The discovery of a facile access to the synthesis of NSAID dendritic prodrugs

Article abstract of DOI:10.3184/174751913X13602443643042

An efficient and straightforward method for the preparation of dendritic prodrugs is reported. Based on this new approach, a class of biodegradable dendrimers has been synthesised from L-tartaric acid and one of the nonsteroidal anti-inflammatory drugs, namely, aspirin or ibuprofen Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin Universit ,Tianjin 300072, P. R. China.

Full text of DOI:10.3184/174751913X13602443643042

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 177
MARCH, 177–180
The discovery of a facile access to the synthesis of NSAID dendritic
prodrugs
Zuyin Du, Yanhui Lu, Xuedong Dai, Daisy Zhang-Negrerie and Qingzhi Gao*
Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science andTechnology, Tianjin University,
Tianjin 300072, P. R. China
An efficient and straightforward method for the preparation of dendritic prodrugs is reported. Based on this new
approach, a class of biodegradable dendrimers has been synthesised from L-tartaric acid and one of the nonsteroidal
anti-inflammatory drugs, namely, aspirin or ibuprofen.
Keywords: dendritic prodrugs, dendrimers, L-tartaric acid, nonsteroidal anti-inflammatory drugs, drug delivery
Controlled release systems can improve the effectiveness of
drug therapy by sustained release of drugs over a desired
period of time or specific release aimed at a particular target.1,2
Indeed, by controlling the time and location of delivery, side
effects can be minimised and drug efficacy can be significantly
improved which leads to lower dosages for patients. Polymers,
as well as macromolecules, have played an important role in
the development of drug delivery systems possessing controlled
release ability, due to the advantages they offer in comparison
to conventional methods including increased water solubility,
improved pharmacokinetics, reduced antigenic activity, and so
on.3 Although many polymeric materials and polymer-drug
conjugates have revealed promising results as drug carriers in
in vitro studies, a large number failed the in vivo testings as a
consequence of either lack of improved therapeutic index or
polymer-related toxicity.4 Furthermore, low drug-carrying
capacity of the polymer moledules is a crucial limiting factor
in the design of polymer-drug conjugates.
Dendrimers are highly branched, spherical, monodisperse
macromolecules that have sparked significant interest in the
last two decades because of their unique architectures and
properties.5–7 Such distinctive structures along with terminal
surface functionalities and well-defined interior nano-voids
make these macromolecules more suitable as drug carriers
when compared with traditional linear polymers.8–13 Nonste-
roidal anti-inflammatory drugs (NSAIDs) are commonly used
to control pain, fever and inflammation. Based on the unique
features of dendrimers, many dendrimer-NSAID conjugates
have been prepared, proven to be more effective but have fewer
side effects.14–19 There are two methodologies for the prepara-
tion of dendrimer-based prodrugs. The first involves direct
conjugation of drug molecules to the surface of dendrimers,
while the second constructs dendrimers with drug molecules
as branching units. Chai and coworkers20–23 reported on the
synthesis of L-DOPA dendrimers and salicylate dendritic pro-
drugs using L-DOPA and salicylic acid as branching units,
respectively. Both of these dendritic prodrugs have the drug
entities chemically incorporated into the dendrimer backbone,
but not just attached as pendants on the surface or physically
encapsulated inside the cavities. We report here the synthesis
of a similar type of biodegradable dendritic prodrug which is a
promising precursor to a broad range of drugs, starting from
L-tartaric acid and NSAIDs such as aspirin and ibuprofen.
L-Tartaric acid is multifunctional has low toxicity, is readily
available, and has been utilised as a building block to synthe-
sise chiral dendrimers, for which chiroptical properties have
been investigated.24–29 However, there has been no report on
dendritic prodrugs synthesised from L-tartaric acid.
afford acid chloride 4. Next, 2 and 4 were condensed to yield
the building block 5 (Scheme 1). Starting from L-glutamic
acid 6, through benzylation (to give compund 7), acylation
with sebacic acid (to give compund 8), and hydrogenolysis, the
tetracarboxyl core 9 was prepared (Scheme 2). The yields of
these conversions were good to excellent. Note that a diverse
class of building blocks (branching units), can be prepared by
just changing the drug molecules coupled to L-dibenzyl tartrate
2. Therefore, it is convenient to construct a library of dendritic
prodrugs in which not only can the same drug molecules
be incorporated into the dendrimer scaffold, but so also can
different drug molecules as long as these drugs can be
administered synergistically.
