, 153.9, 171.9, 179.0;
HRFABMS m/z 616.3619 [M+•] (calcd for C34H56O6Si2, 616.3615).
Gen er a l P r oced u r e for P r ep a r a tion of Estr a d iol-
Ta xol Con ju ga tes. To a solution of estradiol derivative 5 (13.7
mg, 0.0234 mmol) in 2 mL of toluene was added EDC (4.5 mg,
0.0234 mmol). After 15 min stirring, DMAP (2 mg, cat.) was
added and stirring continued for 5 min before taxol (20 mg,
0.0234 mmol) was added. The reaction mixture was allowed
to stir at 60 °C for 24-48 h. Then, 50 mL of EtOAc was added
to the reaction mixture, and the organic phase was washed
with sodium bicarbonate, water, and brine, dried over sodium
sulfate, and concentrated in a vacuum. The residue was
applied to preparative TLC (50% EtOAc/hexane) to give silyl-
protected estradiol-taxol conjugate 8 (15.1 mg, 73%). A similar
HRFABMS m/z 1452.6803 [M + H+] (calcd for C81H106NO19
Si
-
2, 1452.6898).
7-{4-[3-ter t-Bu tyld im eth ylsilyloxy-17â-tr ieth ylsilyloxy-
estr a-1,3,5(10)-tr ien e-16r-yl]-2E-bu t-2-en oyl}-2′-ter t-bu tyl-
1
d im eth ylsilyl ta xol (13): H NMR (CDCl3) δ -0.30 (3H, s),
-0.02 (3H, s), 0.18 (6H, s), 0.61 (6H, q, J ) 7.9 Hz), 0.79 (3H,
s), 0.80 (9H, s), 0.98 (9H, t, J ) 7.9 Hz), 1.18 (3H, s), 1.21 (3H,
s), 1.86 (3H, s), 2.01 (3H, brs), 2.11 (3H, s), 2.59 (3H, s), 1.10-
2.85 (20H, taxol and steroid skeletons), 3.29 (1H, d, J ) 7.1
Hz), 4.00 (1H, d, J ) 7.1 Hz), 4.23 (1H, d, J ) 8.1 Hz), 4.36
(1H, d, J ) 8.1 Hz), 4.68 (1H, d, J ) 2.0 Hz), 5.00 (1H, d, J )
9.4 Hz), 5.64 (1H, dd, J ) 10.5, 7.2 Hz), 5.68-5.82 (3H,
overlapped), 6.26 (1H, t, J ) 9.2 Hz), 6.35 (1H, s), 6.54 (1H, d,
J ) 2.5 Hz, Ar), 6.61 (1H, dd, J ) 8.5, 2.5 Hz, Ar), 6.89 (1H,
m), 7.09 (1H, d, J ) 8.8 Hz), 7.11 (1H, d, J ) 8.5 Hz, Ar), 7.28-
7.66 (11H, Ar), 7,76 (2H, m, Ar), 8.14 (2H, m, Ar); 13C NMR
(CDCl3) δ -5.6, -4.9, -4.2, 5.7, 7.3, 11.2, 12.4, 14.9, 18.35,
18.40, 20.8, 21.6, 23.3, 25.8, 25.9, 26.6, 27.5, 29.3, 29.8, 33.6,
35.8, 37.5, 37.6, 38.8, 43.0, 43.6, 44.2, 44.5, 47.0, 48.4, 55.9,
56.4, 71.52, 71.55, 74.8, 75.2, 75.3, 76.7, 78.9, 81.2, 84.3, 87.8,
117.3, 120.2, 122.0, 126.3, 126.6, 127.2, 128.2, 128.97, 129.02,
129.3, 130.4, 132.0, 133.0, 133.4, 134.0, 134.3, 138.1, 138.5,
141.1, 149.1, 153.5, 165.6, 167.20, 167.21, 168.6, 170.0, 171.7,
202.3; HRFABMS m/z 1534.7910 [M + H+] (calcd for C87H120
NO17Si3, 1534.7864).
