Solid-phase organic synthesis of unnatural polyamine analogues bearing a dansyl or acridine moiety

Article abstract of DOI:10.1211/146080899128734712

The synthesis of unnatural polyamines and polyamine conjugates from a protected triamine anchored to Wang resin is described. The use of solid-phase organic synthesis for such hydrophilic compounds is of interest because it removes the need for often awkward chromatographic purification of intermediates and is easily applied to the synthesis of compound libraries. Chain elongation was achieved by reductive amination and the resulting resin bound tetraamine was functionalized with dansyl and acridine moieties. The conjugates were cleaved from the resin and these studies should lead to the rapid synthesis of libraries for biological evaluation.

Full text of DOI:10.1211/146080899128734712

Pharm. Pharmacol. Commun. 1999, 5: 151±157
# 1999 Pharm. Pharmacol. Commun.
Solid-phase Organic Synthesis of Unnatural Polyamine
Analogues Bearing a Dansyl or Acridine Moiety
S. CARRINGTON, J. RENAULT*, S. TOMASI*, S. SINBANDHIT{, I. S. BLAGBROUGH
AND P. URIAC*
Department of Pharmacy and Pharmacology, University of Bath, BA2 7AY, UK, *Pharmacochimie des
Â
Á
Â
Â
Molecules de Synthese et des Produits Naturels, Faculte de Pharmacie, 2 Avenue du Professeur Leon
Â
Bernard, 35043 Rennes Cedex, and {CRMPO, Universite de Rennes I, Campus de Beaulieu, 35042 Rennes
Cedex, France
Abstract
The synthesis of unnatural polyamines and polyamine conjugates from a protected triamine
anchored to Wang resin is described. The use of solid-phase organic synthesis for such
hydrophilic compounds is of interest because it removes the need for often awkward
chromatographic puri®cation of intermediates and is easily applied to the synthesis of
compound libraries. Chain elongation was achieved by reductive amination and the
resulting resin bound tetraamine was functionalized with dansyl and acridine moieties.
The conjugates were cleaved from the resin and these studies should lead to the rapid
synthesis of libraries for biological evaluation.
Polyamines are common, low molecular weight
polycationic molecules, essential for cell growth
and replication (Tabor & Tabor 1964, 1984 ). The
speci®c biological roles played by these com-
pounds have led to interest in their synthesis and
that of analogues as potential mimics or biosyn-
thetic enzyme inhibitors. The discovery that
depletion of cellular polyamines leads to the ces-
sation of cell growth has led to the design of
polyamino-derived conjugates with potential as
antitumour and antiparasitic agents (Marton &
Pegg 1995; Blagbrough et al 1997; Tye et al 1998).
Other biological targets of interest include NMDA
and ion-channel receptors which are blocked by
polyamine amides isolated from the venoms of
certain spiders and wasps (Blagbrough et al 1997).
We previously reported the solid-phase organic
synthesis of putrescine and spermine derivatives
and initial biological evaluation of antitumour
activity (Tomasi et al 1998). Two major advantages
of solid-phase organic synthesis are the simpli®-
cation of puri®cation procedures which can often
be dif®cult with such hydrophilic compounds, and
the possibility of readily introducing molecular
diversity by coupling various groups with the
polyamine (e.g. amides, sulphonamides, amines,
ureas, amino acids). However, one limiting factor is
the choice of the polyamine which is ®rst attached
to the resin (Dixit & Leznoff 1977, 1978; Hiroshige
et al 1995; Marsh et al 1996; Nash et al 1996;
Kellam et al 1997; Byk et al 1997; Page et al 1998).
A key area of interest associated with the structure±
activity of polyamines and their analogues is the
spacing between the amino groups along the
polyamine chain. The use of solid-phase organic
synthesis for polyamine synthesis would be greatly
enhanced by the development of a method of
regiospec®cally constructing chains containing 3,
4, 5 or more amino groups, masked by orthogonally
removable protecting groups, allowing for regios-
peci®c conjugation to other moieties.
