Synthesis and Biological Evaluation of 2′-Taxoids Derived from Baccatin III and 14β-OH-Baccatin III 1,14-Carbonate

Article abstract of DOI:10.1021/jm034146v

A series of 2′-methyl taxoids were synthesized and essayed for growth inhibition experiments conducted in human ovarian cancer cell line A2780wt and its counterparts A2780cis, A2780tax, and A2780adr, resistant to cisplatin, paclitaxel, and doxorubicin, re

Full text of DOI:10.1021/jm034146v

4822
J . Med. Chem. 2003, 46, 4822-4825
Ch a r t 1. 14â-OH-DAB and Ortataxel
Syn th esis a n d Biologica l Eva lu a tion of
2′-Meth yl Ta xoid s Der ived fr om Ba cca tin
III a n d 14â-OH-Ba cca tin III
1,14-Ca r bon a te
Arturo Battaglia,*,† Ralph J . Bernacki,‡
Carlo Bertucci,†,| Ezio Bombardelli,§
Samanta Cimitan,†,| Cristiano Ferlini,
Gabriele Fontana,§ Andrea Guerrini,† and
Antonella Riva§
Istituto CNR per La Sintesi Organica e Fotoreattivita`
“I.S.O.F.”, via Gobetti 101, 40129 Bologna, Italy,
Department of Pharmacology and Therapeutics,
Roswell Park Cancer Institute, Buffalo, New York 14263,
Dipartimento di Scienze Farmaceutiche, Universita` di
Bologna, via Belmeloro 6, 40126 Bologna, Italy,
Indena SPA, Viale Ortles 12, 20139 Milano, Italy, and
Laboratorio di Farmacologia Antineoplastica,
Ch a r t 2. Compounds 1-5
Dipartimento di Ostetricia e Ginecologia,
Universita´ Cattolica del Sacro Cuore, Roma, Italy
Received J uly 14, 2003
Abstr a ct: A series of 2′-methyl taxoids were synthesized and
essayed for growth inhibition experiments conducted in human
ovarian cancer cell line A2780wt and its counterparts A2780cis,
A2780tax, and A2780adr, resistant to cisplatin, paclitaxel, and
doxorubicin, respectively, to test the effect of this substituent
on the antitumor activity. Additional experiments were per-
formed on MCF-7 human breast cancer cell line and MCF7-R
resistant to doxorubicin. In several cases these taxoids were
more active than paclitaxel showing subnanomolar IC50 values.
