Synthesis of 7- and 10-spermine conjugates of paclitaxel and 10-deacetyl-paclitaxel as potential prodrugs

Article abstract of DOI:10.1016/j.tetlet.2006.02.108

Efficient syntheses of two taxol analogs bearing the linear polyamine spermine at 7- and 10-positions of paclitaxel and 10-deacetyl-paclitaxel have been developed. These polyamine-taxol-conjugates were isolated as water soluble difluoride salts. The aim o

Full text of DOI:10.1016/j.tetlet.2006.02.108

Tetrahedron Letters 47 (2006) 2667–2670
Synthesis of 7- and 10-spermine conjugates of paclitaxel and
10-deacetyl-paclitaxel as potential prodrugs
a,
b
b
Arturo Battaglia,a,* Andrea Guerrini, Eleonora Baldelli, Gabriele Fontana,
*
a
a
b
`
Greta Varchi, Cristian Samorı and Ezio Bombardelli
a
`
Istituto CNR per la Sintesi Organica e Fotoreattivita ‘I.S.O.F.’, Area della Ricerca di Bologna, via P. Gobetti 101,
40129 Bologna, Italy
bIndena SPA, viale Ortles 12, 20139 Milano, Italy
Received 25 January 2006; revised 15 February 2006; accepted 17 February 2006
Abstract—Efficient syntheses of two taxol analogs bearing the linear polyamine spermine at 7- and 10-positions of paclitaxel and 10-
deacetyl-paclitaxel have been developed. These polyamine-taxol-conjugates were isolated as water soluble difluoride salts. The aim
of the present work was to introduce a chemical modification into taxol skeleton in order to increase drug selectivity toward tumor
cells. The cytotoxic activity of these conjugates was evaluated in MCF7 and MCF7-R cell lines. The observed low cytotoxicity sug-
gests that these conjugates could act as potential prodrugs.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
which plays a key role in tumor invasion and metasta-
sis.5 Furthermore, taxol prodrugs were designed con-
taining a monoclonal antibody (Mab), which selec-
tively bind to antigens expressed on tumor cell and were
activated after internalization into the tumor cell via an
enzymatic hydrolysis according to ADEPT (antibody
directed enzyme prodrug therapy) strategy.6
The naturally occurring anticancer agent paclitaxel and
its analogs are currently recognized as the most impor-
tant available drugs for treatment of solid tumors espe-
cially ovarian, breast, and lung cancers.1 Unfortunately,
these compounds present relevant drawbacks, such as
poor solubility and lack of selectivity toward tumor
cells.2 Thus, water-soluble paclitaxel prodrugs, incorpo-
rating acids or amino acids at the 20-position, which are
readily hydrolyzed to taxol, have been synthesized.3 In
order to improve drug selectivity toward tumor cells,
many efforts have been made to convert taxol into com-
pounds with a considerably lower cytotoxicity but which
maintain their chemical integrity under physiological
conditions and can be rapidly cleaved by tumors
expressed proteolytic enzymes.4 For example, tripartite
prodrugs were prepared by coupling reactions between
taxol and a tripeptide moiety through a 20-carbonate,
or carbamate linkage in order to assure stability against
ubiquitous enzymatic activity. The tripeptide is cleaved
by the tumor-associated proteases, such as plasmin,
An interesting approach for drug deliver is the use of
polyamine based transporters. The ubiquitous poly-
amines, such as cadaverine, putrescine, spermidine,
and spermine are biosynthesized in humans and play
an essential role as regulators of cell growth and differ-
entiation.7 Polyamines exist in vivo as polycations since
the nitrogen is protonated at physiological pH. During
transport, the cationic polyamines bind electrostatically
to intracellular polyanions to modulate their function
and stimulate the synthesis of some proteins.8 Neverthe-
less, more data on these transporter features are re-
quired to make possible the design of prodrugs, which
comprise a cytotoxic constituent attached to a poly-
amine. Although information regarding mammalian
polyamine transporters are at an early stage,9 several
attempts to design a polyamine vector have been made.
These attempts are based on structure–activity studies,10
which suggested that minor structural changes in the
polyamine skeleton gave rise to marked differences in
Keywords: Paclitaxel; Spermine; Prodrug conjugates; Antitumor.
Corresponding authors. Tel.: +39 051 639 8311; fax: +39 051 639
8349; e-mail: battaglia@isof.cnr.it
*
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.108