In the subsequent synthetic steps, compound 5 was coupled
to the core 9 to afford compound 10, and then all benzyl
protecting groups were removed by hydrogenolysis to provide
compound 11, the first generation dendrimer, to which eight
units of compound 5 were coupled by esterification to yield
compound 12. Again, hydrogenolysis afforded the second
generation dendritic prodrug 13 (Scheme 3). The yields for all
the esterification steps were medium to good, while all yields
for hydrogenolysis were excellent. The structures of the desired
dendrimers were confirmed by 1H and 13C NMR, and MALDI-
FTICR-MS. The degradation behaviour and pharmacokinetics
of these dendritic prodrugs are under investigation.
In summary, we have presented a new approach to the
synthesis of dendritic prodrugs. With this approach, a broad
spectrum of drugs, for example, carboxylic NSAIDs and
organic nitrates, can be incorporated into a dendrimer structure
layer by layer. This novel design of dendritic prodrugs may
well provide a versatile platform for creating various controlled
drug delivery systems.
In this study, L-tartaric acid 1 was first reacted with benzyl
alcohol to give L-dibenzyl tartrate 2. Meanwhile, NSAID 3,
i.e., asprin or ibuprofen, was treated with thionyl chloride to
* Correspondent. E-mail: qingzhi@gmail.com
Scheme 1 Synthesis of the building block 5.

178 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 2 Synthesis of the core 9.
(Agilent 6310) spectrometer using electrospray ionisation (ESI) in
positive or negative mode. High-resolution mass spectra (HRMS)
were obtained on a Varian 7.0T FTMS in positive or negative mode.
Melting points were determined with an X-4 micromelting point
apparatus (Beijing, China) without corrections. IR spectra were
recorded on a Nicolet IR200. TLC plates were visualised by exposure
to UV light or stains. All reagents and solvents were purchased as
reagent grade and used without further purification.
Experimental
1H and 13C NMR spectra were recorded on a 500 MHz INOVA
VARIAN spectrometer at 25 °C. Chemical shift values are given in
ppm with the internal reference given by TMS set at 0.0 ppm. The
peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet;
q, quadruplet; qui, quintuplet; m, multiplet; dd, doublet of doublets;
and br, broad singlet. The coupling constants J are reported in Hz.
Low-resolution mass spectra (LRMS) were obtained on an ion trap
Scheme 3 Synthesis of the dendritic prodrug 13.

JOURNAL OF CHEMICAL RESEARCH 2013 179
Synthesis of 5a; general procedure
mixture was concentrated in vacuo to remove most of the solvents,
and the residue was redissolved in EtOAc (50 mL), filtered to remove
the byproduct DCU and washed with a small amount of cold EtOAc.
The filtrate was then washed with saturated citric acid solution (4 ×
30 mL), saturated brine (2 × 30 mL), saturated NaHCO3 solution (3 ×
30 mL) and saturated brine (3 × 30 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. Finally, the residue obtained
was further purified by column chromatography on silica gel (petro-
leum ether/EtOAc/MeOH, 75/25/5) to afford 10a as a white solid
(2855 mg, yield 73%).
CuBr2 (1.1 g, 5 mmol) and triethyl amine (13.9 mL, 100 mmol) were
added to a solution of L-dibenzyl tartrate 2 (33.0 g, 100 mmol) in
CH2Cl2 (200 mL). The flask was then placed in an ice-water bath,
followed by adding dropwise the solution of 4a (19.9 g, 100 mmol) in
CH2Cl2 (120 mL) within 2 h. After completing the addition, the ice-
water bath was removed and the reaction mixture was stirred at room
temperature for another 4 h. The reaction mixture was washed with
1N HCl (3 × 100 mL), saturated brine (2 × 100 mL), saturated NaHCO3
(3 × 100 mL) and saturated brine (2 × 100 mL), dried over Na2SO4,
filtered, concentrated under reduced pressure, and finally purified by
column chromatography on silica gel using petroleum ether/CH2Cl2 as
eluent to afford 5a as a colourless viscous oil (33.4 g, yield 68%).