including increased oral bioavailability as compared to
paclitaxel and docetaxel, and a greater ease of formu-
lation. Moreover, several of these newly synthesized
taxanes revealed remarkable increases in cytotoxicities
in cell lines which express MDR, such as doxorubicin-
resistant human breast cancer cell lines. One of these
new taxanes, Ortataxel (BAY59-8862, IDN5109), ex-
hibited 2 orders of magnitude better cytotoxicity than
paclitaxel against drug-resistant cells, and it has been
selected for clinical development.6 Additional in vitro
assays have shown that the analogues of paclitaxel and
docetaxel with an additional methyl substituent at the
C-2′ position display higher cytotoxic activity compared
to the parent compounds when evaluated in vitro assays
using HCT116 human colon carcinoma cell lines.7-9 The
enhanced potency is probably due to a reduction in the
degree of freedom of rotation at the C′2-C′3 bond or of
some additional hydrophobic interactions between the
2′-methyl and the microtubule binding sites. For this
reason, we started with a research program of synthesis
and in vitro studies of a small library of 2′-methyl
taxanes (Chart 2). Two compounds are derivatives of
baccatin III. The heteroaromatic 2-furyl group was
selected at the 3′ position of the appendant of the two
taxanes which differed in the type of substituent at the
nitrogen atom: a benzoyl group (compound 1), or a BOC
(2).10 We have also synthesized three derivatives of 14â-
OH-baccatin III 1,14-carbonate carrying a BOC group
at the nitrogen atom. These compounds beared a 2-furyl
(3), a phenyl (4), and a trifluoromethyl (5). All taxoids
bear the acetyl group at C-10 because it has been
observed that the presence of a substituent at this
position is essential for modulation of P-gp, hence to
overcome MDR in vitro.5a Compounds 1-5 were tested
in a panel of ovarian carcinoma cell lines and several
have demonstrated increased activity as compared to
In tr od u ction . The naturally occurring taxoids, pa-
clitaxel and docetaxel, exhibit outstanding therapeutic
activity against solid tumors.1 Clinical use of these
agents, however, demonstrates that these drugs have
various undesirable side effects including peripheral
neuropathies. Moreover, therapy often leads to the
development of multidrug resistance (MDR), one of the
most common mechanisms of drug resistance.2 MDR
induced by taxoid treatment may be mediated by a
number of mechanisms, including overexpression of the
energy-dependent drug-transporter P-glycoprotein that
acts as an efflux system for a number of xenobiotics,
thereby reducing their intratumor cell concentration
and effectiveness.3 Therefore, modifications of the diter-
pene moiety and the isoserine appendants of taxoids
were investigated to improve the pharmacological profile
of this class of agents.4 The literature reports a series
of new taxanes which were synthesized from 14â-OH-
10-deacetyl-baccatin III (14â-OH-DAB, Chart 1), a
naturally occurring synthon isolated from the needles
of Taxus wallichiana Zucc.5 Among these compounds,
the taxoids derived from 14â-OH-baccatin III 1,14-
carbonate display improved pharmacological properties,
* To whom correspondence should be addressed. Phone: 0039-051-
6398311. Fax: 0039-051-6398349. E-mail: battaglia@area.bo.cnr.it.
† Istituto CNR “I.S.O.F.”.
‡ Rosewell Park Cancer Institute.
§ Indena SPA.
| Universita` di Bologna.
Universita´ Cattolica del Sacro Cuore.
10.1021/jm034146v CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/15/2003

Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 23 4823
Sch em e 1a
(2S)-8 (2S/2R ) 96:4) by annihilation of the stereogenic
center at C-5 with a base, such as LDA or lithium bis-
(trimethylsilyl)amide (LHMDS). The addition of the
enolate (2S)-8 to the 2-furyl-N-trimethylsilylimine 9,
cyclization, removal of the auxiliary center, and desi-
lylation provided mixtures of the â-lactams (3R,4S)-11
(major isomer) and (3R,4R)-12 (minor). Similarly, the
phenyl-N-trimethylsilylimine 10 gave (3R,4S)-13 (ma-
jor) and (3R,4R)-12 (minor) (Table 1S, Supporting
Information). The (3R,4S) stereochemistry of the major
isomers 11 and 13 was that required for the taxoid
appendants. Enantioselective HPLC analysis showed
that 11 and 13 were obtained as enantiomeric couples
in a ratio (3R,4S)/(3S,4R) ) 96:4 (ee ) 92%). This result
indicated that the cycloaddition occurred under total
facial-diastereocontrol because the obtained 92% ee
corresponds to that expected on the basis of the dia-
stereomeric excess (de) of the starting lactone 6. The
addition of (2S)-8 to trifluoromethyl-N-p-methoxy-
phenyl-imine 15 gave a 4:1 diastereomeric mixture of
â-lactams (3R,4R)-16 and (3R,4S)-17. Differently to that
obtained for compounds 11-14, the addition of 15 to
the enolate lacked stereochemical control at the C5
carbon atom. In fact, the 1H NMR analysis in the
presence of the chiral shift reagent Yt(hfc)3 showed that
both diastereomeric â-lactams were obtained with an
enantiomeric excess (ee) of 54%. The steric interaction
of the small trifluoromethyl substituent of the imine
with the tert-butyl substituent does not preclude the
attack of the enolate to the imine from the more
hindered face, causing the formation of minor amounts
of the enantiomeric â-lactams ent-16 and ent-17.16 The
â-lactams 11 and 13 and the mixture of 16 and ent-16
were protected as triethylsilyl ethers (OTes) by treat-
ment with Et3SiCl and imidazole to afford compounds
18 (R ) 2-furyl), 19 (R ) C6H5), and 20 (R ) CF3). The
C6H4-p-OMe group of 20 was oxidatively cleaved with
cerium ammonium nitrate (CAN) to yield the NH free
â-lactam 21. Schotten-Baumann N-benzoylation of the
â-lactam 18 gave the 1-benzoyl-protected â-lactam
(3R,4S)-22 (R ) 2-furyl). Instead, the treatment of 18,
19, and 21 with di-tert-butyl dicarbonate/DMAP gave
the 1-BOC-protected â-lactams 23 (R ) 2-furyl), 24 (R
) C6H5), and a 77:23 mixture of 25/ent-25 (R ) CF3).
