Synthesis of salicylate dendritic prodrugs
Bob Howell2006, Tetrahedron Letters
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A small drug molecule, salicylic acid, has been converted into well-defined dendritic macromolecules. The mono-disperse nature of these materials may be clearly shown by NMR and GPC. A third generation salicylic acid dendrimer contains sixty salicylic acid residues, which make up its core, branches, and periphery. Individual salicylic acid moieties in the dendrimer are connected to one another via hydrolyzable diester linkages.
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Tetrahedron Letters 47 (2006) 7671–7675
Synthesis of salicylate dendritic prodrugs
Shengzhuang Tang, Stephen M. June, Bob A. Howell and Minghui Chai*
Department of Chemistry, Central Michigan University, Mt. Pleasant, MI 48859, USA
Received 11 August 2006; revised 29 August 2006; accepted 29 August 2006
Abstract—A small drug molecule, salicylic acid, has been converted into well-defined dendritic macromolecules. The mono-disperse
nature of these materials may be clearly shown by NMR and GPC. A third generation salicylic acid dendrimer contains sixty salicylic acid residues, which make up its core, branches, and periphery. Individual salicylic acid moieties in the dendrimer are connected
to one another via hydrolyzable diester linkages.
Ó 2006 Elsevier Ltd. All rights reserved.
Considerable effort has been devoted to the field of drug
delivery devices to prolong the duration of drug release
and to deliver a drug selectively to a targeted location,
such as a tumor site.1 Polymers have played an important role in the development of drug delivery systems
for controlled release formulations as well as site-directed delivery, since polymeric materials can be easily formulated as microspheres, films, tablets or implantation
devices, for achieving sustained drug release with temporal and spatial distribution control in the body.2
Although many polymers and polymer conjugates have
showed promising results as drug carriers during in vitro
studies, a large number of them failed when subjected to
in vivo examinations, largely as a consequence of polymer-related toxicity or lack of improved therapeutic
index.3 Another crucial limiting factor in the design of
polymer-drug conjugates may be low drug carrying
capacity.
lency of a dendrimer can be used to attach a
combination of drug molecules, targeting groups, and
solubilizing groups, to the periphery of the dendrimers
in a well-defined manner. Third, the more globular
shape of dendrimers, instead of the random coil structure of most linear polymers, may enhance their biological performance; furthermore, the low polydispersity of
dendrimers should promote reproducible pharmacokinetic behavior.2 However, the biocompatibility and
non-toxicity of dendrimers must be considered before
the application for drug delivery; in addition, the formation of dendritic defects (i.e., lack of perfect growth of
all arms in a dendrimer) which can result in low drug
loading also needs to be carefully controlled during
the dendrimer synthesis. Herein is reported the first synthesis of a highly loaded novel dendritic prodrug based
on salicylic acid, a commonly used nonsteroidal antiinflammatory drug (NSAID) (see Fig. 1).
In the past decade, more attention has been paid to dendrimers as drug-delivery systems because of their cascade three-dimensional structure with nearly perfect
monodispersity.4 Such highly branched architecture
along with outer functional termini and inner dendritic
nano-voids makes these novel macromolecules more
efficient drug carriers when compared with classic polymers. First, the internal cavity of a dendrimer provides
an ideal site for a hydrophobic drug to achieve noncovalent encapsulation with the possibility of subsequent
controlled release as well as the enhancement of the drug
solubility in water. Second, the controllable multiva-
The most attractive feature of the dendritic prodrug is
that the drug entities are chemically incorporated into
a dendrimer structure, not just attached as pendants
on the surface nor physically encapsulated inside the
cavities. This design not only incorporates a large number of drug units into the dendritic architecture but also
provides the unique potential that the drug molecules
can be controllably released via hydrolytic cleavage of
ester bonds sequentially and even quantitatively layer
by layer from the cascade architecture. In addition, the
functional groups at the surface of the novel dendritic
drug may be modified to permit the introduction of a
synergistic drug. Alternatively, the inner dendritic cavities may be utilized for encapsulation of such a drug.