-
Su ccin ic acid, 3,17â-di-ter t-bu tyldim eth ylsilyloxyestr a-
1,3,5(10)-tr ien e-11r-yl ester 2′-ter t-bu tyld im eth ylsilyl-7-
ta xol ester (15): 1H NMR (CDCl3) δ -0.31 (3H, s), -0.03 (3H,
s), 0.01 (3H, s), 0.02 (3H, s), 0.19 (6H, s), 0.77 (3H, s), 0.80

Steroid-Linked Taxol Analogues
J ournal of Natural Products, 2004, Vol. 67, No. 2 157
(9H, s), 0.88 (9H, s), 0.97 (9H, s), 1.15 (3H, s), 1.21 (3H, s),
1.81 (3H, s), 1.97 (3H, brs), 2.11 (3H, s), 2.58 (3H, s), 1.10-
2.80 (21H, taxol and steroid skeletons), 3.65 (1H, t, J ) 8.4
Hz), 3.97 (1H, d, J ) 6.8 Hz), 4.21 (1H, d, J ) 8.5 Hz), 4.34
(1H, d, J ) 8.5 Hz), 4.67 (1H, d, J ) 2.1 Hz), 4.97 (1H, d, J )
9.3 Hz), 5.40 (1H, td, J ) 10.4, 5.2 Hz), 5.61 (1H, dd, J ) 10.6,
7.1 Hz), 5.70 (1H, d, J ) 7.0 Hz), 5.73 (1H, dd, J ) 8.9, 1.7
Hz), 6.25 (1H, s), 6.27 (1H, t, J ) 9.4 Hz), 6.57 (1H, d, J ) 2.5
Hz, Ar), 6.61 (1H, dd, J ) 8.5, 2.5 Hz, Ar), 6.91 (1H, d, J ) 8.5
Hz, Ar), 7.08 (1H, d, J ) 8.9 Hz), 7.30-7.65 (11H, m, Ar), 7.75
(2H, m, Ar), 8.13 (2H, m, Ar); 13C NMR (CDCl3) δ -5.6, -4.9,
-4.5, -4.2, -4.15, -4.13, 11.1, 12.2, 14.8, 18.28, 18.34, 18.39,
20.9, 21.7, 23.2, 23.4, 25.7, 25.9, 26.1, 26.6, 27.0, 28.5, 29.5,
29.9, 31.1, 33.5, 35.8, 37.7, 42.7, 43.6, 44.6, 46.7, 47.0, 49.7,
55.9, 56.2, 71.5, 71.8, 74.5, 74.7, 75.3, 75.4, 76.6, 77.6, 78.9,
81.2, 84.2, 117.4, 119.9, 125.6, 126.6, 127.2, 128.2, 128.96,
129.01, 129.3, 130.4, 132.0, 132.5, 132.8, 134.0, 134.3, 138.5,
139.2, 141.2, 153.9, 167.15, 167.17, 169.2, 170.0, 171.6, 171.7,
172.2, 202.2; HRFABMS m/z 1566.7789 [M + H+] (calcd for
26.6, 27.0, 28.4, 29.2, 29.4, 29.5, 29.8, 31.2, 33.4, 35.6, 37.6,
42.6, 43.4, 44.5, 46.6, 46.9, 49.6, 52.9, 56.1, 66.9, 71.7, 74.3,
74.4, 74.7, 75.3, 76.4, 78.8, 81.0, 81.1, 84.1, 117.3, 119.8, 125.5,
126.7, 127.4, 128.4, 128.5, 128.6, 128.7, 128.8, 128.9, 129.2,
129.3, 130.4, 132.1, 132.4, 132.6, 133.7, 133.8, 135.6, 137.1,
139.1, 141.4, 153.8, 167.1, 167.4, 168.1, 169.1, 169.7, 171.0,
171.3, 172.2, 202.2; MALDI-TOFMS m/z 1665 [M + Na+] (calcd
for C92H115NO22Si2Na, 1664.8).
Su ccin ic acid, 3,17â-di-ter t-bu tyldim eth ylsilyloxyestr a-
1,3,5(10)-tr ien e-11r-yl ester 7-(3-ben zyloxyca r bon ylp r o-
p a n oyl)-2′-ta xol ester (28): 1H NMR (CDCl3) δ 0.02 (3H, s),
0.03 (3H, s), 0.17 (6H, s), 0.77(3H, s), 0.88 (9H, s), 0.96 (9H,
s), 1.15 (3H, s), 1.20 (3H, s), 1.79 (3H, s), 1.98 (3H, brs), 2.13
(3H, s), 2.45 (3H, s), 1.10-2.83 (25H, taxol and steroid
skeletons), 3.67 (1H, t, J ) 8.5 Hz), 3.95 (1H, d, J ) 6.9 Hz),
4.19 (1H, d, J ) 8.5 Hz), 4.32 (1H, d, J ) 8.5 Hz), 4.93 (1H, d,
J ) 9.4 Hz), 5.12 (2H, AB, J ) 12.4 Hz), 5.41 (1H, td, J )
10.4, 5.3 Hz), 5.58 (1H, d, J ) 3.1 Hz), 5.60 (1H, dd, J ) 10.5,
7.1 Hz), 5.68 (1H, d, J ) 7.0 Hz), 6.01 (1H, dd, J ) 9.3, 3.1
Hz), 6.22 (1H, s), 6.24 (1H, t, J ) 9.1 Hz), 6.55-6.59 (2H,
overlapped, Ar), 6.85 (1H, d, J ) 8.0 Hz, Ar), 7.03 (1H, d, J )
9.3 Hz), 7.27-7.65 (16H, Ar), 7.77 (2H, m, Ar), 8.14 (2H, m,
Ar); 13C NMR (CDCl3) δ -4.5, -4.3, -4.2, 11.0, 12.1, 14.6, 18.2,
18.3, 20.9, 21.5, 22.8, 23.3, 25.9, 26.0, 26.6, 26.9, 28.1, 28.3,
29.2, 29.3, 29.7, 31.2, 33.3, 37.2, 37.6, 42.5, 43.3, 44.5, 46.5,
47.0, 49.6, 52.9, 56.1, 66.5, 71.7, 71.9, 74.1, 74.7, 74.9, 75.4,
76.5, 78.8, 81.00, 81.04, 84.2, 117.3, 119.9, 125.1, 126.7, 127.3,
128.31, 128.35, 128.37, 128.67, 128.71, 128.8, 129.25, 129.30,
130.4, 132.1, 132.4, 132.5, 133.7, 133.8, 136.1, 137.1, 139.3,
141.3, 153.9, 167.1, 167.4, 168.2, 169.0, 169.7, 171.2, 171.3,
171.6, 172.6, 202.2; HRFABMS m/z 1642.8468 [M + H+] (calcd
for C92H116NO22Si2).
Gen er a l P r oced u r e for Dep r otection of Silyl Gr ou p .