The esterification of 23 with metalated 7-Tes-baccatin
III (26, Chart 1) gave the 2′-methyl-taxoid 28 (Scheme
2 and Table 2S, Supporting Information). The reactions
of metalated 7-Tes-14â-OH-baccatin III 1,14-carbonate
(27, Chart 1) and â-lactams 23 and 24 gave compounds
29 (R ) 2-furyl) and 30 (R ) C6H5), while the coupling
with the 77:23 mixture of 25/ent-25 occurred with
kinetic resolution, probably due to the very low reaction
temperature (-50 °C). In fact, only compound 31 was
detected by 1H NMR in the crude reaction mixture. The
high level of kinetic resolution in the coupling reactions
of enantiomeric mixtures of (3R,4S)- and (3S,4R)-â-
lactams and metalated baccatin III at low temperatures
was noticed by Holton.17 The origin of the kinetic
resolution of racemic mixtures of (3R,4R)- and (3S,4S)-
CF3-â-lactams was explained on the basis that only the
(3R,4R)-isomer can adopt a relative orientation, with
respect to the metalated baccatin, which results in a
minimization of steric interactions for this orientation.18
Thus, the total kinetic resolution of the 77:23 mixture
a
Reagents: (i) LDA or LiHMDS/THF/HMPA (85:15)/-78 °C;
(ii) tBuMeCdO; (iii) TesCl/imidazole; (iv) CAN; (v) C6H5COCl/
NaHCO3; (vi) BOC2O/DMAP.
paclitaxel in multidrug resistant ovarian (and breast)
tumor cell lines. The possibility to identify new cytotoxic
agents active on wild-type, and more importantly on
resistant cell lines, has been explored in order to
improve the therapeutic outcome of taxane treatment
on cancer.
R esu lt s a n d Discu ssion . A. Syn t h esis of New
Ta xoid s. The addition of baccatin derivatives to 1-acyl-
â-lactams,11 or N,O-protected isoserinic acids (usually
as oxazolidine derivatives),12 are well established pro-
tocols for the semisynthesis of taxoids. The C7-OH group
of the diterpene moiety must be protected to avoid the
epimerization of this stereocenter.13 We have used the
â-lactam protocol for the synthesis of taxoids 2-5 bearing
a BOC group at the C3′-nitrogen atom. Instead, the
oxazolidine route was used for the synthesis of the
N-benzoyl analogue 1. Some years ago, we developed a
versatile protocol for the asymmetric synthesis of trisub-
situted 3-hydroxy-â-lactams which uses readily avail-
able aldimines and (2S)-R-hydroxy carboxylic acids as
starting reagents.14 This strategy is attractive because
can tolerate a range of substituents at the 3- and
4-position of the resulting 3-hydroxy â-lactams. Accord-
ingly, the (2S)-lactic acid was converted into a diaster-
eomeric mixture of 2-tert-butyl-2, 5-dimethyl-[1,3]-
dioxolan-4-ones (2S,5S)-6 and (2R,5S)-7 by acetalization
with pinacolone (Scheme 1). The major (2S,5S)-isomer
was isolated as a 96:4 (2S,5S)/(2R,5S) mixture.15 The
dioxolanone was converted into the lithium enolate

4824 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 23
Letters
Sch em e 2a
Sch em e 3a
a
Reagents: (i) MeOH/imidazole; (ii) 2,4-(MeO)2C6H3CH(OMe)2,
PPTS; (iii) LiOH/H2O; (iv) (2-pyridylO)2CdS/DMAP; (v) HF/
pyridine/MeCN; (vi) AcCl/MeOH.
Ta ble 1. In Vitro Profile (IC50, nM)a for Compounds 1-5,
Taxol, IDN5109, in A2780, A2780cis, A2780adr, and A2780tax
Cell Lines
A2780CIS
(R/S)
A2780ADR
A2780TAX
compounda
A2780
(R/S)
(R/S)
Taxol
Ortataxel
5.3
4.8
3.1
2.9
5.9
2.5
4.6
4.6 (0.9)
3.6 (0.7)
2.9 (0.9)
3.3 (1.1)
2.5 (0.4)
1.7 (0.7)
2.8 (0.6)
2688 (507)
63 (13)
61.4 (20)
41.3 (14)
27.1 (4)
4498 (849)
56 (12)
420 (135)
312 (107)
30.9 (5)
1
2
3
4
5
a
Reagents: (i) NaHMDS/THF/-40 °C; (ii) HF/pyridine/MeCN/
25 °C.
52.9 (21)
79.3 (17)
299 (118)
285 (61)
of (3R,4R)/(3S,4S)-25 by the chiral metal alkoxide of 27
yielded the taxoid 31 with desired (R)-configuration at
the C-2′ and C-3′ positions. The metalation of the C13-
OH of 26 and 27 was carried out with NaHMDS as the
base.9 The pivotal role of the counterion of the base (Na+
vs Li+) was apparent when 27 was the partner of the
â-lactams. In fact, Na+ was the key ingredient for the
formation of the 2′-methyl taxoids 3-5 since much lower
yields were observed (<10%) when LiHMDS was used.