2668
A. Battaglia et al. / Tetrahedron Letters 47 (2006) 2667–2670
OR1
7
OR1
OAc
O
AcO
O
RO
Bz
Bz
10
i
NH
O
1: R = Ac, R1 = C(O)-SPM;
2: R = C(O)-SPM, R1 = H
NH
O
Paclitaxel
O
O
Ph
O
Ph
O
OR
OAc
OBz
HO
OH
OBz
HO
H
3: R = TES, R1 = H; 4: R = TBS, R1 = H
5: R = TES, R1 = Im; 6: R = TBS, R1 = Im
N
NH2
SPM:
ii
ii
N
N
H
H
Figure 1.
R2NH(CH2)3-NR2-(CH2)4-NR2-(CH2)3-NH2
iii
O
R2
N
their transport behavior, and that linear polyamines
were superior vectors over their branched counterpart.
Selected examples of anticancer agents delivered by
polyamine were DNA intercalators,10 amino acids,11
nitroimidazole,12 porphyrin,13 and binuclear platinum
complexes.14
O
AcO
O
N
H
N
R2
Bz
NH
O
NHR2
O
Ph
O
OR
OAc
OBz
HO
7: R = TES, R2 = BOC; 8: R = TES, R2= CBZ
9: R = H, R2 = BOC; 10: R = H, R2 = CBZ
vi
iv
iv
This report illustrates the synthesis of new conjugates
between the linear polyamine spermine, as the transport
system, and the antitumor drug paclitaxel. The majority
of the efforts for the development of water-soluble pac-
litaxel prodrugs were focused on the synthesis of their
20-acyl derivatives, such as esters or carbamates, since
it was expected the prodrug to lose its cytotoxic activity
by modification of the 20-hydroxyl functionality.15 In
our case a serious drawback for the synthesis of the
20-carbamate linked paclitaxel-spermine conjugate was
the possible instability of the 20-acyl bond, as it has been
observed in a tripartite prodrug of paclitaxel and a tri-
peptide bearing a monosubstituted carbamate group in
the linker. A release of baccatin III was observed due
to an addition–elimination sequence of the carbamate
nitrogen to the acyl group of the isoserine appendant.15
We reasoned that this unspecific hydrolysis by ubiqui-
tous extra-cellular esterases could be avoided by forming
the carbamate linkage at the 7- and 10-positions. In par-
ticular, we have attached the spermine to the hydroxy
groups at the 7-position of paclitaxel and at the 10-posi-
tion of 10-deacetyl-paclitaxel by formation of a carba-
mate bond (compounds 1 and 2, Fig. 1).
v
1
N
R2 = tBOC, CBZ
Im =
N
O
Scheme 1. Reagents and conditions: (i) TES-Cl or TBDMSCl/
imidazole/DMAP; (ii) DCI/DMAP; (iii) CH2Cl2/iPrOH/reflux; (iv)
HF/Py; (v) CF3CO2H/NH4OH (R2 = BOC); (vi) H2/Pd (R2 = CBZ).
triprotected N1,N4,N9-tri-tert-butoxycarbonyl-19 and
N1,N4,N9-tri-benzyloxycarbonyl-spermines19 required
i
reflux conditions (4 days) in a 3:4 PrOH/CH2Cl2 mixed
solvent, affording the corresponding spermine-paclitaxel
conjugates 7 and 8 in 80% and 84% yields, respectively.
HF/Py induced selective deprotection of the 20-oxygen
of 7 and 8 yielded compounds 9 and 10 in 90% isolated
yields. Attempted deprotection of the spermine moiety
of 9 with CF3CO2H, or 10 by reduction with Me3SiI
or H2/Pd in the presence of ammonium formiate, failed
to give the target 1 since the harsh reaction conditions
favored uncontrolled side-reactions involving the taxane
skeleton.
2. Chemistry
Paclitaxel was used as the starting reagent for the semi-
syntheses of compounds 1 and 2, which are reported in
Sections 1 and 2, respectively.
Hence, the use of unprotected spermine as the coupling
partner was probed. Deprotection of the 20-oxygen of
compounds 5 or 6 with HF/Py yielded the 7-imidazolide
derivative 11 in 78% yield. This compound displayed a
high stability at 25 °C and no hydrolysis of the imidazo-
lide group was observed when its purification was per-
formed by silica gel column chromatography. The
coupling of spermine to the imidazolide 11 occurred
under milder conditions with respect to those required
for N1,N4,N9-triprotected spermines (20 °C, 2:1
2.1. Synthesis of compound 1
Different approaches were investigated for the synthesis
of 1 based on coupling reactions of a 20-protected-7-imi-
dazolide paclitaxel derivative to polyamine spermine
(SPM-H) in its free or N1,N4,N9-protected form
(Scheme 1). The synthesis of 7-imidazolides of paclitaxel
requires an initial protection of the 20-hydroxy group.
Thus, paclitaxel was converted into the corresponding
20-triethylsilyl (TES) ether 316 and the 20-tert-butyldi-
methylsilyl (TBS) ether 4,17 which were reacted with car-
bonyldiimidazole (DCI) and a catalytic amount of 4-
dimethylaminopyridine (DMAP)18 to afford the imi-
dazolides 5 and 6, respectively. The coupling of 5 with
1
iPrOH/CH2Cl2 mixed solvent, 6 h). H and 13C NMR
spectroscopic analysis of the reaction mixture showed
the presence of compound 1 as the major product
(Scheme 2). Surprisingly, this conjugate was unstable
on standing at 20 °C since it rearranged to the baccatin
derivative 12 within 24 h. Most likely an addition–elim-
ination reaction occurred between the nucleophilic
unsubstituted terminal nitrogen of the spermine moiety