5a: 1H NMR (CDCl3, 500 MHz): δ 2.32 (3H, s), 3.33 (1H, br), 4.92
(1H, d, J = 2.5 Hz), 5.20 (2H, m), 5.27 (2H, m), 5.76 (1H, d, J =
2.0 Hz), 7.13 (1H, d, J = 8.0 Hz), 7.25 (6H, m), 7.36 (5H, br), 7.59
(1H, dt, J = 8.0 Hz and 1.5 Hz), 7.90 (1H, dd, J = 8.0 Hz and 1.5 Hz);
13C NMR (CDCl3, 125 MHz): δ 21.3, 68.0, 68.7, 70.9, 73.5, 122.0,
124.2, 126.3, 128.4, 128.7, 128.8, 128.9, 129.0, 132.2, 134.7, 135.2,
151.3, 163.1, 166.5, 169.9, 170.8. LRMS observed: [M + H]+ 493.2;
Calcd for C27H24O9H+: 493.1.
10a: M.p. 58–62 °C; 1H NMR (CDCl3, 500 M): δ 1.21 (8H, t, J =
8 Hz), 1.55 (4H, br), 1.92 (4H, m), 2.12 (6H, br), 2.16–2.27 (4H, m),
2.29 (12H, s), 2.34–2.44 (2H, br), 4.54 (1H, br), 4.66 (1H, m), 5.07–
5.17 (12H, m), 5.23–5.28 (4H, m), 5.83–5.85 (4H, m), 5.92–5.95 (4H,
m), 6.04 (1H, d, J = 7.5 Hz), 6.19 (1H, d, J = 7.5 Hz), 7.09 (4H, m),
7.18–7.22 (24H, m), 7.29–7.31 (20H, m), 7.52–7.57 (4H, m), 7.88
(4H, d, J = 7.5 Hz); 13C NMR (CDCl3, 125 M): δ 21.0, 25.2, 25.3,
26.4, 26.5, 29.2, 29.3, 29.5, 29.7, 36.0, 36.1, 51.2, 51.6, 67.9, 68.0,
68.1, 68.2, 70.9, 71.0, 71.4, 71.6, 121.3, 121.4, 123.9, 126.1, 126.2,
126.3, 128.3, 128.4, 128.5, 128.6, 128.7, 132.0, 132.1, 132.2, 134.3,
134.4, 134.5, 134.6, 134.7, 134.8, 151.1, 151.2, 162.4, 162.5, 162.6,
165.0, 165.1, 165.3, 165.4, 165.6, 169.4, 170.3, 170.7, 171.3, 171.6,
173.1, 173.2. MALDI-FTICR-MS observed: [M + Na]+ 2379.7181;
Calcd for C128H120O42N2Na+: 2379.7213.
Synthesis of 5b
Following the similar procedure for 5a, 5b was prepared and purified
by column chromatography on silica gel using petroleum ether/EtOAc
as eluent.
Synthesis of 10b
5b: Colourless oil; yield 73%; 1H NMR (CDCl3, 500 MHz): δ 0.86
(6H, m), 1.44 (3H, dd, J = 13.0 Hz and 8.0 Hz), 1.79 (1H, m), 2.39
(2H, m), 3.15 (1H, br), 3.64 and 3.78 (1H, m), 4.51 and 4.92 (1H, m),
4.75 (1H, d, J = 23.0 Hz), 4.97 and 5.09 (1H, m), 5.15–5.27 (2H, m),
5.47 (1H, dd, J = 18.5 Hz and 2.5 Hz), 7.05 (2H, t, J = 7.5 Hz),
7.08–7.10 (1H, m), 7.16 (2H, q, J = 8.0 Hz), 7.21–7.23 (1H, m), 7.26–
7.30 (3H, m), 7.31–7.35 (5H, m). LRMS observed: [M + H]+ 519.2;
Calcd for C31H34O7H+: 519.2.