A similar effect, but less impressive, is also reported in
the literature with the baccatin derivative 26.9 The 2′-
methyl-taxoids 28-31 were desilylated by treatment
with HF/pyridine to yield compounds 2-5. The esterifi-
cation of metalated 26 with the N-benzoyl-â-lactam 22
gave 33 in only 10% (Table 1S). The 13-O-benzoyl-7-
Tes-baccatin III was recovered as the major product.
This result was unexpected considering that the reac-
tion of 26 with the N-BOC analogue of 22 gave the
corresponding taxoid in much higher yields (55%).9 The
desylilation of 33 with HF/pyridine yielded compound
1. For this reason, the synthesis of 1 via N,O-protected
isoserine route was attempted. We have already re-
ported the synthesis of the oxazolidine derivative 34,
as a 4:1 mixture of epimers at C5, from the ester 33.19
LiOH induced hydrolysis of 34 afforded the carboxylic
acid 35. Alternatively, 33 was also prepared by metha-
nolysis of â-lactam 22 (Scheme 3). The esterification of
the acid 35 with 26, in the presence of dicyclohexylcar-
bodiimide and DMAP, failed. Instead, the variant
protocol which uses di-2-pyridyl thionocarbonate as the
dehydrating agent gave a mixture of epimeric taxoids
36 in moderate amounts (Table 2S). This mixture was
subjected to sequential desilylation and N,O-deprotec-
tion to yield 1.
a
The concentration of compound which inhibits 50%.
compounds 1-5. For this reason, the in vitro growth
inhibition experiments were conducted in the A2780wt
ovarian cell line, a model that demonstrated excellent
sensitivity to paclitaxel and in the counterpart A2780cis
cell line resistant to cisplatin, which is characterized
by a MDR-independent mechanism. In addition, the
citotoxicity was also tested against A2780adr and
A2780tax cell lines resistant to doxorubicin and pacli-
taxel, respectively. Both these cell lines exhibit an MDR
phenotype with P-glycoprotein overexpression. The
results, expressed as IC50 values, are reported in Table
1. The potency differential in the resistant vs sensitive
cell line is expressed as a ratio of their IC50 values (R/S
ratio). High in vitro potency against both the sensitive
and the resistant cell lines is expressed by a low R/S
ratio. To better appreciate compounds properties, the
ratio with respect to the paclitaxel activity was also
calculated by dividing the IC50 obtained in each cell line
over the IC50 of paclitaxel in the same cells (Figure 1,
Supporting Information). Values lower than 1 indicates
an activity higher than that of paclitaxel. The newly
developed analogues are very potent cytotoxic com-
pounds especially in resistant cell lines. Compound 1
is several times more active than paclitaxel in A2780tax
and A2780adr and cell lines that overexpress P-gp.
Compound 2 is slightly less active than 1 in the P-gp
negative cell lines, but it is more potent in A2780tax
and A2780adr cells. Cytotoxicity of carbonates 3, 4, and
5 were similar to paclitaxel in A2780wt and A2780 cis.
However, all the carbonates (3-5) were more active
than paclitaxel in P-gp positive cell lines. The most
potent antitumor agent was the taxoid 3. In sensitive
and cis-platinum resistant cell lines, 3 and paclitaxel
produced similar results, while in taxol and doxorubicin
resistant cell lines the new analogue is more than 2
orders of magnitude more active than paclitaxel and also
B. Gr ow th In h ibition Effects of Ta xoid s 1-5. Our
initial goal was to evaluate the effect of the restriction
in the degree of freedom of rotation at the C′2-C′3 bond
on the cytotoxic activity of the 2′-methyl-substituted

Letters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 23 4825
Ta ble 2. In Vitro Profile (IC50, nM) for Compound 3, Taxol,a
Docetaxel,a Idn5109,a and 37a in MCF7 and MCF7-R Cell Lines
(6) IDN5109 is characterized by an improved preclinical profile in
terms of efficacy and tolerability. See: (a) Nicoletti, M. I.;
Colombo, T.; Rossi, C.; Monardo, C.; Stura, S.; Zucchetti, M.;
Riva, A.; Morazzoni, P.; Donati, M. B.; Bombardelli, E.; D’Incalci,
M.; Giavazzi, R. IDN5109, a taxane with oral bioavailability and
potent antitumor activity. Cancer Res. 2000, 60, 842-846.
(7) Kant, J .; Schwartz, W. S.; Fairchild, C.; Gao, Q.; Huang, S.; Long,
B. H.; Kadow, J . F.; Langley, D. R.; Farina, V.; Vyas, D.
Diastereoselective Addition of Grignard Reagents to Azetidine-
1,3-dione: Synthesis of Novel Taxol Analogues. Tetrahedron Lett.