A. Battaglia et al. / Tetrahedron Letters 47 (2006) 2667–2670
2669
OR1
OAc
O
H
N
OH
O
RO
H
N
Ph
Bz
Ph
O
AcO
O
N
H
N
H
NH
i
O
4
O
NHBz
O
O
O
OTBS
OBz
HO
HO
12
OAc
14: R = H, R1 = H
OBz
HO
iii or v
ii
15: R = H, R1 = TES
16: R = Im, R1 = TES
O
iii
O
AcO
O
v
iv
N
17: R = C(O)-SPM, R1 = TES
(2) . 2HF
Bz
N
i
NH
O
5 or 6
ii
1
Im = C3H3N2-CONH-; SPM: H2N-(CH2)3-NH-(CH2)4-NH-(CH2)3-NH
O
Ph
O
H
OBz
OAc
OH
Scheme 3. Reagents and conditions: (i) N2H2; (ii) TESCl/imidazole/
DMAP; (iii) DCI/DMAP; (iv) SPM-H (iPrOH/CH2Cl2, 4:1); (v)
Et3NÆ3HF.
HO
11
ii
v
O
AcO
O
O
Table 1. In vitro profile (IC50, nM)a for compounds 1, 2 and taxol, in
SPM
Bz
Ph
NH
MCF7 and MCF7-R cell lines
O
iv
(1) . 2HF
Taxola
1
2
O
Compound
O
OTBS
H
OBz
OAc
HO
MCF7
1.7
1928 38
894 85
MCF7-R
299
P3000
P3000
13
a See Ref. 23.
Scheme 2. Reagents and conditions: (i) HF/Py; (ii) SPM-H (iPrOH/
CH2Cl2, 4:1); (iii) 20 °C, 24 h; (iv) Et3NÆ3HF (1.2 equiv, 20 °C, 15 h);
(v) NaHCO3.
ine was carried out as reported above providing the
20-OTBS conjugate 17 in 52% isolated yield. Target
compound 2 was obtained as difluoride salt in 63%
yield by Et3NÆ3HF induced desilylation of 17.21
and the acyl group of the isoserine appendant of 1.
Compound 12 displayed high stability and could be
separated in 71% yields by chromatography.
3. Growth inhibition effects of taxoid-spermine
conjugates 1–2
We reasoned that reversing the reaction sequence, the
desired spermine-conjugated derivative would have been
more stable, due to the steric hindrance exerted by the
20-OTBDMS group, which inhibits the nucleophilic
attack of the terminal nitrogen of the spermine to the
carbonyl group of the isoserine side chain. Accordingly,
20-OTBS derivative 6 was reacted with spermine follow-
ing the standard protocol. The resulting conjugate 13
was stable at 85 °C and it was purified by silica gel
column chromatography (82%). The desilylation of 13
was performed with the complex Et3NÆ3HF, which
yielded the target compound 1.20 ESI-MS/MS experi-
ments (Micromass type Waters ZQ 4000 quadrupole)
showed that compound 1 was formed as the di-fluoride
salt since the spectrum appears with a number of
charges of z = 2. In fact, only the peak of the bis-cation
at the m/z value of 542 [(1+2H+)/2]+ is shown. Satisfy-
ing, this salt was stable in water solutions at 60 °C after
several days. Only the hydrolysis under basic conditions
(NaHCO3) favored its conversion into the baccatin
derivative 12.
The fluoride salts of the paclitaxel-spermine conjugates 1
and 2 were stable in water solutions. After 3 days of
incubation no degradation products were detected.
Their cytotoxic activity was evaluated by in vitro growth
inhibition experiments conducted on MCF7 sensitive
and MCF7-R resistant human breast cancer cell lines.22
These experiments showed a three order decrease in
cytotoxicity with respect to paclitaxel in the sensitive cell
line (Table 1), while no activity (63000) was found
toward resistant cell line. Hence, these water soluble,
low-toxic, and extra-cellular stable conjugates could be
suitable candidates as tumor specific prodrug after their
internalization provided that the carbamate group is
cleaved by tumor-associated enzymes.23 In vivo studies
on the activity of these compounds are currently
underway.
References and notes
2.2. Synthesis of compound 2
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lowed by selective protection of the position 7 of 14 as
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10-OH of 15 with DCI, which afforded 10-imidazolide
16 in 86% yield. Coupling of 16 with unprotected sperm-