To a solution of silyl-protected estradiol-taxol conjugate 8
(15.1 mg, 0.0106 mmol), in 0.6 mL of dried THF, was added
0.1 mL of anhydrous pyridine, then the solution was cooled to
0 °C, and 0.1 mL of HF-pyridine was added. The reaction
mixture was allowed to warm to room temperature and stirred
overnight. The reaction mixture was then diluted with EtOAc,
and the organic phase was washed with sodium bicarbonate,
water, and brine, dried over sodium sulfate, and concentrated
in a vacuum. The residue was purified by preparative TLC
(50% EtOAc/hexane) to give 9 (12.3 mg, 97%). Compounds 11,
14, 16, 21, 24, and 27 were prepared similarly.
2′-{4-[3,17â-Dih yd r oxyestr a -1,3,5(10)-tr ien e-16r-yl]-2E-
bu t-2-en oyl}ta xol (9): 1H NMR (CD3OD) δ 0.78 (3H, s), 1.11
(3H, s), 1.13 (3H, s), 1.65 (3H, s), 1.93 (3H, brs), 2.16 (3H, s),
2.40 (3H, s), 2.15-2.80 (20H, taxol and steroid skeletons), 3.23
(1H, d, J ) 8.0 Hz), 3.81 (1H, d, J ) 7.2 Hz), 4.18 (2H, brs),
4.34 (1H, dd, J ) 11.0, 6.7 Hz), 4.99 (1H, dd, J ) 9.6, 1.9 Hz),
5.50 (1H, d, J ) 6.8 Hz), 5.63 (1H, d, J ) 7.1 Hz), 5.85 (1H, d,
J ) 6.8 Hz), 5.99 (1H, d, J ) 15.6 Hz), 6.06 (1H, t, J ) 9.1
Hz), 6.45 (1H, s), 6.47 (1H, d, J ) 2.6 Hz, Ar), 6.53 (1H, dd, J
) 8.5, 2.6 Hz, Ar), 7.05 (1H, d, J ) 8.5 Hz, Ar), 7.16 (1H, td,
J ) 15.6, 7.1 Hz), 7.23-7.70 (11H, Ar), 7.81 (2H, m, Ar), 8.11
(2H, m, Ar); 13C NMR (CD3OD) δ 9.3, 11.3, 13.8, 19.6, 21.2,
22.1, 25.7, 26.2, 27.3, 29.1, 29.5, 35.2, 36.3, 36.8, 37.6, 39.0,
42.0, 43.4, 43.9, 44.1, 46.7, 48.3, 54.2, 58.0, 71.1, 71.7, 74.7,
75.1, 75.6, 76.3, 77.8, 81.0, 84.7, 86.7, 112.5, 114.9, 120.3, 126.0,
127.4, 127.5, 128.4, 128.5, 128.9, 130.0, 130.2, 131.3, 131.7,
133.4, 133.7, 134.4, 137.2, 137.6, 141.3, 151.6, 154.7, 165.8,
166.4, 169.3, 169.4, 170.1, 170.4, 204.0; HRFABMS m/z
1192.5267 [M + H+] (calcd for C69H78NO17, 1192.5270).
Su ccin ic a cid , 3,17â-d ih yd r oxyest r a -1,3,5(10)-t r ien e-
11â-yl ester 2′-ta xol ester (11): 1H NMR (CD3OD) δ 0.74 (3H,
s), 1.15 (3H, s), 1.16 (3H, s), 1.65 (3H, s), 1.97 (3H, brs), 2.17
(3H, s), 2.42 (3H, s), 1.24-2.86 (21H, taxol and steroid
skeletons), 3.59 (1H, t, J ) 8.7 Hz), 3.84 (1H, d, J ) 7.2 Hz),
4.20 (2H, brs), 4.36 (1H, dd, J ) 11.1, 6.7 Hz), 5.02 (1H, dd, J
) 9.6, 2.0 Hz), 5.29 (1H, td, J ) 10.4, 5.3 Hz), 5.48 (1H, d, J
) 5.2 Hz), 5.65 (1H, d, J ) 7.1 Hz), 5.89 (1H, d, J ) 5.2 Hz),
6.17 (1H, t, J ) 9.1 Hz), 6.43 (1H, s), 6.52 (1H, d, J ) 2.7 Hz,
Ar), 6.54 (1H, dd, J ) 8.4, 2.7 Hz, Ar), 6.83 (1H, d, J ) 8.4 Hz,
Ar), 7.25-7.69 (11H, Ar), 7.77 (2H, m, Ar), 8.13 (2H, m, Ar);
13C NMR (CD3OD) δ 9.3, 11.0, 14.1, 19.8, 21.2, 22.7, 25.9, 26.8,
C
87H120NO19Si3, 1566.7762).