1996, 37, 6495-6498.
Taxola Docetaxela IDN5109a
1.7 1.0 1.1
299 235 36
176 235 33
3b
37a
MCF7
MCF7-R
(R/S)
1.7 (0.54)
16 (7.8)
9.4 (14)
0.5
49
96
a
b
See ref 5a. Duplicate experiment in parentheses.
(8) Denis, J .-N.; Fkyerat, A.; Gimbert, Y.; Coutterez, C.; Mantellier,
P.; J ost, S.; Greene, A. E. Docetaxel (Taxote`re) derivatives: novel
NbCl3-based stereoslective approach to 2′-methylated docetaxel.
J . Chem. Soc., Perkin Trans. 1, 1995, 1811-1816.
more active than Ortataxel. On the basis of these
findings, we have focused our attention on compound 3
which was tested in additional cytotoxic experiments
on human breast cell lines, MCF-7 and its counterpart
MCF7-R resistant to doxorubicin. The obtained results
confirmed the previous ones. The activity of 3 is
comparable to that of paclitaxel in the sensitive MCF7
cell line, while it was almost 20-fold more active than
paclitaxel against the resistant MCF7-R (Table 2).
Moreover, this compound was more potent than its 2′-
demethyl derivative 375a (Chart 3, Supporting Informa-
tion) and Ortataxel (IDN5109)5a in both the sensitive
and the Pgp positive, multidrug resistant cell lines,
associated with a lower R/S value.
Con clu sion s. Our results clearly outlined the ben-
eficial effect of the additional methyl substituent, hence
of the conformational restriction in the rotation around
the C2′-C′3 bond, on the cytotoxicity of the sensitive
cell lines A2780 and MCF7, and their resistant coun-
terparts. For this reason, the taxoids here tested are
characterized by low differential potencies, hence are
potential candidates to develop new drugs able to
overcome the resistant phenotype. However, mecha-
nisms through which this overcoming is obtained merit
further investigations. Also, further experiments are
actively underway to elucidate the in vivo antitumor
activities of these new molecules.
(9) Ojima, I.; Wang, T.; Delaloge, F. Extremely Stereoselective
Alkylation of 3-Silyloxy-â-lactams and Its Applications to the
Asymmetric Syntheses of Novel 2-Alkylisoserines, Their Dipep-
tides, and Taxoids. Tetrahedron Lett. 1998, 39, 3663-3666.
(10) In vitro studies evidentiated that taxanes derived from baccatin
III or 14â-OH-baccatin III 1,14-carbonate, which bear a hetero-
aromatic group at the 3′ position, display superior cytotoxic
activity with respect to taxol. See: (a) ref 5a. (b) Georg, G. I.;
Harriman, G. C. B.; Hepperle, M.; Clowers, J . S.; Vander Velde,
D. G.; Himes, R. H. Synthesis, Conformational analysis, and
biological Evaluation of Heteroaromatic Taxanes. J . Org. Chem.
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(11) (a) Ojima, I.; Habus, I.; Zhao, M.; Georg, G. I.; J ayasinghe, R.
Efficient and Practical Asymmetric Synthesis of the Taxol C-13
Side Chain, N-Benzoyl-(2R,3S)-3-phenylisoserine, and Its Ana-
logues via Chiral 3-Hydroxyl-4-aryl-â-lactams Through Chiral
Ester Enolate - Imine Cyclocondensation. J . Org. Chem. 1991,
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(12) Kingston, D. G. I.; Chaudhary, A. G.; Gunatilaka, A. A. L.;
Middleton, M. L. Synthesis of Taxol from Baccatin III via an
Oxazoline Intermediate. Tetrahedron Lett. 1994, 35, 4483-4484.
(13) For the synthesis of 7-Tes-baccatin III, see: Kant, J .; O’Keffe,
W. S.; Chen, S.-H.; Farina, V.; Fairchild, C.; J ohnston, K.;
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ref 15a.
(14) (a) Barbaro, G.; Battaglia, A.; Guerrini, A.; Bertucci, (3R)-Chiral
Control of 3-Alkyl-3-hydroxy-â-lactams via Addition Reaction of
Imines to Enolates of 1,3-Dioxolan-4-ones. J . Org. Chem. 1999,
64, 4643-4651. (b) Barbaro, G.; Battaglia, A.; Di Giuseppe, F.;
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(15) However, it is possible to obtain the enantiomerically pure
(2S,5S)-isomer by repeated crystallizations.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the new compounds, Tables 1S and 2S, Figure 1, and
Chart 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
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