Substituent-dependent disassembly of self-immolative dendrimers

Article abstract of DOI:10.1039/b615762a

Self-immolative dendrimers are tree-like platforms, which can spontaneously release all their end-group molecules through a single activation event at the dendrimer's focal point. This triggering event induces domino-like fragmentations, which leads to co

Full text of DOI:10.1039/b615762a

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www.rsc.org/njc | New Journal of Chemistry
Substituent-dependent disassembly of self-immolative dendrimerswzy
Rotem Perry, Roey J. Amir and Doron Shabat*
Received (in Montpellier, France) 30th October 2006, Accepted 8th January 2007
First published as an Advance Article on the web 15th February 2007
DOI: 10.1039/b615762a
Self-immolative dendrimers are tree-like platforms, which can spontaneously release all their end-
group molecules through a single activation event at the dendrimer’s focal point. This triggering
event induces domino-like fragmentations, which leads to complete disassembly of the dendrimer
into its separate building blocks. In this report, we demonstrate a simple approach to control the
disassembly-rate of self-immolative dendrimers. Two types of dendrons were synthesized. One
with a methyl substituent on the benzene building-block and the other with ethylcarboxy-ester.
The dendrons (first- and second-generation) with electron-withdrawing substituents showed
approximately 30 times faster disassembly-rate than dendrons with methyl substituents.
drugs simultaneously at the same location.8 We have also
Introduction
designed and synthesized fully biodegradable dendrimers that
The structural precision of dendrimers has motivated numer-
are disassembled through multi-enzymatic triggering followed
by self-immolative chain fragmentation.9 The model of multi-
ous studies aimed at biological applications, such as, the
amplification of molecular effects or the creation of high
triggered, self-immolative dendron was recently applied to the
concentrations of drugs, molecular labels, or probe moi-
synthesis of a prodrug activated through a molecular ‘‘OR’’
eties.1–3 However, most of the applications of dendrimers rely
logic trigger (a dual-trigger activated by either one of two
different enzymes).10
mainly on the tail-group functionality. An appropriate den-
drimer could be structurally designed to conduct a cleavage
Like in other drug-delivery systems, we sought to control
signal through the molecular dendritic system, similarly to
the disassembly rate of the dendritic platform. Here we present
domino bricks falling on each other. Dendritic architectures
a new study that describes the design and synthesis of two self-
are often used in nature to achieve divergent or convergent
immolative dendritic systems with different disassembly rates.
conducting effects. For example, the structural properties of a
The deceleration or acceleration is achieved through a sub-
tree allow it to transfer water and nutrients from the trunk
stituent effect on the aromatic building block.
toward the branches and the leaves. The structural design of
nerve cells is another striking example of dendritic architecture
with a signal transduction system. Inspired by the dendritic
Results and discussion
transduction pathways existing in nature, we focused our
research on the development of the concept of self-immolative
dendrimers.4 These novel molecular systems were recently
introduced as a platform for the amplification of chemical or
biological signals. The dendrimers can release all of their tail
units through a domino-like chain fragmentation, which is
initiated by a single cleavage at the dendrimer’s core (Fig. 1).4–6
Self-immolative dendrimers have been applied towards the
design and evaluation of novel dendritic prodrug systems.7 We
synthesized a single-triggered hetero-dimeric prodrug with the
anticancer agents doxorubicin and camptothecin. For the first
time it was possible to release two different chemotherapeutic
Design and synthesis of first- and second-generation dendrons
with p-nitroaniline
In this study, we chose to evaluate dendrons with p-nitroani-
line (PNA) end-groups that can be released by chemical
activation. As a trigger we used the tert-butylcarbamate
(Boc) group that is removed under acidic conditions. The
disassembly mechanism of our self-immolative dendrons is
presented in Scheme 1. When dendron I is subjected to the
acidic environment of TFA (trifluoroacetic acid), amine II is
formed. The latter is cyclized to generate phenol III and a
dimethylurea derivative. The phenol undergoes double quino-
ne–methide rearrangement and decarboxylation to release the
two molecules of PNA (compound IV is formed after the
reactive quinone–methide is trapped with methanol).