We report here preliminary attempts at the ela-
boration of polyamines on a solid support. To extend
the polyamine chain we have carried out reductive
amination of a tri-amine, tethered to a solid support
with an azidoketone, followed by reduction of the
azido group (Benalil 1991) using triphenylphosphine
and water to generate a new amine. The dansyl group
(Chao et al 1997; Seiler et al 1998) and the acridine
group (Blagbrough et al 1998) were then coupled
with the terminal amine to give, after resin cleavage,
novel polyamine conjugates.
Â
Correspondence: P. Uriac, Pharmacochimie des Molecules
de Synthese et des Produits Naturels, Faculte de Pharmacie,
Á
Â
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2 Avenue du Professeur Leon Bernard, 35043 Rennes Cedex,
France.

152
S. CARRINGTON ET AL
Materials and Methods
(d: 8Á05, 1H), Ar-H (d: 8Á35, 1H), Ar-H (d: 8Á50,
1H), Ar-H (d: 8Á75, 1H).
IR spectra were recorded on a 16 PC FTIR Perkin-
Elmer Spectrometer. Solids were examined with a
diffuse re¯ectance accessory. 1H NMR spectra
were recorded on a Bruker DMX spectrometer at
500 MHz. Chemical shifts were expressed in ppm
down®eld from tetramethylsilane.
Preparation of polymer 6
Acridine-9-carboxylic acid hydrate (1Á1 g, 5Á6 mmol)
wassuspended in anhydrous DMF (20 mL)thenDCC
(1Á43 g, 6Á86 mmol) in anhydrous DMF (5 mL) and
HOBt (0Á68 g, 5Á03 mmol) in anhydrous DMF (5 mL)
were added to the suspension. The reaction was stir-
red for 18 h at 60ꢀC and then cooled and ®ltered. The
®ltrate was mixed with 0Á4 g (0Á26 mmol) polymer 3
in DMF (3Á5 mL) and then the reactor was ¯ushed
with N2, sealed and agitated for 16 h. The resin was
washed with anhydrous DMF (5 6 5 mL) and the
procedure was repeated with the same quantity of
reagent, agitating for 3 h. The resin was washed
according to the general procedure and dried under
reduced pressure.
Preparation of polymer 3
A solution of the monoprotected triamine 2 (1Á90 g,
8Á1 mmol) in anhydrous CH2Cl2 (5 mL) was added
dropwise to a suspension of the polymer 1 (2Á5 g,
1Á62 mmol) in anhydrous dichloromethane
(CH2Cl2, 8 mL). After agitation for 18 h at room
temperature, the suspension was washed succes-
sively
with
CH2Cl2
(2 6 10 mL),
THF
(2 6 10 mL), water±THF (1 : 1, 10 mL), water
(2 6 10 mL), THF (2 6 10 mL), Et2O (2 6 10 mL)
(general washing procedure) and then dried under
reduced pressure.
1
1
IR:
1800 cm
n NH 3310 cm , n CO 1870 cm ,
1
1
IR: n NH 3400 cm , n CO 1685 cm 1; 13C NMR
Cleavage of compound 7
(gel phase in CDCl3): 3 6 CH3 (28Á40), C-2, C-6
(31Á6, 32Á40), C-1 (39Á35), C-7 (40Á45), C-3, C-5
(43Á90), C(CH3)3 (79Á75), CO (155Á85).
Polymer 6 (0Á9 g, 0Á58 mmol) was treated with a
mixture of TFA±CH2Cl2 (1 : 1, 2 mL) for 1 h at
0ꢀC. The residue was concentrated under reduced
pressure, puri®ed by ¯ash column chromatography
on silica gel eluting with CH2Cl2 CH3OH±
concentrated aqueous NH3 (8 : 5 : 1) and converted
into the hydrochloride salt as described for com-
pound 5 to yield the product as a pale yellow glass
(0Á08 g, 40%).
Preparation of polymer 4
A
solution of 4-methylmorpholine (0Á70 g,
0Á65 mmol) in CH2Cl2 (1 mL) and a solution of
dansyl chloride (0Á17 g, 0Á65 mmol) in CH2Cl2
(2 mL) were added successively to a suspension of
polymer 3 (0Á5 g, 0Á32 mmol). The suspension was
stirred for 18 h and washed according to the general
procedure. The polymer was reacted and washed a
second time under the same conditions to ensure
the reaction went to completion.
