Synthesis of NO-NSAID dendritic prodrugs via Passerini reaction:new approach to the design of dendrimer-drug conjugates

Article abstract of DOI:10.3184/174751913X13602469418189

We report the synthesis of a novel class of dendritic prodrugs via Passerini reaction in one pot. Such dendrimers feature a simultaneous attachment of a conventional non-steroidal anti-inflammatory drug (NSAID) (such as ibuprofen and aspirin) and a nitric oxide (NO)-releasing moiety (such as an organic nitrate) onto their surface, and are therefore regarded as new drug delivery systems for NO-releasing NSAIDs (NO-NSAIDs).

Full text of DOI:10.3184/174751913X13602469418189

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 181
MARCH, 181–185
Synthesis of NO–NSAID dendritic prodrugs via Passerini reaction:
new approach to the design of dendrimer-drug conjugates
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
We report the synthesis of a novel class of dendritic prodrugs via Passerini reaction in one pot. Such dendrimers
feature a simultaneous attachment of a conventional non-steroidal anti-inflammatory drug (NSAID) (such as ibupro-
fen and aspirin) and a nitric oxide (NO)-releasing moiety (such as an organic nitrate) onto their surface, and are
therefore regarded as new drug delivery systems for NO-releasing NSAIDs (NO–NSAIDs).
Keywords: Passerini reaction, dendritic prodrugs, dendrimers, non-steroidal anti-inflammatory drugs, NO-releasing NSAIDs
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of
the most commonly used groups of drugs in the world, primar-
ily used for the treatment of pain, fever and inflammation.
However, chronic ingestion of NSAIDs may cause a wide
variety of adverse events, including gastrointestinal (GI) side
effects (such as dyspepsia, GI bleeding, obstruction and even
perforation), renal side effects, and some additional side effects
such as hypersensitivity reactions and distinct salicylate
intoxication,1 thus largely limiting their use.
Furthermore, dendrimers have been utilised as the scaffold for
NO release.22,23 Mutlticomponent reactions have been known
for over 150 years, and in these reactions, more than two reac-
tants combine in a sequential manner to give highly selective
products that retain the majority of the atoms of the starting
material. Jee and coworkers reported on the convergent
synthesis of a diverse class of dendimers via Passerini
reaction,24 and a recent patent revealed the manufacture of
peptidic, peptoidic, and chimeric peptoidic–peptidic dendri-
mers by Ugi and (or) Passerini multicomponent reactions
starting with a multifunctional core.25 We now describe a
new method for the synthesis of a novel class of dendrimers
(NO-NSAID dendrimers), onto the surface of which an NSAID
moledule (e.g., aspirin and ibuprofen), and NO-donating
moieties are attached simultaneously. This new methodology
features an efficient and straightforward one-pot Passerin
reaction, a three-component reaction, involving a carboxylic
acid, a carbonyl compound, and an isocyanide.
In this study, L-Glutamic acid 1 was firstly reacted with
benzyl alcohol to give compound 2, which was then coupled
with suberic acid to afford compound 3. Subjected to
hydrogenolysis, 3 was converted to the tetracarboxy core 4, to
which 2 (4 equiv.) was coupled again to provide compound 5,
whose benzyl protecting groups were later removed by
hydrogenolysis to yield the desired octacarboxy dendrimer 6
in an overall yield of 54% (Scheme 1). This procedure is
similar to that reported by Mitchell et al.26,27
The second components for Passerini reaction are isocya-
nides. First of all, ethylene glycol 7 was treated with concen-
trated HNO3, AcOH, and Ac2O to afford the mononitrate 8. At
the same time, starting from glycine 9, through benzylation (to
yield compound 10), formylation (to yield compound 11),
hydrogenolysis (to yield compound 12), esterification (to yield
compound 13), and finally dehydration, isocyanide 14 was
obtained (Scheme 2). The third components in Passerini reac-
tion, namely, aldehydes 17 and 20 (derived from ibuprofen
and aspirin, respectively), were obtained via two oxidation
reactions described in Scheme 3. Ibuprofen was treated with
thionyl chloride to give compound 15, which was then reacted
with ethylene glycol to afford compound 16. This intermediate
was readily converted to aldehyde 17 by using o-iodoxyben-
zoic acid (IBX) as the oxidising agent. On the contrary, paral-
lel oxidation reaction of the intermediate (synthesised from
aspirin and ethylene glycol following the protocol employed to
the preparation of compound 16, but not shown in Scheme 3)
with IBX did not provide aldehyde 20, but gave a complicated
reaction mixture where the main product was difficult to be
identified, according to the TLC results. However, the reaction
of asprin 18 with 3-bromopropene gave rise to the production
of compound 19, upon ozonolysis of which aldehyde 20
was successfully produced after reductive workup with
triphenylphosphine.