Following the similar procedure for 10a, 10b was prepared and
purified by column chromatography on silica gel (petroleum ether/
EtOAc, 85/15).
1
10b: Colourless oil; yield 63%; H NMR (CDCl3, 500 M): δ 0.84
(24H, m), 1.29 (8H, br), 1.43 (12H, m), 1.59 (4H, br), 1.77 (4H, m),
1.87 (4H, m), 2.15 (6H, br), 2.38 (10H, m), 3.63–3.80 (4H, m), 4.42–
4.53 (2H, m), 4.63 (2H, m), 4.84 (2H, m), 4.94 (2H, m), 5.03–5.30
(10H, m), 5.68–5.79 (7H, m), 6.07 (1H, m), 7.04 (12H, br), 7.15–7.21
(16H, br), 7.27–7.32 (28H, br); 13C NMR (CDCl3, 125 M): δ 18.1,
18.2, 18.3, 22.3, 22.4, 25.3, 25.4, 26.5, 29.3, 29.4, 29.6, 29.7, 30.1,
36.0, 36.1, 44.2, 44.3, 44.6, 44.9, 45.0, 51.5, 51.6, 67.7, 67.8, 67.9,
68.0, 68.1, 70.6, 70.7, 70.8, 70.9, 71.3, 71.4, 127.3, 127.4, 128.1,
128.2, 128.4, 128.6, 128.7, 129.2, 129.4, 134.3, 134.4, 134.5, 134.6,
134.7, 134.8, 136.3, 136.4, 136.8, 140.7, 140.8, 164.5, 164.9, 165.1,
165.2, 165.3, 165.4, 165.5, 165.6, 170.2, 170.7, 171.2, 171.3, 171.4,
173.0, 173.1, 173.2, 173.3, 173.4. MALDI-FTICR-MS observed:
[M + Na]+ 2484.0692; Calcd for C144H160O34N2Na+: 2484.0750.
Synthesis of 8
Sebacic acid (3.3 g, 16.3 mmol), 7 (11.0 g, 33.6 mmol), triethyl amine
(5.1 mL, 37.0 mmol) and HOBt (5.0 g, 37.0 mmol) were added to
CH2Cl2 (50 mL). Then the flask was placed in an ice-water bath, and
DCC (9.0 g, 43.6 mmol) was dissolved in CH2Cl2 (50 mL) and added
dropwise to the aforementioned solution within 50 min. After
completing the addition, the reaction mixture was stirred at the same
temperature for another 2 h, and then the ice-water bath was removed
and the reaction temperature was warmed to room temperature, main-
tained for about 5 h. Subsequently, the reaction mixture was concen-
trated under reduced pressure to remove most of the solvent, and the
residue was redissolved in EtOAc (100 mL), filtered to remove the
byproduct DCU and washed with a small amount of cold EtOAc.
The filtrate was then washed with saturated citric acid solution (4 ×
30 mL), saturated brine (2 × 30 mL), saturated NaHCO3 solution (3 ×
30 mL) and saturated brine (3 × 30 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. Finally, the residue obtained
was further purified by column chromatography on silica gel (petro-
leum ether/EtOAc, 70/25 to 50/50) to give 8 as a white solid (11.9 g,
yield 89%).
Synthesis of 11a; general procedure
To a solution of 10a (949 mg, 0.4 mmol) in EtOAc (40 mL) was added
10% Pd/C (190 mg). Then the flask was flushed with dry nitrogen
twice and charged with hydrogen (in a balloon, ca 3 atm). The reac-
tion mixture was stirred at 40 °C for 15 h and filtered. The filtrate was
concentrated under reduced pressure to provide the desired compound
11a as a white solid (633 mg, yield 97%).
11a: M.p. 129–132 °C. MALDI-FTICR-MS observed: [M + Na]+
1659.3403; Calcd for C72H72O42N2Na+: 1659.3457.