1H NMR (D2O) CH2 (m: 2Á18, 2H), CH2
(m: 2Á27, 2H), CH2N (m: 3Á15, 3Á27, 3Á31, 6H),
CH2NCO (m: 3Á80, 2H), Ar-H (t: 7Á82, 2H,
J ˆ 7), Ar-H (t: 8Á09, 2H, J ˆ 7), Ar-H (d: 8Á14,
2H, J ˆ 8), Ar-H (d: 8Á26, 2H, J ˆ 8).
1
1
IR: n NH 3350 cm , n CO 1685 cm .
Preparation of 5-azidopentan-2-one 8
To a solution of 5-chloropentan-2-one (6 g, 50 mmol)
in methyl sulphoxide (DMSO, 100 mL) in the pre-
sence of a catalytic amount of sodium iodide (0Á25 g),
sodium azide (4Á85 g, 75 mmol) was added. The
suspension was stirred at 50ꢀC for 18 h and the mix-
ture was then diluted with water (150 mL) and
extracted with Et2O (4 6 50 mL). The combined
organic layers were washed with brine (2 6 50 mL),
dried over magnesium sulphate and evaporated to
dryness at 30ꢀC under reduced pressure to yield 8 as a
pale yellow oil (5Á60 g, 90%).
Cleavage of compound 5
Polymer 4 (0Á5 g, 0Á32 mmol) was stirred in a
mixture of TFA±CH2Cl2 1 : 1 (1 mL) for 2 h at
room temperature. The polymer was removed by
®ltration. The ®ltrate was concentrated to dryness
under reduced pressure, dissolved in a minimal
amount of water (2 mL), basi®ed with 10% aqueous
NaOH and then extracted with CH2Cl2
(3 6 20 mL). The organic layer was dried over
K2CO3 and the solvent removed under reduced
pressure. The crude residue was dissolved in EtOH
(2 mL) and a 1Á5 M ethanolic solution of hydro-
chloric acid (1Á2 equiv.) was added at 0ꢀC. After
30 min of stirring, the EtOH was evaporated and
the residue was triturated with Et2O to yield 5 as a
1
1 1
IR: n N3 2090 cm , n CO 1710 cm ; H NMR
(CDCl3): H-4 (m: 1Á85, 2H), H-1 (s: 2Á15, 2H), H-3
(t: 2Á55, 2H), H-5 (t: 3Á30, 2H).
1
Preparation of polymer 9
solid (0Á05 g, 33%). H NMR (D2O) H-3 (m: 1Á85,
2H), H-7 (m: 2Á10, 2H), H-2, 4, 6, 8 (m: 3Á10, 8H),
2 6 CH3 (s: 3Á45, 6H), Ar-H (m: 7Á90, 2H), Ar-H
Method a. Polymer 3 (1 g, 0Á65 mmol) was sus-
pended in trimethyl orthoformate (10 mL) for

SYNTHESIS OF UNNATURAL POLYAMINE ANALOGUES
153
Preparation of polymer 13
30 min under nitrogen ¯ush. 5-Azidopentan-2-one
8 (1Á15 g, 13 mmol), was added. The suspension
was agitated for 18 h at room temperature under
nitrogen atmosphere then washed successively with
THF (2 6 20 mL), EtOH (5 6 20 mL), CH2Cl2
(2 6 20 mL), Et2O (2 6 20 mL) and then dried
under reduced pressure. A second procedure was
carried out under the same conditions and the
polymer obtained was suspended in trimethyl
orthoformate (10 mL), stirred for 48 h at room
temperature in the presence of sodium cyanoboro-
hydride (0Á80 g, 13 mmol), washed successively
with EtOH (2 6 20 mL), a mixture of water and
EtOH (20 mL), water (3 6 20 mL), EtOH
Polymer 11 (0Á9 g, 0Á58 mmol) was suspended in
THF (5 mL) in the presence of water (0Á1 mL) and
triphenylphosphine (0Á30 g, 1Á16 mmol) and stirred
for 18 h at room temperature. The polymer was
washed according to the general procedure and
treated again under the same conditions.