The potential toxicity of NSAIDs and their side effects have
prompted considerable effort to search for safer alternatives
with similar pharmacological properties. It was reported that
patients receiving high doses of multiple NSAIDs, or NSIADs
concomitant with a corticosteroid suffer an increased risk of
GI complications,2 suggesting that these therapeutic strategies
may fail the treatment due to GI side effects. A fascinating
strategy has been generated from the discovery of two cyclo-
oxygenase (COX) enzyme systems controlling the production
of prostanoids, i.e. COX-1 and COX-2. The latter is believed
to regulate the production of prostaglandins involved in
inflammation, pain and fever. At the beginning of this century,
two new highly selective COX-2 inhibitors, known as coxibs
(celecoxib and rofecoxib), emerged on the market and are
claimed to have low GI side effects. However, an alarming turn
of events occurred in late 2004 when rofecoxib was withdrawn
from the market worldwide due to the serious cardiovascular
events. Subsequently, other coxibs were shown to have the
same adverse reaction, although to various degrees.3 Thus,
there remains a compelling need for developing new NSAIDs
with improved safety. Considering that nitric oxide (NO) can
exert some prostaglandin functions for GI tract defence,4–6
researchers have developed a promising strategy to reduce
these side effects by coupling an NO-donating moiety to a
conventional NSAID molecule. A class of new chemical
entities, namely, the NO-releasing NSAIDs (NO–NSAIDs) is
formed, which claims the potential to improve cardiovascular
safety and at the same time spare the GI tract. Del Soldato and
coworkers synthesised the first NO–NSAIDs,7 and many
advances have been made in the last decade.8–13
Parallel to the preparation of NO–NSAIDs, a number of
macromolecular drug delivery systems have been developed
in order to enhance the bioavailability of the NSAIDs and
reduce or eliminate their side effects.14,15 Dendrimers represent
a relatively novel class of macromolecules with salient features
such as monodispersity, well-defined globular shape, and high
density of peripheral functional groups. Their unique structural
properties make dendrimers suitable candidates for a wide
range of applications, especially as nano-devices for drug
delivery.16–20 As for NSAIDs, dendrimers have proved to be
efficient carriers when compared to classical linear polymers.21
* Correspondent. E-mail: qingzhi@gmail.com

182 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 1 Synthesis of the octacarboxy dendrimer 6.
Scheme 2 Synthesis of isocyanide 14.

JOURNAL OF CHEMICAL RESEARCH 2013 183
Scheme 3 Synthesis of aldehydes 17 and 20.
The one-pot reaction of the three components of 6, 14 and
17 (20) which produces the dendritic prodrug 21 is described
in Scheme 4. As expected, two dendritic prodrugs were
obtained via Passerini reaction, albeit in low to medium yields.
Our investigation also shows that high concentration of the
substrates and nonpolar aprotic solvents (such as THF) are
favourable for the Passerini reaction, which is well-established
in the literature.28 Besides the simplicity of the synthetic
procedure, another attractive feature of this strategy is the
room it leaves for convenient variation of the dendrimer
scaffolds as well as the drug molecules attached at the
periphery. This ability provides an efficient approach to
construct a library of dendritic prodrugs. The structures of all
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 (Agilent 6310) spec-
trometer 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.
1
newly synthesised compounds were characterised by H and
13C NMR spectroscopy, and MALDI-FTICR-MS or LRMS.
Additionally, the biological and pharmaceutical activities of
these NO–NSAID dendritic prodrugs are under investigation.