Synthesis of 11b
8: M.p. 81–82 °C. LRMS observed: [M + H]+ 821.4; Calcd for
C48H56O10N2H+: 821.4.
Following the similar procedure for 11a, 11b was prepared.
11b: White solid; yield 99%; m.p. 99–103 °C. MALDI-FTICR-MS
observed: [M
1763.6994.
+
Na]+ 1763.6918; Calcd for C88H112O34N2Na+:
Synthesis of 9
10% Pd/C (1.0 g) was added to a solution of 8 (10.5 g, 12.8 mmol) in
THF (120 mL). Then the flask was flushed with dry nitrogen twice
and charged with hydrogen (in a balloon, ca 3 atm). The reaction
mixture was stirred at 40 °C for 10 h and filtered. The filtrate was
concentrated under reduced pressure to provide the desired compound
9 as a colourless and crystalline powder (5.4 g, yield 92%).
9: M.p. 124–125 °C. LRMS observed: [M + H]+ 461.2; Calcd for
C20H32O10N2H+: 461.2.
Synthesis of 12a; general procedure
One portion of 11a (491 mg, 0.3 mmol) was dissolved in DMF
(5 mL), to which CH2Cl2 (30 mL), DPTS (883 mg, 3 mmol) and 5a
(1772 mg, 3.6 mmol) were added consecutively. Subsequently, the
reaction mixture was cooled to 0 °C in an ice-water bath and DCC
(743 mg, 3.6 mmol) was added. Then the ice-water bath was removed
to allow the reaction temperature to be warmed to room temperature.
After being stirred for 20 h at room temperature the reaction mixture
was concentrated in vacuo to remove most of the solvents, and the
residue was redissolved in EtOAc (100 mL), filtered to remove the
byproduct DCU and washed with a small amount of cold EtOAc.
The filtrate was then washed with saturated citric acid solution (4 ×
30 mL), saturated brine (2 × 30 mL), saturated NaHCO3 solution (3 ×
30 mL) and saturated brine (3 × 30 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. Finally, the residue obtained
Synthesis of 10a; general procedure
One portion of 9 (763 mg, 1.66 mmol) was dissolved in DMF
(3.5 mL), to which CH2Cl2 (35 mL), DPTS (489 mg, 1.66 mmol) and
5a (4903 mg, 9.96 mmol) were added consecutively. Subsequently,
the reaction mixture was cooled to 0 °C in an ice-water bath and DCC
(2055 mg, 9.96 mmol) was added. Then the ice-water bath was
removed to allow the reaction temperature to be warmed to room tem-
perature. After being stirred for 16 h at room temperature the reaction

180 JOURNAL OF CHEMICAL RESEARCH 2013
was further purified by column chromatography on silica gel (petro-
leum ether/EtOAc/MeOH, 70/30/5) to afford 12a as a white solid
(932 mg, yield 57%).
(12H, br), 1.90 (4H, s), 2.13 (4H, br), 2.39 (24H, br), 2.45–2.54 (4H,
br), 3.84 (12H, br), 4.59 (2H, br), 5.52–5.68 (24H, br), 7.07 (24H, br),
7.20 (24H, br); 13C NMR (DMSO-d6, 125 MHz): δ 18.5, 18.7, 18.8,
19.0, 19.1, 19.3, 22.3, 24.6, 25.3, 29.1, 29.7, 35.3, 43.7, 43.8, 44.0,
44.4, 50.2, 70.0, 70.6, 72.2, 127.1, 127.5, 129.1, 137.1, 139.9, 164.5,
166.5, 167.0, 172.5, 173.0, 173.2. MALDI-FTICR-MS observed:
[M + Na]+ 4324.7011; Calcd for C224H272O82N2Na+: 4324.7073.