Earlier studies11,12 showed that the cyclization is the rate-
limiting step of the disassembly process. Therefore, we ratio-
nalized that one could gain control of the disassembly rate by
changing the substituent R on the aromatic ring. Electron-
withdrawing substituents should accelerate the cyclization step
since phenol III will become a better leaving group in the
acyl-substitution of II to III. Four dendrons were synthesized
(Scheme 2).
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact
Sciences, Tel-Aviv University, Tel Aviv, 69978, Israel. E-mail:
chdoron@post.tau.ac.il; Fax: +972 (0) 3 640 9293; Tel: +972 (0) 3
640 8340
w This paper was published as part of the special issue on Dendrimers
and Dendritic Polymers: Design, Properties and Applications.
z Electronic supplementary information (ESI) available: Dendron
activation protocol. Scheme S1: Deprotection of dendrons 1–4 with
TFA. Fig. S1: Disappearance of dendrons 1 and 2 after chemical
activation. Fig. S2: Disappearance of dendrons 3 and 4 after chemical
activation. See DOI: 10.1039/b615762a
y The HTML version of this article has been enhanced with colour
images.
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Fig. 1 Self-immolative dendrimers, as shown in the picture, spontaneously release all the end-group molecules following a single activation event.
This triggering event induces domino-like fragmentations, which leads to a complete disassembly of the dendrimer into its separate building blocks.
Two dendrons (1 and 3) with a methyl substituent and two
others with an ethylcarboxy-ester substituent (2 and 4) were
prepared. All dendrons had the same end-groups (PNA) and
activating triggers (Boc).
which dissolved in dimethyl sulfoxide (DMSO). Then, the
solutions were diluted into methanol with 10% triethylamine.
The sequential fragmentation of compounds 1–4 was moni-
tored by reverse-phase analytical HPLC, using a C-18 analy-
tical column, at a wavelength of 348 nm. The release of PNA
from dendrons 1 and 2 is presented in Fig. 2. The disassembly
of dendron 2 occurred within a little more than 1 h, while 25 h
were needed to complete the disassembly of dendron 1.
Similarly, Fig. 3 shows that second-generation dendron 4
disassembled much faster than dendron 3; 50 h for dendron
3 cf. 3 h for dendron 4 (the disassembly rate was quantified
based on the peak area of the HPLC chromotograms). The
data were normalized to percentage units where the sum of all
peaks is equal to 100%. We observed 100% conversion of the
starting material to PNA).
Synthesis. Dendrons 1 and 3 were synthesized as published
before.4 First-generation dendron 2 was synthesized according
to Scheme 3. The core unit 57 was first treated with tert-
butyldimethylsilyl chloride (TBSCl) to afford phenol 6,7 which
was acylated with p-nitrophenyl chloroformate to give carbo-
nate 7. Reaction of 7 with mono-Boc-protected N,N0-dimethyl-
ethylenediamine (Boc = tert-butyloxycarbonyl) generated
compound 8, which was deprotected in the presence of
Amberlyst-15 to give diol 9. Two equivalents of p-nitroaniline
were treated with phosgene generating an isocyanate deriva-
tive, which conjugated to diol 9, yielding first-generation
dendron 2.
Kinetic studies. The dendritic platform is designed to
disassemble upon triggering, through a process of self-
immolative chain fragmentation, based on cyclization and
elimination reactions. We have previously reported a kinetic
model that explains the release mechanism from dendrons
with a methyl substituent.13 The model showed that the amine
cyclization is the rate-limiting step in the overall release
pathway.4 In order to provide a quantitative evidence for
the increase of disassembly rate of dendrons with a carboxy-
ester substituent, we calculated the rate constants of the
first cyclization step (II - III, Scheme 1) for both types of
dendrons. Since the disassembly of amine intermediate II
The synthesis of second-generation dendron 4 is shown in
Scheme 4. Acylation of diol 9 with two equivalents of
p-nitrophenyl chloroformate afforded dicarbonate 10. Two
equivalents of dendron 2 were deprotected with TFA to afford
the salt of amine 11, which treated in situ with compound 10 to
give dendron 4 (the intramolecular cyclization of amine 11 to
give a five-membered cyclic urea derivative is slower than
cross-linked reaction with dicarbonate 11).