In conclusion, an efficient and straightforward method for
the synthesis of a versatile class of NO–NSAID dendrimers
has been presented. This type of dendritic prodrug is promis-
ing in having therapeutic activities of NO and NSAIDs, and
sustained-release behaviour as well. The methodology is not
restricted to the Passerini reaction and the substrates mentioned
in this study, but is readily applied to other multicomponent
reactions (such as Ugi-type four-component reaction),
dendrimers (such as PAMAM dendrimers), and drugs that can
be administered synergistically. Due to its efficiency and
diversity in nature, we believe this approach can be considered
as one of the most valuable strategies towards the design of
new controlled drug-delivery systems.
Synthesis of 6
10% Pd/C (1.0 g) was added to a solution of 5 (5.0 g, 3.0 mmol) in
THF (100 mL), and then the flask was flushed with dry nitrogen twice
and charged with hydrogen (in a balloon, ca 3 atm), heated to 70 °C
and stirred for 24 h. The reaction mixture was filtered, and the filtrate
was concentrated under reduced pressure to afford the desired
compound 6 as a white solid (2.7 g, yield 95%).
1
6: M.p. 66–69 °C; H NMR (CDCl3, 500 MHz): δ 1.23 (4H, br),
1.47 (4H, br), 1.69–1.77 (6H, br), 1.87 (2H, m), 1.95–1.99 (4H, br),
2.09–2.18 (8H, br), 2.23–2.29 (8H, br), 4.20 and 4.30 (6H, m), 7.93
(2H, dd, J = 20.0 Hz and 8.0 Hz), 8.13 (4H, m); 13C NMR (CDCl3, 125
MHz): δ 25.8, 26.9, 27.0, 28.7, 29.1, 30.6, 30.7, 32.3, 35.8, 51.7, 51.8,
52.6, 172.3, 172.5, 173.0, 174.0, 174.3, 174.4. LRMS observed: [M +
Na]+ 971.2; calculated for C38H56O22N6Na+: 971.3.
Scheme 4 Synthesis of the NO-NSAID dendritic prodrug 21.

184 JOURNAL OF CHEMICAL RESEARCH 2013
Synthesis of 13
reaction mixture was warmed to room temperature, stirred for approx-
imate 24 h, concentrated under reduced pressure, and finally purified
by column chromatography on silica gel (petroleum ether/EtOAc,
95/5 to 85/15) to afford 20 as a colourless oil (4.2 g, yield 83%).
20: 1H NMR (CDCl3, 500 MHz): δ 2.33 (3H, s), 4.83 (2H, s), 7.13
(1H, d, J = 8.0 Hz), 7.34 (1H, t, J = 8.0 Hz), 7.60 (1H, t, J = 8.0 Hz),
8.09 (1H, d, J = 8.0 Hz), 9.65 (1H, s); 13C NMR (CDCl3, 125 MHz):
δ 21.2, 69.2, 122.2, 124, 2, 126.4, 132.103, 134.8, 151.2, 164.0, 169.9,
195.9. LRMS observed: [M + H]+ 223.0; calculated for C11H10O5H+:
223.1.
Ethylene glycol mononitrate 8 (2.27 g, 22 mmol), 12 (2.14 g, 20 mmol)
and HOAt (2.86 g, 21 mmol) were added to CH2Cl2 (40 mL). Then the
flask was placed in an ice-water bath, to which EDC•HCl (4.98 g,
26 mmol) was added in portions. After completing addition, the
reaction mixture was stirred at 0 °C for 2 h, and then warmed to room
temperature and stirred for another 22 h. The reaction mixture was
washed with H2O (40 mL), and the aqueous phase was extracted
with EtOAc (2 × 20 mL). The combined organic phase was dried
over MgSO4, filtered, concentrated under reduced pressure, and the
residue was finally purified by column chromatography on silica gel
(petroleum ether/EtOAc, 80/20 to 40/60) to afford 13 as a yellowish
oil (1.7 g, yield 46%).
Synthesis of 21a
Compound 6 (95 mg, 0.1 mmol) was dissolved in THF (3 mL), and
the solution was then concentrated under reduced pressure until the
volume decreased to approximate 1.5 mL, to which isocyanide 14
(209 mg, 1.2 mmol) and aldehyde 17 (298 mg, 1.2 mmol) were added.