Su ccin ic acid, 3,17â-di-ter t-bu tyldim eth ylsilyloxyestr a-
1,3,5(10)-tr ien e-11r-yl ester 2′-ter t-bu tyld im eth ylsilyl-10-
d ea cetyl-7-epi-ta xol ester (20): 1H NMR (CDCl3) δ -0.30
(3H, s), -0.04 (3H, s), 0.02 (3H, s), 0.03 (3H, s), 0.19 (6H, s),
0.77 (3H, s), 0.78 (9H, s), 0.88 (9H, s), 0.98 (9H, s), 1.13 (3H,
s), 1.19 (3H, s), 1.67 (3H, s), 1.88 (3H, brs), 2.67 (3H, s), 1.10-
2.96 (21H, taxol and steroid skeletons), 3.67 (1H, t, J ) 8.3
Hz), 3.71 (1H, m), 3.92 (1H, d, J ) 7.5 Hz), 4.40 (2H, brs),
4.66 (1H, d, J ) 2.2 Hz), 4.71 (1H, d, J ) 11.7 Hz), 4.94 (1H,
dd, J ) 8.9, 3.5 Hz), 5.44 (1H, td, J ) 10.3, 5.2 Hz), 5.75 (1H,
d, J ) 7.5 Hz), 5.78 (1H, dd, J ) 9.0, 1.8 Hz), 6.30 (1H, t, J )
8.9 Hz), 6.58 (1H, d, J ) 2.6 Hz, Ar), 6.61 (1H, dd, J ) 8.4, 2.6
Hz, Ar), 6.86 (1H, s), 6.91 (1H, d, J ) 8.4 Hz, Ar), 7.07 (1H, d,
J ) 9.0 Hz), 7.30-7.63 (11H, Ar), 7.72 (2H, m, Ar), 8.17 (2H,
m, Ar); 13C NMR (CDCl3) δ -5.7, -5.0, -4.5, -4.3, -4.1, 12.2,
15.2, 16.5, 18.3, 18.38, 18.39, 21.9, 23.1, 23.4, 25.7, 25.9, 26.12,
26.14, 27.1, 28.4, 29.3, 30.1, 31.3, 35.6, 36.5, 37.7, 40.5, 42.6,
42.9, 44.5, 46.6, 49.6, 55.8, 57.7, 71.1, 74.7, 75.52, 75.56, 76.0,
77.9, 78.5, 79.5, 81.2, 82.3, 83.0, 117.4, 119.9, 125.4,126.6,
127.2, 128.2, 128.9, 129.0, 129.1, 129.5, 130.5, 132.0, 132.6,
133.1, 133.9, 134.3, 138.5, 139.3, 140.6, 153.9, 167.1, 167.4,
170.9, 171.2, 171.9, 172.5, 207.3; HRFABMS m/z 1524.7583
[M + H+] (calcd for C85H118NO18Si3, 1524.7657).
2′-(3-Ben zyloxyca r bon ylp r op a n oyl)ta xol (22): 1H NMR
(CDCl3) δ 1.14 (3H, s), 1.23 (3H, s), 1.68 (3H, s), 1.88 (1H, m),
1.93 (3H, brs), 2.16 (1H, m), 2.22 (3H, s), 2.38 (1H, m), 2.45
(3H, s), 2.55 (1H, m), 2.66 (2H, m), 2.77 (2H, m), 3.81 (1H, d,
J ) 7.0 Hz), 4.20 (1H, d, J ) 8.4 Hz), 4.31 (1H, d, J ) 8.4 Hz),
4.44 (1H, dd, J ) 10.9, 6.6 Hz), 4.97 (1H, dd, J ) 9.6, 2.0 Hz),
5.51 (1H, d, J ) 3.1 Hz), 5.69 (1H, d, J ) 7.0 Hz), 5.99 (1H,
dd, J ) 9.2, 3.1 Hz), 6.25 (1H, t, J ) 9.0 Hz), 6.30 (1H, s), 7.11
(1H, d, J ) 9.2 Hz), 7.25-7.65 (16H, Ar), 7.80 (2H, m, Ar),
8.14 (2H, m, Ar); 13C NMR (CDCl3) δ 9.8, 15.0, 21.1, 22.4, 22.9,
27.0, 29.4, 29.5, 35.76, 35.80, 43.3, 45.8, 53.0, 58.7, 67.0, 72.1,
72.4, 74.5, 75.3, 75.8, 76.7, 79.3, 81.2, 84.7, 126.8, 127.5, 128.4,
128.6, 128.7, 128.8, 128.9, 129.0, 129.3, 129.4, 130.5, 132.2,
133.0, 133.8, 133.9, 135.7, 137.2, 143.0, 167.2, 167.5, 168.1,
170.0, 171.3, 171.5, 172.2, 204.1; HRFABMS m/z 1044.4032
[M + H+] (calcd for C58H62NO17, 1044.4018).
Su ccin ic acid, 3,17â-di-ter t-bu tyldim eth ylsilyloxyestr a-
1,3,5(10)-tr ien e-11r-yl ester 2′-(3-ben zyloxyca r bon ylp r o-
p a n oyl)-7-ta xol ester (23): 1H NMR (CDCl3) δ 0.00 (3H, s),
0.01 (3H, s), 0.17 (6H, s), 0.76 (3H, s), 0.86 (9H, s), 0.95 (9H,
s), 1.14 (3H, s), 1.19 (3H, s), 1.79 (3H, s), 1.97 (3H, brs), 2.10
(3H, s), 2.44 (3H, s), 1.10-2.80 (25H, taxol and steroid
skeletons), 3.64 (1H, t, J ) 8.5 Hz), 3.94 (1H, d, J ) 6.9 Hz),
4.18 (1H, d, J ) 8.5 Hz), 4.31 (1H, d, J ) 8.5 Hz), 4.94 (1H, d,
J ) 9.3 Hz), 4.99 (2H, s), 5.39 (1H, td, J ) 10.4, 5.2 Hz), 5.52
(1H, d, J ) 3.0 Hz), 5.58 (1H, dd, J ) 10.5, 7.2 Hz), 5.68 (1H,
d, J ) 7.0 Hz), 5.99 (1H, dd, J ) 9.2, 3.0 Hz), 6.22 (1H, t, J )
9.4 Hz), 6.23 (1H, s), 6.56 (1H, d, J ) 2.6 Hz, Ar), 6.60 (1H,
dd, J ) 8.5, 2.6 Hz, Ar), 6.91 (1H, d, J ) 8.5 Hz, Ar), 7.11 (1H,
d, J ) 9.2 Hz), 7.25-7.65 (16H, Ar), 7.80 (2H, m, Ar), 8.13
(2H, m, Ar); 13C NMR (100 MHz, CDCl3) δ -4.6, -4.3, -4.2,
11.0, 12.1, 14.6, 18.2, 18.3, 20.8, 21.5, 22.8, 23.3, 25.9, 26.0,

158 J ournal of Natural Products, 2004, Vol. 67, No. 2
Liu et al.