12a: M.p. 69–73 °C; FT-IR (KBr, cm–1): ν 3402, 3036, 2946, 1768,
1
1682, 1607, 1487, 1454, 1370, 1195, 1131, 1074, 915, 752, 698; H
NMR (CDCl3, 500 MHz): δ 0.97 (8H, br), 1.40 (4H, br), 1.97 (7H, br),
2.14 (3H, br), 2.17 (7H, br), 2.26–2.35 (27H, br), 2.44 (1H, br), 2.66
(3H, br), 4.80–4.98 (12H, m), 5.03–5.29 (22H, m), 5.89–6.20 (24H,
m), 7.02–7.13 (53H, m), 7.17–7.28 (52H, m), 7.45 (12H, m), 7.78
(7H, m), 8.05 (4H, m); 13C NMR (CDCl3, 125 MHz): δ 20.8, 20.9,
25.3, 27.1, 29.2, 29.3, 29.4, 30.0, 36.1, 36.2, 50.7, 51.4, 68.1, 68.2,
68.3, 68.4, 68.6, 70.1, 70.2, 70.3, 70.4, 70.6, 70.7, 70.9, 71.7, 71.8,
71.9, 121.0, 121.1, 121.2, 121.5, 121.6, 121.8, 121.9, 123.8, 123.9,
126.0, 126.2, 126.3, 126.4, 128.3, 128.4, 128.5, 128.6, 128.7, 132.1,
132.2, 132.4, 132.5, 134.3, 134.4, 134.5, 134.6, 151.0, 151.1, 151.3,
162.3, 162.4, 162.5, 162.7, 163.9, 164.0, 164.1, 164.2, 164.3, 164.5,
164.6, 164.7, 164.8, 164.9, 165.0, 165.1, 169.3, 170.1, 170.6, 171.5,
172.8, 172.9. MALDI-FTICR-MS observed: [M + Na]+ 5455.3902;
Calcd for C288H248O106N2Na+: 5455.4068.
We are grateful to the Tianjin Municipal Applied Basic
Research and Cutting-Edge Technology Research Scheme of
China (11JCYBJC14400) for financial support.
Received 9 December 2012; accepted 8 January 2013
Paper 1201667 doi: 10.3184/174751913X13602443643042
Published online: 12 March 2013
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28 K. Hager, A. Franz, and A. Hirsch, Chem.-Eur. J., 2006, 12, 2663.
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Synthesis of 13a; general procedure
To a solution of 12a (674 mg, 0.124 mmol) in EtOAc (50 mL) was
added 10% Pd/C (100 mg). Then the flask was flushed with dry
nitrogen twice and charged with hydrogen (in a balloon, ca 3 atm).
The reaction mixture was stirred at 40 °C for 24 h and filtered. The
filtrate was concentrated under reduced pressure to provide the desired
compound 13a as a white solid (472 mg, yield 95%).
1
13a: M.p. 152–157 °C; H NMR (DMSO-d6, 500 MHz): δ 1.02–
1.12 (8H, br), 1.46 (4H, br), 1.92 (4H, s), 2.11 (8H, br), 2.26 (34H, br),
2.55–2.63 (2H, br), 4.62 and 4.76 (2H, br), 5.80–6.03 (24H, br),
7.20–7.25 (12H, br), 7.36–7.41 (12H, m), 7.68 (12H, br), 7.92 (12H,
br), 8.16 (2H, br); 13C NMR (DMSO-d6, 125 MHz): δ 20.8, 20.9, 25.3,
28.9, 29.0, 35.2, 35.3, 70.3, 71.0, 72.2, 72.6, 121.6, 121.7, 121.8,
121.9, 124.4, 124.5, 124.6, 126.3, 126.6, 131.5, 131.6, 132.0, 134.8,
135.0, 135.2, 150.6, 150.7, 150.8, 150.9, 162.2, 162.3, 162.4, 162.5,
162.6, 164.0, 164.1, 164.2, 164.4, 166.2, 166.3, 166.4, 166.7, 166.8,
167.0, 167.5, 169.1, 169.2, 170.5, 172.2. MALDI-FTICR-MS
observed: [M + Na]+ 4011.6401; Calcd for C176H152O106N2Na+:
4011.6463.
Synthesis of 13b
Following the similar procedure for 13a, 13b was prepared.
13b: White solid; yield 93%; m.p. 130–134 °C; 1H NMR (DMSO-
d6, 500 MHz): δ 0.83 (72H, br), 1.22 (8H, br), 1.41 (40H, br), 1.78

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