The reaction mixture was stirred at room temperature for 6 days under
N2, and immediately purified by silica gel chromatography (petroleum
ether/EtOAc/MeOH, 30/30/1 to 30/70/1) to give the dendrimer 21a as
a white powder (121 mg, yield 28%).
13: LRMS observed: [M + H]+ 192.9; calculated for C5H8O6N2H+:
193.0.
Synthesis of 14
Phosphoryl chloride (0.88 mL, 9.4 mmol) and 13 (1.62 g, 8.5 mmol)
were added to CH2Cl2 (40 mL) at 0 °C, to which triethyl amine
(3.9 mL, 28 mmol) was added dropwise under N2 within 15 min. After
completing the addition, the reaction mixture was stirred for another
2 h at the same temperature. Then saturated NaHCO3 solution (40 mL)
was added, and the aqueous phase was extracted with CH2Cl2 (2 ×
20 mL). The combined organic phase was dried over Na2SO4, filtered,
concentrated under reduced pressure, and finally purified by column
chromatography on silica gel (petroleum ether/EtOAc, 90/10) to
afford 14 as a yellowish-brown oil (1.24 g, yield 84%).
21a: M.p. 55–57 °C; 1H NMR (CDCl3, 500 MHz): δ 0.88 (48H, d,
J = 6.5 Hz), 1.28 (4H, br), 1.46 (24H, br), 1.57 (4H, br), 1.82 (8H, m),
1.94 (4H, br), 2.06 (2H, br), 2.18–2.43 (38H, br), 3.71 (8H, br), 3.96
(16H, br), 4.22 (2H, br), 4.38 (24H, br), 4.53 (10H, br), 4.64 (18H, br),
5.41 (8H, br), 7.08 (16H, br), 7.16 (16H, br); 13C NMR (125 MHz,
CDCl3): δ 18.3, 18.4, 22.4, 25.2, 26.2, 28.6, 29.5, 29.7, 30.2,
31.9, 35.9, 40.8, 41.0, 44.8, 44.9, 52.1, 61.1, 61.4, 63.0, 69.7, 70.3,
72.0, 72.1, 72.2, 72.9, 73.0, 73.1, 127.2, 129.3, 137.2, 140.8, 166.8,
166.9, 167.0, 167.4, 167.5, 169.1, 169.2, 171.4, 174.3, 174.4, 174.5.
MALDI-FTICR-MS observed: [M+Na]+ 4348.6755; calculated for
14: FT-IR (film, cm–1): ν 2970, 2905, 2168, 1766, 1652, 1424, 1376,
1288, 1197, 1051, 998, 904, 861, 705, 577; 1H NMR (CDCl3,
500 MHz): δ 4.30 (2H, s), 4.53 (2H, t, J = 2.0 Hz), 4.72 (2H, t, J =
2.0 Hz); 13C NMR (CDCl3, 125 MHz): δ 43.6, 62.4, 70.1, 161.6, 164.2.
LRMS observed: [M + H]+ 175.1; calculated for C5H7O5N2H+: 175.0.
C
198H264O86N22 Na+: 4348.6859.
Synthesis of 21b
Synthesis of 17
Compound 6 (95 mg, 0.1 mmol) was dissolved in THF (5 mL), and
the solution was then concentrated under reduced pressure until
the volume decreased to approximate 2 mL, to which isocyanide 14
(209 mg, 1.2 mmol) and aldehyde 20 (267 mg, 1.2 mmol) were added.
The reaction mixture was stirred at room temperature for 6 days under
N2, and immediately purified by silica gel chromatography (petroleum
ether/EtOAc/MeOH, 60/40/2) to afford the dendrimer 21b as a white
powder (255 mg, yield 62%).
16 (1.5 g, 6.0 mmol) was addedd to the solution of IBX (2.5 g,
9.0 mmol) in DMSO (10 mL), and the reaction mixture was stirred
at room temperature for ca 16 h. Then H2O (30 mL) and EtOAc
(30 mL) were added, and the reaction mixture was stirred for 5 min,
filtered. The filtrate was washed with saturated NaHCO3 solution (3 ×
10 mL) and saturated brine (3 × 10 mL), dried over MgSO4, filtered,
concentrated under reduced pressure, and finally purified by column
chromatography on silica gel (petroleum ether/EtOAc, 95/5) to afford
17 as a colourless oil (1.3 g, yield 85%).