The incorporation of salicylic acid into polymeric
* Corresponding author. Tel.: +1 989 774 3955; fax: +1 989 774
3883; e-mail: [email protected]
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.110
7672
S. Tang et al. / Tetrahedron Letters 47 (2006) 7671–7675
HO
OH
O
O
O
O
HO
O
O
O
O
O C
C O
O
C
O C
O
O
O
O
O
O
O
OH
O
O
C
O
O
O
O
O
C
O
O
O
C
O
OH
O
O
O
O
OH
O
HO
O
C
O
O
C O
O
O
O
C
O
C
O
C
O
O
O
O
O
C
O
C
O
O
HO
O
O
O
HO
O
O
O
O
O
O C
O
C O
O
O C
O
C O
O
HO
O
O
C
O
O
C
O
O
C O
O
C
C
O
O
C
O
O
O
O C
O
O
C
O
C
O
O
OH
HO
O
O
O
O
O
C
O
O
O
O
C
O
C
O
O
OH
O
O
O
O
O
O
O
OH
O
O
HO
OH
Figure 1. Structure of a dendritic salicylic acid prodrug.
backbones has been reported.5 Salicylic acid-based polyesters have been shown to display in vitro degradation
lag time of a couple of days.6 The newly synthesized salicylic acid-based dendrimers described here will also be
useful for sustained delivery.
Salicylic acid-based dendrimers HO-Gn (n = 0–3: the
generation number of the dendrimer) were synthesized
by means of ‘Lego’ or ‘click’ chemistry7 using biocompatible building blocks (salicylic acid, glycerol, and succinic acid) by typical stepwise and iterative processes of
a
O
O
OH
O
O C
C OH
O
O
O
2
b
O
O
O C
O
c
O
C O
O
O
O C
HO
OH
C O
O
HO
O
OH
4
3
d
OH
O
C
O
C
O
O
HO
O
O C
O
C O
O
OH
6:core (HO-G0)
O
O
C
OBn
c
O
C
O
C
O
O
C
O
HO
OBn
BnO
O
O
O C
O
C O
O
5
C
O
C
O
BnO
Scheme 1. The syntheses of building block 4 and core 6. Reagents and conditions: (a) succinic anhydride, pyridine, rt, 18 h, 91%; (b) succinic acid,
DCC, DPTS, CH2Cl2, rt, 18 h, 87%; (c) 20% Pd(OH)2, 50 psi H2, THF, rt, 3 h, 85% for 4, and 94% for 6; (d) 2-benzyloxybenzoic acid, DCC, DPTS,
CH2Cl2, rt, 18 h, 78%.
7673
S. Tang et al. / Tetrahedron Letters 47 (2006) 7671–7675
esterification and hydrogenolysis. The glycerol–succinic
acid monoester 2 and the pre-core 4 with a tetrahydroxy
focal point were first prepared.8 Compound 4 was coupled to 4 equiv of 2-benzyloxybenzoic acid, followed
by subsequent hydrogenolysis to produce the core HOG0 6 in an overall 71% yield (Scheme 1).
tion dendritic drug HO-G1.0, 10, in an overall 47%
yield. The second generation dendritic prodrug 14,
HO-G2.0, was synthesized in four similar steps. Compound 10 was treated with 2 to generate compound
11. Hydrogenolysis of 11 afforded compound 12, which
were subsequently coupled with 16 units of 2-benzyloxybenzoic acid to produce 13. The acetal protecting groups
were subsequently removed by hydrogenolysis. The
third generation dendritic prodrug HO-G3.0, 18, was
prepared in an analogous stepwise procedure, whereby
2 was coupled to 14 followed by hydrogenolysis to afford compound 16. 2-Benzyloxybenzoic acid was subsequently coupled to 16 followed by routine
hydrogenolysis (Scheme 2).
Compound 2 (4 equiv) was coupled to the core HO-G0,
6, to afford compound 7, Ben-G0.5. The benzylidene
acetal protecting groups were later removed by hydrogenolysis to provide compound 8, HO-G0.5, to which
the eight units of 2-benzyloxybenzoic acid were then
coupled by esterification to yield compound 9, BnOG1.0. Again, hydrogenolysis afforded the first genera-
O
O
O
O
O
a
O
O
O
O
O
O
O
O
b
O
7: Ben-G0.5
O
O
O
O
O
O
O
O
O
O
8: HO-G0.5
O
O
OH
OH
HO
HO
O
O
O
O
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O
O
O
6: HO-G0
O
O
O
O
O
O
OH
OH
HO
HO
O
O
O
c
HO
OH
O
OH
O
O
C
O
O
O
O
O
O
O
O
b
O
O
O
O
O
O
O
O OH
O
O
10: HO-G1.0
O
OH
O
O
OBn
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
9: BnO-G1.0
O
O
HO
OBn
BnO
O
O
O
O
O
O OBn
O
O
O
O
O
O
O
O
O
O
O
O
OH O
O
OBn
O
O
O
O
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
BnO
OBn
O
O
O
O
O
BnO
a
b
c
b
14: HO-G2.0
13: BnO-G2.0
12: HO-G1.5
11: Ben-G1.5
a
b
c
b
18: HO-G3.0
17: BnO-G2.5
16: HO-G2.5
15: Ben-G2.5
Scheme 2. The syntheses of salicylate dendritic prodrug G1.0–G3.0 (10–18). Reagents and conditions: (a) Compound 2, DCC, DPTS, DCM, rt, 18 h
for 7, 24 h for 11, 36 h for 15; (b) 20% Pd(OH)2, 50 psi H2, THF, rt, 3 h; (c) 2-benzyloxybenzoic acid, DCC, DPTS, DCM, rt, 24 h for 9, 36 h for 13,
48 h for 17.