28.1, 28.2, 29.2, 29.5, 35.3, 36.3, 37.9, 41.6, 43.5, 43.9, 45.7,
46.6, 49.5, 53.7, 58.0, 71.2, 71.6, 74.6, 75.09, 75.11, 75.7, 76.3,
77.8, 80.4, 81.1, 84.7, 112.5, 114.8, 125.0, 127.3, 127.4, 128.3,
128.54, 128.56, 128.9, 130.0, 130.2, 130.9, 131.6, 133.4, 133.8,
134.4, 137.1, 139.0, 141.3, 155.2, 166.5, 168.9, 169.6, 170.2,
170.4, 171.9, 172.3, 204.0; HRFABMS m/z 1224.5200 [M + H+]
(calcd for C69H78NO19, 1224.5168).
21.3, 23.0, 23.1, 26.6, 27.1, 28.5, 29.3, 29.5, 29.6, 29.7, 30.2,
33.5, 35.5, 37.8, 42.7, 43.5, 44.1, 46.5, 47.4, 49.8, 53.0, 56.2,
67.0, 71.6, 72.0, 74.46, 74.55, 74.57, 75.7, 76.7, 78.6, 81.1, 84.5,
113.1, 115.2, 126.6, 126.8, 127.5, 128.4, 128.6, 128.7, 128.8,
128.9, 129.0, 129.28, 129.34, 130.4, 131.1, 132.3, 132.6, 133.8,
134.0, 135.7, 137.0, 139.2, 141.4, 154.6, 167.1, 167.8, 168.2,
169.1, 170.6, 171.6, 171.8, 172.4, 173.0, 202.2; HRFABMS m/z
1436.5613 [M + Na+] (calcd for C80H87NO22Na, 1436.5617).
Su ccin ic a cid , 3,17â-d ih yd r oxyest r a -1,3,5(10)-t r ien e-
11r-yl ester 7-(3-ben zyloxyca r bon ylp r op a n oyl)-2′-ta xol
ester (29): 1H NMR (CDCl3) δ 0.77 (3H, s), 1.15 (3H, s), 1.19
(3H, s), 1.78 (3H, s), 2.01 (3H, brs), 2.12 (3H, s), 2.42 (3H, s),
1.10-2.95 (25H, taxol and steroid skeletons), 3.71 (1H, t, J )
8.5 Hz), 3.93 (1H, d, J ) 6.8 Hz), 4.17 (1H, d, J ) 8.5 Hz),
4.32 (1H, d, J ) 8.5 Hz), 4.95 (1H, d, J ) 9.3 Hz), 5.11 (2H,
AB, J ) 12.3 Hz), 5.39 (1H, td, J ) 10.4, 5.2 Hz), 5.44 (1H, d,
J ) 3.1 Hz), 5.63 (1H, dd, J ) 10.6, 7.0 Hz), 5.69 (1H, d, J )
6.8 Hz), 5.92 (1H, dd, J ) 9.0, 2.9 Hz), 6.22 (1H, t, J ) 9.0
Hz), 6.24 (1H, s), 6.55-6.60 (2H, overlapped, Ar), 6.86 (1H, d,
J ) 8.2 Hz, Ar), 7.10 (1H, d, J ) 9.0 Hz), 7.26-7.64 (16H, Ar),
7.77 (2H, m, Ar), 8.11 (2H, m, Ar); 13C NMR (CDCl3) δ 11.0,
11.9, 14.7, 21.0, 21.4, 22.9, 23.2, 26.6, 26.9, 28.3, 28.6, 29.2,
29.51, 29.54, 30.6, 33.3, 35.6, 37.7, 42.1, 43.5, 44.1, 46.2, 47.2,
49.9, 53.0, 56.2, 66.7, 71.8, 72.0, 74.2, 74.6, 74.7, 75.6, 76.5,
78.8, 81.0, 81.2, 84.1, 112.8, 115.5, 125.6, 126.9, 127.4, 128.4,
128.5, 128.7, 128.8, 128.9, 129.0, 129.2, 129.3, 130.4, 131.2,
132.2, 132.6, 133.8, 134.0, 136.1, 137.1, 139.4, 141.7, 154.7,
167.1, 167.6, 168.3, 169.4, 170.2, 171.6, 171.7, 172.3, 172.6,
7-{4-[3,17â-Dih yd r oxyestr a -1,3,5(10)-tr ien e-16r-yl]-2E-
bu t-2-en oyl}ta xol (14): 1H NMR (CD3OD) δ 0.82 (3H, s), 1.11
(3H, s), 1.15 (3H, s), 1.81 (3H, s), 1.90 (3H, brs), 2.13 (3H, s),
2.37 (3H, s), 1.20-2.80 (20H, taxol and steroid skeletons), 3.27
(1H, d, J ) 7.7 Hz), 3.92 (1H, d, J ) 7.1 Hz), 4.20 (2H, brs),
4.75 (1H, d, J ) 5.2 Hz), 5.00 (1H, d, J ) 9.3), 5.60 (1H, dd, J
) 10.6, 7.4 Hz), 5.63-5.68 (2H, overlapped), 5.75 (1H, d, J )
15.6 Hz), 6.15 (1H, t, J ) 9.1 Hz), 6.31 (1H, s), 6.37 (1H, d, J
) 2.5 Hz, Ar), 6.53 (1H, dd, J ) 8.5, 2.5 Hz, Ar), 6.92 (1H, td,
J ) 15.6, 7.3 Hz), 7.26-7.69 (11H, Ar), 7.85 (2H, m, Ar), 8.11
(2H, m, Ar); 13C NMR (CD3OD) δ 10.3, 11.3, 13.5, 19.5, 20.9,
22.0, 25.55, 25.58, 26.3, 27.3, 29.50, 29.55, 35.3, 36.9, 39.1, 42.2,
43.4, 44.0, 44.1, 46.8, 48.3, 56.2, 56.5, 71.0, 71.7, 73.6, 74.7,
75.4, 76.1, 77.7, 80.8, 84.0, 86.5, 112.5, 114.9, 121.6, 126.0,
127.3, 127.8, 128.4, 128.55, 128.57, 130.0, 130.1, 131.4, 131.7,
133.3, 133.5, 134.4, 137.6, 138.8, 140.9, 149.1, 154.7, 165.6,
166.4, 169.1, 169.7, 170.8, 173.3, 202.5; HRFABMS m/z
1192.5237 [M + H+] (calcd for C69H78NO17 1192.5270).