Chemical activation of dendritic molecules 1–4. The dendrons
were initially incubated with TFA to afford their amine salts,
Scheme 1 Disassembly mechanism of a first-generation self-immolative dendron.
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Scheme 2 Chemical structures of first- and second-generation self-immolative dendrons.
Scheme 3 Synthesis of first-generation self-immolative dendron 2.
(Scheme 1) to give a phenol and a urea derivative is a first-
order reaction, the equation for the disassembly is described as
Therefore, a plot of the natural logarithm of the dendron
concentration ([Dendron](t)), as a function of time (t) should
present a good correlation with a straight line (y = ax + b), as
derived from eqn (3):
q/qt [Dendron] = ꢁkn[Dendron](t) (1)
where kn (n is the generation number) is the cyclization rate
ln [Dendron](t) = knt + ln [Dendron](t=0)
(3)
constant. The solution of eqn (1) is given by
The results for the first- and second-generation dendrons are
presented in Fig. 4 and 5, respectively. Excellent correlations
were found for all four structures. The cyclization rate con-
stants for the first- and second-generation dendrons 1 and 3
[Dendron](t) = [Dendron](t=0)exp(ꢁknt)
(2)
Fig. 2 Release of PNA from dendrons 1 (m) and 2 (’) after chemical
activation. Starting concentration: 500 mM; l = 348 nm; 90%
MeOH–10% Et3N; room temperature.
Scheme 4 Synthesis of second-generation self-immolative dendron 4.
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charge on the phenolic-oxygen, the methyl substituent desta-
bilizes it through an electron-donating inductive effect. The
kinetic measurements indicate that dendrons 2 and 4 dis-
assembled approximately 30 times faster than dendrons 1
and 3. This result is further supported by the pKa values
difference of cresol and 4-hydroxybenzoic acid, ethyl ester
(10.26 and 8.34, respectively).14 The increase of the disassem-
bly rate by one and a half orders of magnitude is proportional
to difference in the pKa values.
Conclusions
In summary, we have demonstrated a simple approach to
control the disassembly-rate of self-immolative dendrimers.
Two types of dendrons were synthesized; one with a methyl
substituent on the benzene building-block and the other with
ethylcarboxy-ester. The dendrons (first- and second-genera-
tion) with electron-withdrawing substituents showed faster
disassembly rate than dendrons with methyl substituents.
Gaining control of self-immolative dendrimer disassembly
could be especially applicable in drug-delivery systems, when
a specific release-rate is needed to control the dose of an active
drug.
Fig. 3 Release of PNA from dendrons 3 (m) and 4 (’) after chemical
activation. Starting concentration: 500 mM; l = 348 nm; 90%
MeOH–10% Et3N; room temperature.
Experimental
General
All reactions requiring anhydrous conditions were performed
under an Ar or N2 atmosphere. Chemicals and solvents were
either A.R. grade or purified by standard techniques. Thin
Fig. 4 First-order kinetic plots for the disassembly of first-generation
self-immolative dendrons 1 (E) and 2 (m).
layer chromatography (TLC): silica gel plates Merck 60 F254
;
compounds were visualized by irradiation with UV light and/
or by treatment with a solution of phosphomolybdic acid
(20% wt. in ethanol), followed by heating. Flash chromato-
graphy (FC): silica gel Merck 60 (particle size 0.040–0.063
mm), eluent given in parentheses. 1H NMR: Bruker AMX 200
or 400 instrument. The chemical shifts are expressed in d
relative to TMS (d = 0 ppm) and the coupling constants J
in Hz. The spectra were recorded in CDCl3 or CD3OD as a
solvent at room temperature. All reagents, including salts and
solvents, were purchased from Sigma-Aldrich.