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S. Tang et al. / Tetrahedron Letters 47 (2006) 7671–7675
(a)
(b)
2.00
**
*
G0
G0
***
3.92
*
***
**
G1
2.08
G1
7.73
*
4.14
**
2.13
***
G2
*
G2
15.78
**
11.98
2.24
G3
G3
7.5
6.5
5.5
4.5
3.5
ppm
5.58
5.54
5.50
5.46
ppm
1
Figure 2. (a) H NMR spectra of salicylate dendritic prodrugs G0.0–G3.0, here, *peaks are from the residual protons of the solvent (CDCl3), **peaks
are from the protons of CH2Cl2 (DCM used as the solvent in the synthesis), and ***peaks are from the methylene protons of ethyl acetate used in the
column chromatography separation; (b) the plots of 1H NMR spectral expansions for the methine proton resonance region of the glycerol entities in
the salicylate dendritic prodrugs G0.0–G3.0.
The structures of all generations of salicylic acid-based
dendrimers were confirmed by FTIR, 1H and 13C
NMR, and MALDI-TOF-MS.8 The strong O–H characteristic stretch around 3220 cm 1 in the FTIR spectrum confirmed the presence of free hydroxyls in the
dendritic structures. The 1H NMR spectra (Fig. 2) of
the different generation dendritic drug HO-Gn (n = 0–
3) exhibit a clear correlation of the growth of higher generation dendrimers with the increasing characteristic sets
of well resolved peaks. Additionally, the relative integration area of exterior and interior benzyl and glycerol
proton resonances in the NMR spectra clearly indicates
that the next higher generation of the desired prodrugs
had been formed from the previous generation, that is,
the conversion of one generation to the next was cleanly
accomplished.9
The polydispersity indices (PDI) of these dendritic prodrugs listed in Table 1 were determined by gel-permeation
chromatography (GPC) (Fig. 3), indicating the high purity and monodispersity of the dendrimers formed.10
This represents the first synthesis of salicylic acid-based
dendrimers. These newly synthesized dendritic prodrugs
Table 1. GPC data for the dendritic salicylate prodrugs G0.0–G3.0
Dendrimer
G0.0
G1.0
G2.0
G3.0
Retention volume (mL)
PDI (Mw/Mn)
Run 1
Run 2
Average
Run 1
Run 2
Average
10.22
9.59
9.15
8.83
10.21
9.59
9.15
8.82
10.22
9.59
9.15
8.83
1.030
1.042
1.056
1.044
1.031
1.040
1.049
1.047
1.031
1.041
1.053
1.046
Figure 3. Overlay of GPC chromatograms of salicylate dendritic prodrugs G0.0–G3.0. Here, *peaks are from the solvent (THF).
S. Tang et al. / Tetrahedron Letters 47 (2006) 7671–7675
possess a number of drug entities cascading from the
core, interior and exterior regions, and also display a
large number of functional groups at the periphery.
Such a novel dendritic prodrug design provides a promising hydrolyzable drug delivery system for sequential
and quantitative drug release. With a much higher drug
loading than has heretofore been archived, the dendritic
prodrug could potentially greatly exceed the effectiveness of the current repertoire of drug vehicles and offer
a new platform for drug delivery.
Acknowledgements
Support for this research from US National Science Foundation (NUE-0407298), Research Corporation (CC-6059), American Chemical Society Petroleum
Research Fund (PRF # 40998-GB4) and Central
Michigan University (FRCE and PRIF) is gratefully
acknowledged.