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20. Compound [1Æ2HF]. Compound 13 (0.31 g, 0.26 mmol)
was reacted with 1.2 equiv of Et3NÆ3HF in THF at 20 °C
for 15 h. The solvent was evaporated and the residue was
washed with Et2O and recrystallized to afford 0.21 g
(0.19 mmol, 73%) of compound 1 as the difluoride salt: 1H
NMR (400 MHz, D2O, 60 °C): d 8.06 (m, 2H), 7.80–7.77
(m, 3H), 7.70–7.40 (m, 10H), 7.46–7.40 (br, 1H,
J = 9.0 Hz, NH), 6.36 (s, 1H, H10), 6.07 (t, 1H,
J = 9.0 Hz, H13), 5.56 (d, 1H, J = 7.0 Hz, H30), 5.47 (d,
1H, J = 6.8 Hz, H2), 5.30 (m, 1H, H7), 5.10 (m, 1H,
J1 = 9.5 Hz, J2 = 2.0 Hz, H5), 4.87 (d, 1H, H20), 4.36 (d,
1H, J = 8.2 Hz, H20), 4.22 (d, 1H, H020), 3.79 (d, 1H,
H3), 3.30–3.00 (m, 14H, 7 CH2), 2.55–2.45 (m, 1H, H6),
2.35 (s, 3H, Me), 2.20 (s, 3H, Me), 2.10–1.90 (m, 3H, H14,
H140, and H60), 1.90–1.60 (m, 12H, 2Me, 3CH2), 1.14 (s,
3H, Me), 1.10 (s, 3H, Me). 13C NMR (100 MHz, D2O) d
206.1, 174.0, 173.1, 172.0, 171.3, 167.6, 157.0, 141.1, 137.1,
134.7, 133.5, 132.9, 132.5, 130.1, 129.3, 129.1, 129.0, 128.9,
128.8, 127.4, 127.2, 84.0, 80.6, 78.4, 76.5, 75.7, 74.7, 73.6,
72.5, 71.4, 57.4, 56.3, 47.2, 47.0, 45.3, 44.7, 43.0, 37.7, 36.7,
34.8, 32.7, 25.9, 25.6, 24.0, 23.0, 22.5, 21.1, 20.3, 13.8, 10.6.
ESI-MS m/z 542 [(1+2H+)/2]+.
21. Compound [2Æ2HF]. Compound 13 (0.47 g, 0.40 mmol)
was reacted with 1.2 equiv of Et3NÆ3HF in THF at 20 °C
for 15 h. The solvent was evaporated and the residue was
washed with Et2O, then recrystallized from THF/Et2O to
afford 0.29 g (0.27 mmol, 66%) of compound 2 as the
difluoride salt: 1H NMR (400 MHz, CDCl3, 60 °C): d 8.18
(m, 2H), 7.92 (m, 3H), 7.80–7.72 (m, 2H), 7.75–7.68 (m,
1H), 7.65–7.50 (m, 7H), 7.40–7.33 (br, 1H, NH), 6.31 (s,
1H, H10), 6.14 (t, 1H, J = 9.0 Hz, H13), 5.63 (d, 1H,
J = 6.5 Hz, H30), 5.54 (d, 1H, J = 6.5 Hz, H2), 5.19 (d,
1H, J = 9.7 Hz, H7), 4.91 (m, 1H, J1 = 9.0 Hz,
J2 = 1.5 Hz, H5), 4.75 (m, 1H, H20), 4.16 (d, 1H,
J = 8.0 Hz, H20), 4.04 (d, 1H, H20), 3.55 (d, 1H,
J = 7.0 Hz, H3), 3.10–2.90 (m, 14H, 7 CH2), 2.68–2.60
(m, 1H, H6), 2.41 (s, 3H, Me), 2.24–21.10 (m, 3H, H14,
H140, and H60), 2.0–1.70 (m, 12H, 2Me, 3CH2), 1.22 (s,
3H, Me), 1.18 (s, 3H, Me); 13C NMR (100 MHz, D2O) d
204.5, 174.2, 173.0, 171.3, 167.7, 156.9, 140.8, 137.0, 134.6,
133.4, 133.3. 132.5, 130.1, 129.3, 129.1, 129.0, 128.9, 128.8,
127.4, 127.2, 84.6, 80.9, 78.4, 76.5, 76.4, 75.0, 73.6, 71.4,
71.0, 68.0, 57.9, 57.4, 47.1, 47.0, 45.1, 44.6, 43.0, 39.7, 37.4,
36.6, 35.5, 26.1, 25.1, 23.9, 22.9, 22.8, 22.5, 21.1, 13.8, 9.7.
ESI-MS m/z 521 [(2+2H+)/2]+.
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´
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