Su ccin ic a cid , 3,17â-d ih yd r oxyest r a -1,3,5(10)-t r ien e-
11r-yl ester 7-ta xol ester (16): 1H NMR (CD3OD) δ 0.76 (3H,
s), 1.11 (3H, s), 1.15 (3H, s), 1.78 (3H, s), 1.89 (3H, brs), 2.11
(3H, s), 2.38 (3H, s), 1.17-2.81 (21H, taxol and steroid
skeletons), 3.67 (1H, t, J ) 8.7 Hz), 3.91 (1H, d, J ) 7.1 Hz),
4.18 (1H, d, J ) 8.5 Hz), 4.22 (1H, d, J ) 8.5 Hz), 4.77 (1H, d,
J ) 5.3 Hz), 5.00 (1H, d, J ) 9.5 Hz), 5.32 (1H, td, J ) 10.6,
5.2 Hz), 5.68-5.78 (3H, overlapped), 6.16 (1H, t, J ) 9.1 Hz),
6.21 (1H, s), 6.53 (1H, d, J ) 2.7 Hz, Ar), 6.58 (1H, dd, J )
8.6, 2.7 Hz, Ar), 6.91 (1H, d, J ) 8.6 Hz), 7.26-7.69 (11H, Ar),
7.85 (2H, m, Ar), 8.11 (2H, m, Ar); 13C NMR (CD3OD) δ 10.3,
11.0, 13.7, 19.5, 20.9, 22.0, 22.7, 25.6, 26.8, 28.1, 29.0, 29.3,
29.4, 33.0, 35.3, 37.9, 42.3, 43.4, 43.9, 46.3, 46.9, 49.7, 56.0,
56.5, 71.0, 72.0, 73.6, 74.59, 74.63, 75.5, 76.1, 77.7, 80.4, 80.8,
84.1, 112.6, 114.8, 125.4, 127.3, 127.8, 128.4, 128.56, 128.59,
130.0, 130.1, 130.6, 131.7, 133.1, 133.5, 134.4, 138.8, 139.0,
141.0, 155.2, 166.4, 169.1, 169.7, 170.9, 171.8, 172.8, 173.3,
202.2; HRFABMS m/z 1436.5562 [M + Na+] (calcd for C80H87
-
NO22Na, 1436.5617).
Gen er a l P r oced u r e for Dep r otection of th e Ben zyl
Gr ou p . To a solution of benzyl-protected estradiol-taxol
conjugate 24 (38.3 mg, 0.0266 mmol), in 10 mL of EtOAc, was
added 10 mg of Pd-C (10%), and the mixture was hydroge-
nated at 30 psi at room temperature for 24 h. The reaction
mixture was filtered, and the organic phase was concentrated
in a vacuum. The residue was purified by preparative TLC
(70% EtOAc/hexane) to give 25 (27.0 mg, 74%).
Su ccin ic a cid , 3,17â-d ih yd r oxyest r a -1,3,5(10)-t r ien e-
11r-yl ester 2′-(3-ca r boxyp r op a n oyl)-7-ta xol ester (25):
1H NMR (CDCl3) δ 0.75 (3H, s), 1.14 (3H, s), 1.17 (3H, s), 1.81
(3H, s), 1.96 (3H, brs), 2.11 (3H, s), 2.43 (3H, s), 1.20-2.80
(25H, taxol and steroid skeletons), 3.67 (1H, t, J ) 8.7 Hz),
3.91 (1H, d, J ) 6.8 Hz), 4.17 (1H, d, J ) 8.7 Hz), 4.32 (1H, d,
J ) 8.7 Hz), 4.97 (1H, d, J ) 9.5 Hz), 5.36 (1H, td, J ) 10.4,
7.8 Hz), 5.68 (1H, d, J ) 6.7 Hz), 5.96 (1H, dd, J ) 9.1, 3.9
Hz), 6.17 (1H, t, J ) 8.7 Hz), 6.20 (1H, s), 6.55 (1H, d, J ) 2.7,
Ar), 6.67 (1H, dd, J ) 8.5, 2.7 Hz, Ar), 7.02 (1H, d, J ) 8.5 Hz,
Ar), 7.24 (1H, d, J ) 9.2 Hz), 7.28-7.65 (11H, Ar), 7.77 (2H,
m, Ar), 8.10 (2H, m, Ar); 13C NMR (CDCl3) δ 11.2, 11.8, 14.8,
21.0, 21.3, 22.9, 23.1, 26.6, 27.1, 28.5, 28.77, 28.80, 29.13, 29.15,
29.2, 33.5, 35.4, 37.8, 42.6, 43.5, 44.1, 46.5, 47.4, 49.8, 53.3,
56.2, 71.7, 72.0, 74.4, 74.54, 74.56, 75.7, 76.6, 78.7, 81.2, 81.3,
84.4, 113.1, 115.1, 126.9, 127.4, 128.8, 129.0, 129.25, 129.34,
130.4, 131.3, 132.3, 132.6, 133.7, 134.0, 136.9, 139.3, 141.4,
154.3, 167.0, 167.7, 168.3, 169.2, 170.7, 171.8, 172.0, 172.9,
175.0, 202.2; HRFABMS m/z 1346.5162 [M + Na+] (calcd for
202.4; HRFABMS m/z 1224.5176 [M + H+] (calcd for C69H78
NO19, 1224.5168).