References and notes
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2. Li, Y.-Q.; You, H.-B. Pharm. Res. 2006, 23, 1.
3. Duncan, R. Anti-Cancer Drugs 1992, 3, 175.
4. Svenson, S.; Tomalia, D. A. Adv. Drug Delivery Rev. 2005,
57, 2106.
5. Kricheldorf, H.; Gerken, A.; Yulchibaev, B.; Friedrich, C.
J. Polym. Sci., Part A: Polym. Chem. 2000, 38, 2013.
6. Schmeltzer, R.; Schmealenberg, K.; Uhrich, K. Biomacromolecules 2005, 6, 359.
7. (a) Maraval, V.; Caminade, A.-W.; Majoral, J.-P.; Blais,
J.-C. Angew. Chem., Int. Ed. 2003, 42, 1822–1826; (b)
Maraval, V.; Pyzowski, J.; Caminade, A.-W.; Majoral,
J.-P. J. Org. Chem. 2003, 68, 6043–6046; (c) Wu, P.;
Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.;
Voit, B.; Pyun, J.; Fréchet, J. M. J.; Sharpless, K. B.;
Fokin, V. V. Angew. Chem., Int. Ed. 2004, 23, 3928–3932.
8. Luman, N.; Smeds, K.; Grinstaff, M. Chem. Eur. J. 2003,
9, 5618.
9. Spectroscopic data of the dendritic salicylate prodrugs
G0.0–G3.0: HO-G0 6: 1H NMR (CDCl3) (500 MHz,
ppm): 2.699 (4H, s, succ.-CH2), 4.490–4.526 (4H, m,
Glycerol–CH2), 4.617–4.651 (4H, m, Glycerol–CH2),
5.521 (2H, pentet, J = 5.0 Hz, Glycerol–CH), 6.878 (4H,
td, J = 7.5 and 1.0 Hz, Ar-H), 6.977 (4H, dd, J = 8.5 and
1.0 Hz, Ar-H), 7.462 (4H, td, J = 8.0 and 1.0 Hz, Ar-H),
7.805 (4H, dd, J = 8.0 and 1.5 Hz, Ar-H); 13C NMR
(CDCl3) (75 MHz, ppm): 28.838 (succ.-CH2), 62.747
(Glycerol–CH),
69.095
(Glycerol–CH2),
111.687,
117.700, 119.363, 129.893, 136.203, and 161.742 (Ar-C),
169.471 (Ar-CO), 171.249 (succ.-CO); MALDI-TOF-MS
observed: [M+Na]+ 769.0 and [M+K]+ 785.0; calculated
for C38H34O16: 746.2.
HO-G1 10: 1H NMR (CDCl3) (500 MHz, ppm): 2.631(4H,
s, core succ.-CH2), 2.792 (8H, t, J = 6.8 Hz, exterior succ.CH2), 2.961 (8H, t, J = 6.8 Hz, exterior succ.-CH2), 4.362–
4.398 (4H, m, core Glycerol–CH2) 4.446–4.479 (4H, m,
core Glycerol–CH2), 4.497–4.532 (8H, m, exterior Glycerol–CH2), 4.616–4.649 (8H, m, exterior Glycerol–CH2),
5.445 (2H, t, J = 5.0 Hz, core Glycerol–CH), 5.576 (4H, t,
J = 5.0 Hz, exterior Glycerol–CH), 6.804 (8H, td, J = 4.0
7675
and J = 1.0 Hz, exterior Ar-H), 6.950 (8H, d, J = 7.5 Hz,
exterior Ar-H), 7.121 (4H, dd, J = 8.0 and J = 1.0 Hz,
core Ar-H), 7.248 (4H, td, J = 7.5 and J = 1.0 Hz, core
Ar-H), 7.428 (8H, td, J = 7.0 and J = 1.5 Hz, exterior ArH), 7.486 (8H, td, J = 7.0 and 1.5 Hz, exterior Ar-H),
7.774 (8H, dd, J = 8.0 and 1.5 Hz, exterior Ar-H), 7.934
(4H, dd, J = 8.0 and 1.5 Hz, core Ar-H), 10.485 (8H, s,
Ar-OH); 13C NMR (CDCl3) (75 MHz, ppm): 28.731 (core
succ.-CH2), 28.914 and 29.021 (exterior succ.-CH2), 62.770
and 62.853 (exterior and core Glycerol–CH), 69.011 and
69.225 (exterior and core Glycerol–CH2), 111.680,
117.647, 119.371, 129.916, 136.58, and 161.696 (exterior
Ar-C), 122.133, 123.827, 126.177, 131.702, 134.281, and
150.770 (core Ar-C), 163.444 (Ar-CO), 169.494, 170.746,
and 171.364 (succ.-CO); MALDI-TOF-MS observed:
[M+Na]+ 2427.4 and [M+K]+ 2443.4; calculated for
C122H106O52: 2404.1.