21b: M.p. 68–71 °C; FT-IR (KBr, cm–1): ν 3369, 3079, 2957, 1759,
1
1683, 1637, 1537, 1373, 1283, 1195, 1082, 916, 856, 755, 704; H
1
17: H NMR (CDCl3, 500 MHz): δ 0.90 (6H, d, J = 6.5 Hz), 1.56
NMR (CDCl3, 500 MHz): δ 1.19 (4H, br), 1.48 (4H, br), 1.80 (4H, br),
2.09 (8H, br), 2.17 (4H, br), 2.30 (24H, br), 2.47 (12H, br), 4.01 (14H,
br), 4.18–4.34 (20H, br), 4.60 (28H, br), 4.76 (8H, br), 5.46–5.50 (8H,
br), 7.07 (8H, br), 7.29 (8H, br), 7.56 (8H, br), 8.01 (8H, br); 13C NMR
(CDCl3, 125 MHz): δ 20.9, 21.0, 22.7, 25.1, 25.2, 25.5, 28.4, 29.4,
29.6, 29.7, 29.9, 31.1, 31.9, 35.7, 35.8, 40.9, 52.1, 58.8, 61.0, 63.1,
70.3, 71.9, 72.7, 122.3, 123.9, 126.2, 126.3, 132.0, 134.4, 134.5,
134.6, 150.8, 150.9, 163.6, 163.7, 163.8, 167.1, 167.5, 169.2, 169.3,
169.9, 170.0, 170.1, 171.4, 171.5. MALDI-FTICR-MS observed:
[M+Na]+ 4139.9705; calculated for C166H184O102N22Na+: 4139.9785.
(3H, d, J = 7.0 Hz), 1.85 (1H, m), 2.46 (2H, d, J = 7.5 Hz), 3.85 (1H,
q, J = 7.5 Hz), 4.63 (2H, AB, J = 37.5 Hz and 17.5 Hz), 7.12 (2H, d,
J = 8.0 Hz), 7.23 (2H, d, J = 8.0 Hz), 9.54 (1H, s); 13C NMR (CDCl3,
125 MHz): δ 18.5, 22.3, 30.1, 44.7, 45.0, 68.7, 127.097, 129.4, 137.0,
140.8, 174.2, 195.9. LRMS observed: [M + H]+ 249.1; calculated for
C15H20O3H+: 249.1.
Synthesis of 19
Aspirin (8.0 g, 44.4 mmol), 3-bromopropene (4.2 mL, 48.8 mmol)
and triethyl amine (6.8 mL, 48.8 mmol) were added to acetonitrile
(45 mL) and stirred for 2 h at room temperature. Then the reaction
mixture was concentrated under reduced pressure, and the residue was
redissolved in EtOAc (80 mL), washed with a small amount of water,
dried over Na2SO4, filtered, concentrated under reduced pressure, and
finally purified by column chromatography on silica gel (petroleum
ether/EtOAc, 85/15) to afford 19 as a colourless oil (8.6 g, yield
88%).
We are grateful to theTianjin MunicipalApplied Basic Research
and Cutting-Edge Technology Research Scheme of China
(11JCYBJC14400) for financial support.
Received 10 December 2012; accepted 8 January 2013
Paper 1201672 doi: 10.3184/174751913X13602469418189
Published online: 12 March 2013
1
19: H NMR (CDCl3, 500 MHz): δ 2.31 (3H, s), 4.75 (2H, d, J =
5.5 Hz), 5.27 (1H, dd, J = 10.5 Hz and 1.0 Hz), 5.98 (1H, m), 7.08
(1H, d, J = 8.0 Hz), 7.29 (1H, t, J = 8.0 Hz), 7.53 (1H, dt, J = 8.0 Hz
and 1.5 Hz), 8.02 (1H, dd, J = 8.0 Hz and 1.5 Hz); 13C NMR
(CDCl3, 125 MHz): δ 21.3, 66.0, 119.0, 123.5, 124.0, 126.3, 132.0,
132.1, 134.2, 150.9, 164.4, 169.9. LRMS observed: [M + H]+ 221.2;
calculated for C12H12O4H+: 221.1.
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