1
1
IR: n NH 3340 cm , n CO 1700 cm .
Preparation of polymer 14
Polymer 13 (0Á9 g, 0Á58 mmol) was treated with 4-
methylmorpholine (1Á20 g, 1Á16 mmol) and dansyl
chloride (0Á31 g, 1Á16 mmol) under the conditions
described for the polymer 4.
1
1
IR: n NH 3340 cm , n CO 1685 cm .
(3 6 20 mL),
CH2Cl2
(2 6 20 mL),
Et2O
(2 6 20 mL) and dried under reduced pressure.
Cleavage of compound 15
Polymer 14 (0Á8 g, 0Á52 mmol) was treated with a
mixture of TFA±CH2Cl2 (1 : 1, 2 mL) under the
conditions described for the compound 5 to yield a
white solid. (0Á15 g, 35%).
Method b. Polymer 3 (2 g, 1Á30 mmol) was sus-
pended in a mixture of dimethylformamide (DMF)
and EtOH (3 : 1, 10 mL). The azidoketone 8 (1Á15 g,
13 mmol) and borane±pyridine complex (13 mmol)
were added successively to the polymer under
argon atmosphere. The polymer was stirred at room
temperature for 48 h and washed according to the
general procedure.
1H NMR (D2O): CH3 (d: 1Á15, 3H), H-2, 3, 7, 11
(m: 2Á10, 8H), H-1,4, 6, 8, 10, 12 (m: 3Á10, 11H),
2 6 CH3 (s: 3Á35, 6H), 2 6 CH3 (s: 3Á45, 6H), Ar-H
(m: 7Á85, 4H), Ar-H (m: 7Á95, 1H), Ar-H (m: 8Á15,
1H), Ar-H (m: 8Á30, 1H), Ar-H (m: 8Á45, 1H), Ar-H
(m: 8Á50, 2H), Ar-H (m: 8Á55, 1H), Ar-H (m: 8Á70,
1H).
1
1
IR: n NH 3350 cm , n N3 2095 cm , n CO
1685 cm .
1
Cleavage of compound 10
Polymer 9 (0Á1 g, 0Á065 mmol) was treated with a
mixture of TFA±CH2Cl2 (1 : 1, 0Á5 mL) for 2 h at
room temperature. The residue was concentrated
under reduced pressure to yield a pale solid.
1H NMR (D2O): CH3 (d: 1Á35, 3H), H-2, 3, 7, 11
(m: 3Á10, 8H), H-4, 6, 8, 10, 12 (m: 3Á20, 9H), H-1
(m: 3Á30, 2H).
Preparation of polymer 16
Polymer 9 (1 g, 0Á65 mmol) was suspended in CH2Cl2
(8 mL) and a solution of di-tert-butyl dicarbonate
(0Á70 g, 3Á25 mmol) in CH2Cl2 was added. The sus-
pension was stirred at room temperature for 18 h,
washed and treated again under the same conditions
to drive the reaction to completion.
1
1
IR: n NH 3330 cm , n N3 2090 cm , n CO
1690 cm .
1
Preparation of polymer 11
Polymer 9 (1 g, 0Á65 mmol, prepared according to
Method b) was treated with 4-methylmorpholine
(1Á4 g, 1Á30 mmol) and dansyl chloride (0Á35 g,
1Á30 mmol) under the conditions described for the
polymer 4.
Preparation of polymer 17
Polymer 16 (0Á9 g, 0Á58 mmol) was treated with
water (0Á1 mL) and triphenylphosphine (0Á30 g,
1Á16 mmol) under the conditions described for the
preparation of 13.
1
1
IR: n NH 3330 cm , n N3 2090 cm , n CO
1680 cm .
1
1
1
IR: n NH 3400 cm , n CO 1690 cm .
Cleavage of compound 12
Preparation of polymer 18
Polymer 11 (0Á1 g, 0Á065 mmol) was treated with a
mixture of TFA±CH2Cl2 (1 : 1, 0Á5 mL) under the
conditions described for the compound 10, to yield
a white solid.
Polymer 17 (0Á9 g, 0Á58 mmol) was treated with 4-
methylmorpholine (1Á20 g, 1Á16 mmol) and dansyl
chloride (0Á31 g, 1Á16 mmol) under the conditions
described for the polymer 4.