HO-G2 14: 1H NMR(CDCl3) (500 MHz, ppm): 2.620 (4H,
s, core succ.-CH2), 2.749–2.803 (24H, m, exterior and
middlesucc.-CH2), 2.912–2.976 (24H, m, exterior and
middle succ.-CH2), 4.337–4.422 (12H, m, interior Glycerol–CH2), 4.439–4.516 (28H, m, exterior and interior
Glycerol–CH2), 4.601–4.634 (16H, m, exterior Glycerol–
CH2), 5.446 (2H, m, core Glycerol–CH), 5.509 (4H, p,
J = 5.0 Hz, middle Glycerol-CH), 5.570 (8, p, J = 5.0 Hz,
exterior Glycerol–CH), 6.793 (16H, t, J = 7.5 Hz, exterior
Ar-H), 6.943 (16H, d, J = 8.0 Hz, exterior Ar-H), 7.014–
7.030 (12H, m, interior Ar-H), 7.403–7.481 (28H, t,
exterior and interior Ar-H), 7.766 (16H, dd, J = 8.0 and
1.5 Hz, exterior Ar-H), 7.911–7.927 (12H, m, interior ArH); 13C NMR (CDCl3) (75 MHz, ppm): 28.922 and 29.036
(succ.-CH2), 62.869 (Glycerol–CH), 69.026 and 69.324
(Glycerol–CH2), 111.703, 117.639, 119.371, 129.924,
136.142, and 161.704 (exterior Ar-C), 122.156, 123.797,
123.926, 126.177, 131.709, 134.227, 150.747, and 150.876
(interior Ar-C), 163.360 and 163.482 (Ar-CO), 169.494,
170.723, 170.807, 171.356, and 171.410 (succ.-CO);
MALDI-TOF-MS observed: [M+Na]+ 5742.4; calculated
for C290H250O124: 5719.0.
HO-G3 18: 1H NMR (CDCl3) d 1H (500 MHz, ppm):
2.622 (4H, s, core succ.-CH2), 2.761–2.796 (56H, m, succ.CH2), 2.923–2.966 (56H, m, succ.-CH2), 4.334–4.405
(28H, m, interior Glycerol–CH2), 4.446–4.508 (60H, m,
exterior and interior Glycerol–CH2), 4.593–4.625 (32H, m,
exterior Glycerol–CH2), 5.452 (2H, m, core Glycerol–CH),
5.501 (12H, m, middle Glycerol–CH), 5.561 (16H, p,
J = 5.0 Hz, exterior Glycerol–CH), 6.783 (32H, t,
J = 7.5 Hz, exterior Ar-H), 6.934 (32H, d, J = 8.5 Hz,
exterior Ar-H), 7.004–7.021 (28H, m, interior Ar-H),
7.129–7.215 (28H, m, interior Ar-H), 7.393–7.466 (60H,
m, exterior and interior Ar-H), 7.758 (32H, d, J = 8.0,
exterior Ar-H), 7.892–7.918 (28H, m, interior Ar-H),
10.474 (32H, s, Ar-OH); 13C NMR (CDCl3) (75 MHz,
ppm): 28.922 and 29.036 (succ.-CH2), 62.869 (Glycerol–
CH), 69.034 and 69.324 (Glycerol–CH2), 111.710, 117.639,
119.371, 129.931, 136.142, and 161.696 (exterior Ar-C),
122.164, 123.789, 126.185, 131.709, 134.227, 150.739, and
150.854 (interior Ar-C), 163.390 and 163.489 (Ar-CO),
169.494, 170.730, 170.814, 171.356, and 171.417 (succ.CO); MALDI-TOF-MS observed: [M+H]+ 12349.7; calculated for C290H250O124: 12348.5.
10. GPC experimental: All samples were analyzed using a
Viscotek GPCmax VE 2001 Module equipped with a
Viscotek TDA 302 Triple Detector Array, a ViscoGEL
microstyrogel mixed-bed column, linear poly(styrene)
calibration and THF as elution solvent at 1.0 mL/min.
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