Syntheses
Compound 7. Compound 67 (1.62 g, 3.56 mmol) was dis-
solved in 50 ml of THF, Et3N (1.7 ml, 12.4 mmol) and a
catalytic amount of DMAP (5 mg) were added. The reaction
was cooled to 0 1C, and a solution of 4-nitrophenyl chloro-
formate (1.07 g, 5.34 mmol) in 20 ml THF was added drop-
wise. The reaction was stirred in room temperature and
monitored by TLC (EtOAc–hexane 10 : 90). After 3 h the
reaction was complete and diluted with EtOAc and washed
with saturated NH4Cl solution. The organic layer was dried
over sodium sulfate and the solvent was removed under
reduced pressure. The crude product was purified by using
column chromatography on silica gel (EtOAc–hexane =
1 : 19) to give compound 7 (1.65 g, 75%) as a colorless oil.
1H NMR (200 MHz, CDCl3): d 8.32 (2H, d, J = 9.2); 8.14
(2H, s); 7.48 (2H, d, J = 9.2); 4.78 (4H, s); 4.38 (2H, q,
Fig. 5 First-order kinetic plots for the disassembly of second-gen-
eration self-immolative dendrons 3 (E) and 4 (m).
were similar (0.110 ꢂ 0.002 and 0.089 ꢂ 0.002 hꢁ1, respec-
tively) and in good agreement with our previously reported
results. The same phenomenon was observed for dendrons 2
and 4 (kn = 3.08 ꢂ 0.06 and 2.88 ꢂ 0.06 hꢁ1, respectively).
The acceleration of disassembly of dendrons 2 and 4 can be
explained by the stabilization of the phenolate species, which is
released upon the intra-cyclization of amine intermediate II
(Fig. 2). While the ester-substituent (an electron-withdrawing
group) oriented para to the phenol, stabilizes the negative
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J = 7.1); 1.37 (3H, t, J = 7.1); 0.94 (18H, s); 0.09 (12H, s).
13C NMR (100 MHz, CDCl3): d 166.5, 156.1, 150.16, 149.26,
146.4, 134.5, 129.9, 129.6, 126.2, 122.1, 61.9, 61.2, 26.7, 19.1,
15.1, ꢁ4.5. HRMS (MALDI-TOF): calc. for C30H45NO9Si2
642.2525 [M + Na+], found 642.2482.
Mp 100 1C (decomp.). 1H NMR (200 MHz, CDCl3): d 8.16
(4H, d, J = 8.2); 7.66 (2H, s); 7.56 (4H, d, J = 8.2); 5.16
(4H, s); 4.40 (2H, q, J = 6.8); 3.7–3.3 (4H, m); 3.2 (3H, s); 2.94
(3H, s); 1.41 (9H, s); 1.27 (3H, t, J = 6.8). 13C NMR
(100 MHz, CDCl3): d 166.7, 158.2, 154.8, 146.5, 144.6,
135.1, 133.2, 131.6, 126.9, 119.6, 82.7, 63.7, 63.4, 49.1, 48.5,
38.2, 37.5, 30.4, 16.247. HRMS (MALDI-TOF): calc. for
C35H40N6O14 791.2494 [M + Na]+, found 791.2470.
Compound 8. Compound 7 (1.17 g, 1.92 mmol) was dissolved
in 30 ml DMF and mono-Boc-protected N,N0-dimethyl-
ethylenediamine (543 mg, 2.88 mmol) was added. The reaction
was stirred in room temperature and was monitored by TLC
(EtOAc–hexane = 1 : 3). After 1 h the reaction was complete,
the solvent was removed under reduced pressure, and the
crude product was purified by using column chromatography
on silica gel (EtOAc–hexane = 15 : 85) to give compound 8
(835 mg, 65%) as a viscous oil.1
1H NMR (200 MHz, CDCl3): d 8.10 (2H, s); 4.64 (4H, s);
4.32 (2H, q, J = 7.0); 3.55–3.42 (4H, m); 3.12–3.00 (3H, m);
2.92–2.89 (3H, m); 1.53–1.45 (9H, m); 1.38 (3H, t, J = 7.0); 0.9
(18H, s); 0.07 (12H, s). 13C NMR (100 MHz, CDCl3) d 167.0,
153.7, 149.4, 135.1, 128.8, 126.8, 116.3, 80.6, 61.6, 60.2, 48.1,
47.1, 36.2, 35.9, 29.2, 26.6, 19.1, 14.9, ꢁ4.5. HRMS (MALDI-
TOF): calc. for C33H60N2O8Si2 691.3780 [M + Na+], found
691.374.