-
Su ccin ic a cid , 3,17â-d ih yd r oxyest r a -1,3,5(10)-t r ien e-
11r-yl ester 10-d ea cetyl-7-epi-ta xol ester (21): 1H NMR
(CDCl3) δ 0.74 (3H, s), 1.12 (3H, s), 1.14 (3H, s), 1.63 (3H, s),
1.77 (3H, brs), 2.47 (3H, s), 1.20-2.94 (21H, taxol and steroid
skeletons), 3.6-3.74 (2H, overlapped), 3.87 (1H, d, J ) 7.2 Hz),
4.22 (1H, brs), 4.37 (2H, brs), 4.78 (1H, d, J ) 1.8 Hz), 4.84-
4.92 (2H, overlapped), 5.38 (1H, td, J ) 10.3, 5.5 Hz), 5.73
(1H, d, J ) 7.2 Hz), 5.77 (1H, dd, J ) 9.0, 2.0 Hz), 6.19 (1H,
t, J ) 8.7 Hz), 6.46-6.55 (2H, Ar), 6.76 (1H, s), 6.88 (1H, d, J
) 8.1 Hz, Ar), 7.28 (1H, d, J ) 8.9 Hz, Ar), 7.29-7.63 (12H,
Ar and -NH), 7.72 (2H, d, J ) 7.9 Hz, Ar), 8.14 (2H, d, J )
7.9 Hz, Ar); 13C NMR (CDCl3) δ 11.8, 15.0, 16.7, 21.6, 22.8,
23.2, 26.1, 27.0, 28.4, 29.4, 30.0, 30.3, 35.4, 36.3, 37.7, 40.5,
42.2, 42.8, 44.2, 46.3, 49.8, 55.4, 57.7, 72.3, 73.4, 74.6, 75.5,
76.1, 77.9, 78.7, 79.1, 81.1, 82.3, 82.9, 112.9, 115.3, 125.9, 127.1,
127.4, 128.4, 128.9, 129.0, 129.2, 129.5, 130.4, 131.3, 132.2,
133.4, 133.8, 133.9, 138.3, 139.4, 140.3, 154.4, 167.2, 167.9,
171.2, 172.1, 172.6, 173.1, 207.2; MALDI-TOFMS m/z 1204.5
[M + Na+] (calcd for C67H75NO18Na, 1204.5).
C
73H81NO22Na, 1346.5148).
Su ccin ic a cid , 3,17â-d ih yd r oxyest r a -1,3,5(10)-t r ien e-
11r-yl ester 7-(3-ca r boxyp r op a n oyl)-2′-ta xol ester (30):
(Hydrogenation was carried out at 50 psi.) 1H NMR (CDCl3) δ
0.77 (3H, s), 1.15 (3H, s), 1.19 (3H, s), 1.80 (3H, s), 2.01 (3H,
brs), 2.13 (3H, s), 2.41 (3H, s), 1.23-2.93 (25H, taxol and
steroid skeletons), 3.73 (1H, t, J ) 8.6 Hz), 3.92 (1H, d, J )
6.9 Hz), 4.17 (1H, d, J ) 8.4 Hz), 4.32 (1H, d, J ) 8.4 Hz),
4.97 (1H, d, J ) 9.3 Hz), 5.40 (1H, dt, J ) 10.7, 5.2 Hz), 5.44
(1H, d, J ) 3.2 Hz), 5.63 (1H, dd, J ) 10.4, 7.2 Hz), 5.69 (1H,
d, J ) 6.9 Hz), 5.91 (1H, dd, J ) 9.1, 3.0 Hz), 6.21 (1H, t, J )
9.3 Hz), 6.23 (1H, s), 6.55-6.62 (2H, overlapped, Ar), 6.86 (1H,
d, J ) 8.2 Hz, Ar), 7.15 (1H, d, J ) 9.1 Hz), 7.31-7.65 (11H,
Ar), 7.77 (2H, m, Ar), 8.11 (2H, m, Ar); 13C NMR (CDCl3) δ
11.0, 11.9, 14.7, 21.0, 21.3, 22.9, 23.2, 26.6, 26.9, 28.3, 28.5,
28.7, 29.4, 29.5, 30.5, 33.3, 35.6, 37.7, 42.1, 43.4, 44.1, 46.2,
47.2, 49.9, 53.0, 56.3, 71.8, 72.1, 74.3, 74.6, 74.7, 75.7, 76.5,
78.8, 81.1, 81.2, 84.1, 112.8, 115.5, 125.5, 126.9, 127.4, 128.7,
Su ccin ic a cid , 3,17â-d ih yd r oxyest r a -1,3,5(10)-t r ien e-
11r-yl ester 2′-(3-ben zyloxyca r bon ylp r op a n oyl)-7-ta xol
1
ester (24): H NMR (CDCl3) δ 0.76 (3H, s), 1.16 (3H, s), 1.20
(3H, s), 1.83 (3H, s), 1.99 (3H, brs), 2.12 (3H, s), 2.47 (3H, s),
3.66 (1H, t, J ) 8.6 Hz), 3.95 (1H, d, J ) 6.8 Hz), 4.19 (1H, d,
J ) 8.4 Hz), 4.35 (1H, d, J ) 8.4 Hz), 4.96 (2H, s), 5.00 (1H, d,
J ) 9.4 Hz), 5.37 (1H, td, J ) 10.6, 5.3 Hz), 5.59 (1H, d, J )
3.1 Hz), 5.67-5.75 (2H, overlapped), 6.01 (1H, dd, J ) 9.1, 3.1
Hz), 6.17-6.25 (2H, overlapped), 6.54 (1H, d, J ) 2.5 Hz, Ar),
6.68 (1H, dd, J ) 8.5, 2.5 Hz, Ar), 7.05 (1H, d, J ) 8.5 Hz, Ar),
7.19 (1H, d, J ) 9.1 Hz), 7.23-7.65 (16H, Ar), 7.83 (2H, m,
Ar), 8.12 (2H, m, Ar); 13C NMR (CDCl3) δ 11.2, 11.9, 14.8, 20.9,

Steroid-Linked Taxol Analogues
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128.95, 128.98, 129.24, 129.27, 130.4, 131.3, 132.3, 132.6,
133.8, 134.0, 137.1, 139.5, 141.7, 154.6, 167.1, 167.7, 168.4,
169.7, 170.2, 171.67, 171.71, 172.3, 176.1, 202.1; HRFABMS
m/z 1346.5078 [M + Na+] (calcd for C73H81NO22Na, 1346.5148).