1H NMR (D2O): CH3 (d: 1Á35, 3H), H-2, 3, 7, 11
(m: 2Á10, 8H), H-4, 6, 8, 10, 12 (m: 3Á20, 9H), H-1
(m: 3Á30, 2H), 2 6 CH3 (s, 3Á40, 6H), Ar-H (m:
7Á85, 2H), Ar-H (m: 7Á95, 1H), Ar-H (m:8Á45, 2H),
Ar-H (m: 8Á65, 1H).
1
1
IR: n NH 3400 cm , n CO 1690 cm .
Cleavage of compound 19
Polymer 18 (0Á8 g, 0Á52 mmol) was treated with a
mixture of TFA±CH2Cl2 (1 : 1, 2 mL) under the

154
S. CARRINGTON ET AL
conditions described for compound 5 to yield a
white solid. (0Á02 g, 10%).
Dansylation was performed using dansyl chloride
in the presence of 4-methylmorpholine leading to
1-dansyl-1,5,9-triazanonane 5 in a 33% yield after
cleavage by TFA±CH2Cl2. A second fraction of 3
was reacted with the activated amide formed
between acridine-9-carboxylic acid and N-hydroxy-
benzotriazole and was then cleaved and treated
with ethanolic HCl to yield 7 (40%).
1H NMR (D2O): CH3 (d: 1Á15, 3H), H-2, 3, 7, 11
(m: 2Á10, 8H), H-1, 4, 6, 8, 10, 12 (m: 3Á20, 11H),
2 6 CH3 (s: 3Á45, 6H), Ar-H (m: 7Á85, 2H), Ar-H
(d: 8Á05, 1H), Ar-H (d: 8Á35, 1H), Ar-H (d: 8Á45,
1H), Ar-H (d: 8Á80, 1H).
Preparation of polymer 20
In order to chain extend the resin bound poly-
amine two methods of reductive amination were
investigated. The most frequently used method uses
the reducing agent NaBH3CN in trimethyl ortho-
formate (Look et al 1995) and, in an alternative
method, reduction is performed using a borane±
pyridine complex in THF under argon (Khan et al
1996, Bilodeau & Cunningham 1998). In our study,
the best results for condensation of 8 to 3 were
obtained with the borane±pyridine complex. The
formation of 9 was monitored through the appear-
ance of the n N3 vibration clearly located at
Polymer 17 (0Á9 g, 0Á58 mmol) was mixed with the
solution of HOBt-activated acridine (1Á3 mmol) in
DMF (7 mL) under the conditions described for
polymer 6.
1
1
IR: n NH 3310 cm , n CO 1870 cm ,
1800 cm .
1
Cleavage of compound 21
Polymer 20 (0Á9 g, 0Á58 mmol) was treated with a
mixture of TFA±CH2Cl2 (1 : 1, 2 mL) for 1 h at
0ꢀC. The residue was concentrated under reduced
pressure, puri®ed by ¯ash column chromatography
on silica gel eluting with CH2Cl2 CH3OH con-
centrated aqueous NH3 (8 : 5 : 1) and converted to
the hydrochloride salt as described for compound 5,
to yield the product as a pale yellow glass (0Á009 g).
1H NMR (D2O) CH3 (s, 1Á42, 3H) CH2 (m:
2Á15±2Á21, 8H), CH2N (m: 3Á04±3Á32, 8H),
CHCH3 (m: 3Á42±3Á53, 1H), CH2NHCO (t: 379,
2H), Ar-H (t: 7Á98, 2H, J ˆ 7), Ar-H (m: 8Á31, 4H),
Ar-H (d: 8Á48, 2H, J ˆ 8).
1
approximately 2090 cm . A small scale cleavage
(100 mg resin) was performed giving compound 10,
which was clearly characterized by H NMR and
mass spectroscopy.
1
The polymer-supported polyamine precursor 9
has two functional groups, a secondary amine and
an azido group acting as a masked primary amine.