Compound 10. Compound 9 (103 mg, 0.234 mmol) was
dissolved in 10 ml dry THF and the solution was cooled to
0 1C. Then DIPEA (0.33 ml, 1.872 mmol), was added followed
by PNP-chloroformate (283 mg, 1.4 mmol) and a catalytic
amount of pyridine. The reaction was stirred in room tem-
perature and monitored by TLC (EtOAc–hexane = 1 : 1).
After 15 min the reaction was completed and the solvent was
removed under reduced pressure. The crude product was
diluted with EtOAc and washed with saturated NH4Cl and
with saturated NaHCO3 solutions. The organic layer was
dried over magnesium sulfate and the solvent was removed
under reduced pressure. The crude product was purified by
using column chromatography on silica gel (EtOAc–hexane =
1 : 1) to give compound 10 (160 mg, 89%) as a white solid.
Mp 100 1C (decomp.). 1H NMR (400 MHz, CDCl3): d
8.24–8.20 (6H, m); 7.36 (4H, d, J = 7.0); 5.31 (4H, s); 4.38
(2H, q, J = 7.0); 3.60–3.45 (4H, m); 3.20–3.02 (3H, m);
2.94–2.85 (3H, m); 1.43–1.41 (9H, m); 1.38 (3H, t, J = 7.0).
13C NMR (100 MHz, CDCl3): d 165.8, 156.2, 154.1, 153.0,
152.5, 152.4, 146.3, 132.0, 129.6, 126.1, 122.8, 122.6, 80.7, 66.4,
62.3, 48.3, 46.9, 35.6, 32.3, 29.1, 14.9. HRMS (MALDI-TOF):
calc. for C35H38N4O16 793.2175 [M + Na+], found 793.2148.
Compound 9. Compound 8 (800 mg, 1.19 mmol) was
dissolved in 10 ml MeOH and Amberlyst-15 was added. The
reaction was stirred in room temperature for 2 h and was
monitored by TLC (EtOAc–hexane = 3 : 1). After comple-
tion, the Amberlyst-15 was filtered out and the solvent was
removed under reduced pressure. The crude product
was purified by using column chromatography on silica gel
(EtOAc–hexane = 9 : 1) to give compound 9 (455 mg, 86%) as
a white powder.
Mp 100 1C (decomp.). 1H NMR (200 MHz, CDCl3): d 8.08
(2H, s); 4.61 (4H, s); 4.36 (2H, q, J = 7.1); 3.7–3.4 (4H, m);
3.17 (3H, s); 3.04 (3H, s); 2.94 (3H, s); 1.48–1.42 (9H, m); 1.35
(3H, t, J = 7.1). 13C NMR (100 MHz, CDCl3): d 166.6, 156.8,
155.6, 155.4, 135.1, 131.5, 129.2, 81.2, 61.9, 61.0, 47.5, 47.1,
36.9, 35.8, 29.1, 15.1. HRMS (MALDI-TOF): calc. for
C21H32N2O8 463.2051 [M + Na+], found 463.2087.
Dendron 4. Compound 2 (250 mg, 0.32 mmol) was dissolved
in 1 ml TFA and stirred for a few minutes, the excess of acid
was removed under reduced pressure and the crude amine salt
was dissolved in 2 ml DMF. Compound 10 (100 mg, 0.13
mmol) was added followed by the addition of 1 ml Et3N. The
reaction mixture was stirred in room temperature and
monitored by TLC (EtOAc–hexane = 75 : 25). After 2 h the
reaction was completed and the solvent was removed under
reduced pressure. The crude product was purified by using
column chromatography on silica gel (EtOAc–hexane = 70 : 30)
to give compound 4 (189 mg, 80%) as a yellowish powder.