Cell Lin es. MDA-MB-231 and MCF-7 human mammary
carcinoma cells were propagated in Dulbecco’s Modified Eagle’s
Medium (BioWhittaker, Walkersville, MD) supplemented with
10% fetal bovine serum (Summit Biotechnology, Fort Collins,
CO) and 0.04 mg/mL gentamicin in a 7.5% CO2 atmosphere
at 37 °C.
MTS (3-(4,5-Dim et h ylt h ia zol-2-yl)-5-(3-ca r b oxym et h -
oxyp h en yl)-2-(4-su lfop h en yl)-2H-tetr a zoliu m ) Cell P r o-
lifer a tion Assa y. Experiments were performed using repli-
cate plated cells growing in 96-well sterile culture plates and
the Cell Titer96 AQueous One Solution Cell Proliferation Assay
(Promega, Madison, WI) as the source of MTS. Concentrated
stocks of the test compounds dissolved in DMSO were added
to the cells by diluting into culture medium supplemented with
5% serum. The DMSO concentration in each well was 0.1%.
After 48 h incubation, MTS was added to the culture medium.
Cell survival was assayed using the metabolic reduction MTS
to a colored product by intact viable cells as the end point.
Product formation at 37 °C, monitored by the increase in
absorbance at 490 nM, was linear for 3 h. Cell survival curves
were transformed to log-linear concentration response curves
using Prism3.0 (GraphPad Software, Inc., San Diego, CA) and
fit by nonlinear regression to the equation describing a
sigmoidal dose-response relationship. Statistically significant
differences in IC50 values between MCF-7 and MDA-MB-231
cells were determined by the Student’s t-test.
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Ack n ow led gm en t . This work was supported by the
National Institutes of Health (Grant CA-69571) and the
Department of Defense (DAMD17-99-1-9449 and DAMD17-
02-1-0622), and we are grateful for this support. We are also
grateful to William Bebout and Kim C. Harich in the Depart-
ments of Chemistry and Biochemistry, Virginia Polytechnic
Institute and State University, respectively, for mass spec-
troscopic determinations.
(15) http://www.nabco.org
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Refer en ces a n d Notes
5318.
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(20) Taxol derivative 19 was prepared by protecting the known 2′-(tert-
butyldimethylsilyl)-10-deacetyltaxol as its triethylsilyl ether at the
C-7 position: Datta, A.; Hepperle, M.; Georg G. I. J . Org. Chem. 1995,
60, 761-763.
(21) Chaudhary, A. G.; Rimoldi, J . M.; Kingston, D. G. I. J . Org. Chem.
1993, 58, 3798-3799.
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G. A.; Horwitz, S. B. Biochem. Biophys. Res. Commun. 1984, 124,
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(1) The name taxol was assigned to the chemical compound 1 by Drs.
Wall and Wani in 1971, and this name remained in general use until
1991. The name Taxol was then trademarked by Bristol-Myers Squibb
for their formulation of the chemical compound taxol on the basis of
an existing French trademark for a laxative compound with this
name. Since this paper has been submitted in honor of Drs. Wall and
Wani, the original name that they assigned for compound 1 is used,
rather than the alternative name of paclitaxel. No infringement of
the Bristol-Myers Squibb trademark is implied by this usage.
(2) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. J .
Am. Chem. Soc. 1971, 93, 2325-2327.
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