Thus, two strategies for functionalizing this poly-
amine were proposed. In the ®rst (Figure 2), dan-
sylation of the secondary amine was carried out
with dansyl chloride then a small scale cleavage
was performed producing compound 12. The azido
group was reduced to a primary amine using tri-
phenylphosphine and water. Complete transforma-
tion of 11 into 13 was monitored by the
disappearance of the N3 vibration at approximately
Results and Discussion
The starting compounds, 5-(tert-butoxycarbonyl)-
1,5,9-triazanonane 2 (O'Sullivan & Dalrymple
1995; Blagbrough & Geall 1998) and 5-azido-
pentan-2-one 8 (Benalil 1991) were readily pre-
pared in suf®cient quantities. The solid support
used in this work was Wang resin linked to
monoprotected triamine 2 through a carbamate
anchor (Dixit & Leznoff 1977, 1978) for the
synthesis of unsymmetrical diamines. The Wang
1
2090 cm in the IR spectrum.
The primary amine was also dansylated leading
to 14 which was subjected to cleavage by TFA±
CH2Cl2. The bis-dansylated compound 15 was
obtained in a 35% yield after conversion to the
hydrochloride.
In the second strategy (Figure 3), the azido group
was transformed to a primary amine using triphe-
nylphosphine and water as previously described
after Boc-protection of the secondary amine 16.
The polymer-bound polyamine 17 was divided into
two portions. Dansylation and cleavage under the
conditions described for the compound 15 pro-
duced 19 in 10% yield. The second portion of the
polymer 17 was treated with HOBt-activated acri-
dine and was cleaved as described for the pre-
paration of 7. The acridine derivative 21 was thus
isolated in a low yield (5%).
resin
was
activated
with
4-nitrophenyl-
chloroformate then the carbonate 1 was reacted
with protected triamine 2 according to a previously
reported procedure (Tomasi et al 1998) (Figure 1).
This reaction was found to be almost quantitative
using gel phase 13C NMR. Carbon signals corre-
sponding to the Boc group, methylene groups and
carbonyl groups in 3 were apparent, and there was
no sign of a carbonyl resonance corresponding to a
carbonate. Carbamate formation was also assessed
by the n CO vibration appearing at approximately
1
1685 cm . After this step, two small portions of
In these preliminary studies, we have shown that
the synthesis of an aminoazide by condensation of
the polymer were conjugated to chromophores.

SYNTHESIS OF UNNATURAL POLYAMINE ANALOGUES
155
Figure 1. Loading the resin with protected triamine and acylation.
Figure 2. Reductive amination, azide reduction and acylation.

156
S. CARRINGTON ET AL
Figure 3. Boc protection, azide reduction and acylation.
an azidocarbonyl compound to a resin-bound
polyamine is useful for the preparation of unnatural
polyamines and polyamine conjugates. A ®rst
source of diversity originates from the anchored
polyamine which can be either a diamine, a
monoprotected triamine or a diprotected tetramine.
The azidocarbonyl allows us to introduce further
diversity and the potential to build libraries of
polyamines with variable (controlled, unsymme-
trical) methylene spacings.
the rapid synthesis of unnatural polyamines and
polyamine amides for biological evaluation.
Acknowledgements
We are grateful to the GP2A, the ARC (Association
pour la Recherche sur le Cancer) and to the Ligue
Â
Nationale contre le Cancer (Comites d'Ille-et-
Vilaine et des Cotes d'Armor) for ®nancial support
Ã
and to J. -C. Corbel, M. Le Roch and A. J. Geall for
their input into this work.
It is also possible to make selected nitrogen func-
tionalities react without a convoluted protection±
deprotection sequence. As a consequence, we can
attach pharmacologically interesting moieties which
form a third source of diversity. These results must be
comparedwiththoseobtainedbytraditionalsynthetic
methods. Equivalent solution phase synthesis would
have required the careful introduction of protecting
groups regiospeci®cally to the polyamine and
potentially dif®cult chromatographic separation of
the desired product after each step. Yields are often
less than quantitative due to reactions at amines other
than the desired one. In this solid-phase study, low
yielding reductive aminations or acylations have led
to low recovery of products. Nevertheless, improve-
ment of the overall yield (particularly for solid-phase
reductive amination) is in progress. Once conditions
have been optimized there will exist the potential for
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