Mp 100 1C (decomp.). 1H NMR (200 MHz, CDCl3): d
8.20–8.06 (14H, m); 7.48 (6H, m); 5.13 (12H, m); 4.38 (6H, m);
3.61–2.61 (30H, m); 1.40 (9H, m); 1.31–1.23 (9H, m). 13C
NMR (100 MHz, CDCl3): d 167.13, 154.75, 146.68, 144.49,
131.9, 131.69, 130.39, 126.84, 119.59, 64.15, 63.43, 48.67,
46.94, 36.75, 33.35, 30.19, 22.94. HRMS (MALDI-TOF): calc.
for C83H92N14O34 1851.5792 [M + Na]+, found 1851.5638.
Dendron 2. p-Nitroaniline (342 mg, 2.48 mmol) was dis-
solved in 20 ml of dry THF and a solution of 20% phosgene in
toluene (2.6 ml, 4.956 mmol) was added. The reaction was
refluxed for 2 h and monitored by 1H NMR (200 MHz,
DMSO). After the isocyanate derivative was observed, the
solvent was removed under reduced pressure. A solution of
compound 9 (364 mg, 0.826 mmol) in 10 ml THF followed by
Et3N (0.42 ml, 3 mmol) was added to the residue. The reaction
was stirred in room temperature and was monitored by TLC
(EtOAc–hexane = 1 : 1). After 1 h the reaction was completed
and the solvent was removed under reduced pressure. The
crude product was diluted with DCM, salts were filtered out
and the crude was washed again with DCM. The organic layer
was dried over magnesium sulfate and the solvent was re-
moved under reduced pressure. The crude product was pur-
ified by using column chromatography on silica gel
(EtOAc–hexane = 2 : 3) to give compound 2 (573 mg, 90%)
as a yellow powder.
Dendron activation protocol
Dendrons 1–4 were deprotected with trifluoroacetic acid
(TFA) and the corresponding salts were used for the prepara-
tion of 10.0 mM stock solutions in DMSO. The stock solu-
tions were diluted with MeOH and 10% triethylamine to give
final concentrations of 500 mM of dendrons 1–4. The release of
p-nitroaniline from the dendron stock solutions was moni-
tored by an HPLC assay using C-18 reverse-phase analytical
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column; l = 348 nm; flow: 1 mL minꢁ1; eluent: MeCN–H2O;
gradient program: t = 0 (30% MeCN–70% H2O), t = 20
6 (a) M. L. Szalai, R. M. Kevwitch and D. V. McGrath, J. Am.
Chem. Soc., 2003, 125, 15688; (b) M. L. Szalai and D. V. McGrath,
Tetrahedron, 2004, 60, 7261.
7 K. Haba, M. Popkov, M. Shamis, R. A. Lerner, C. F. Barbas, 3rd
and D. Shabat, Angew. Chem., Int. Ed., 2005, 44, 716.
8 M. Shamis, H. N. Lode and D. Shabat, J. Am. Chem. Soc., 2004,
126, 1726.
9 R. J. Amir and D. Shabat, Chem. Commun., 2004, 1614.
10 R. J. Amir, M. Popkov, R. A. Lerner, C. F. Barbas, 3rd and D.
Shabat, Angew. Chem., Int. Ed., 2005, 44, 4378.
(100% MeCN); tR = 12.22 min (TFA salt of 1); tR
12.16 min (TFA salt of 2); tR = 18.34 min (TFA salt of 3);
R = 18.42 min (TFA salt of 4); tR = 8.67 min (p-nitroaniline).
=
t
The relative peak areas (in %) were used for the kinetic
analysis.
11 R. J. Amir and D. Shabat, Adv. Polym. Sci., 2006, 192, 59.
12 D. Shabat, J. Polym. Sci., Part A: Polym. Chem., 2006, 44,
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