Design and synthesis of novel janus dendrimers as lipophilized antioxidants

Article abstract of DOI:10.1055/s-0032-1318457

In the search for better antioxidants with more satisfactory lipophilicity, a series of Janus dendrimers that consisted of gallic acid and alkyl chains as the peripheral groups, were designed and synthesized. These dendrimers take advantage of a dendritic display to carry multi-antioxidants and multi-lipophilic moieties simultaneously. Consequently, the resulting dendrimers, which showed satisfactory lipophilicity and better antioxidant activity than the gallic acid monomer, are potential novel lipophilized antioxidant agents. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0032-1318457

LETTER
▌1011
lDetteersign and Synthesis of Novel Janus Dendrimers as Lipophilized Antioxidants
Janus Dendrimers as Lipophilized Antioxidants
Junzhu Pan,a Lifang Ma,b Yi Zhao,a Jing Zhao,a Liang Ouyang,c Li Guo*a
a
Key Laboratory of Drug Targeting and Drug Delivery System of Education Ministry, Department of Medicinal Chemistry, West China School
of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China
Fax +86(28)85502609; E-mail: rosaguoli2000@yahoo.com.cn
b
School of Chemical Engineering, Sichuan University, Chengdu 610041, P. R. of China
c
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. of China
Received: 17.01.2013; Accepted after revision: 22.02.2013
defined three-dimensional architecture. Dendrimers are
Abstract: In the search for better antioxidants with more satisfacto-
favorable vehicles that can be used to gather multi-bioac-
ry lipophilicity, a series of Janus dendrimers that consisted of gallic
tive compounds so as to form conjugated macromolecules
acid and alkyl chains as the peripheral groups, were designed and
synthesized. These dendrimers take advantage of a dendritic display
with improved bioactivities resulting from dendritic ef-
to carry multi-antioxidants and multi-lipophilic moieties simultane- fects.8 To this point, 1st, 2nd, and 3rd generation GA func-
ously. Consequently, the resulting dendrimers, which showed satis-
factory lipophilicity and better antioxidant activity than the gallic
acid monomer, are potential novel lipophilized antioxidant agents.
tionalized dendrimers have been synthesized and shown
to increase antioxidant activity, collagen cross-linking ac-
tivity, and chemiluminescence intensity compared with
those of the GA monomer.9
Key words: Janus dendrimers, gallic acid, antioxidant, lipophiliza-
tion, polyphenols
Janus dendrimers, which are composed of two differently
functionalized segments (dendrimeric wedges) on oppo-
site sides, have distinctive features in the dendrimer fam-
Phenols and polyphenols occur widely in natural products
ily.10 First, most traditional dendrimers have highly
and have numerous biological activities.1 Among them,
symmetrical dendritic skeletons and possess functional
gallic acid (GA; Figure 1) exhibits antibacterial,2 anti-
groups with statistical numbers and random sites on the
viral,3 and antitumor activities.4 Specifically, the major in-
surface, whereas Janus dendrimers have two (or more)
terest in GA and its derivatives is related to their
types of terminal groups precisely situated on each den-
antioxidant activity, the mechanism of which depends on
dron respectively. Second, Janus dendrimers can be used
the tendency of phenolic hydroxyl groups to act as effec-
to combine several properties in one single molecule and
tive free radical scavengers since they may readily donate
their applications encompass various fields, such as drug
an electron or hydrogen to intercept and convert free rad-
delivery,11 gene transfection,12 and fluorescent labeling.13
icals into a more stable compound.5 Although GA pos-
Third, Janus dendrimers are frequently designed as am-
sesses interesting biological properties, its application in
phiphilic structures. The lipophilic-hydrophilic balance,
oil-based media is limited because of its relatively low
which dramatically affects the biological activity and drug
solubility in aprotic media, which is also a general prob-
delivery properties of the amphiphilic dendrimers, can be
lem for most natural phenolic antioxidants. Therefore, a
adjusted flexibly by the assembly of different dendrons.14
lot of effort has been made to enhance the hydrophobicity
of natural phenols by introducing lipophilic moieties.6
Specifically, different cyclic or chain alkyls were connect-
ed to GA by either chemical or enzymatic esterification to
obtain a series of amphiphilic derivatives as lipophilic
antioxidants.7
In our previous work, Janus dendrimers were prepared as
bone-targeting drug delivery15 and amphiphilic antibacte-
rial agents.16 It is also considered that Janus dendrimers
can be promising platforms for developing antioxidant
agents with highly lipophilized and remarkable antioxi-
dant efficiency. In this paper, we designed and synthe-
sized a series of bifunctionalized Janus dendrimers that
consist of multiple GA moieties (antioxidants) and multi-
ple myristic acids (lipophilic molecules). It can be expect-
ed that this sort of dendrimer will be a satisfactory
amphiphilic antioxidant with not only antioxidant activity
but also improved lipophilicity.
OH
HO
OH
O
OH
Figure 1 The structure of gallic acid (GA)
A typical procedure for the preparation of the Janus den-
drimers involves two steps: (1) the synthesis of different
dendrons, and (2) the assembly of these two functional
dendrons together either directly or through a linker. First,
the two types of functional dendrons were prepared by a
convergent approach. For the synthesis of dendritic GA
(Scheme 1), the core (L-lysine methyl ester) was coupled
Dendrimers are new artificial macromolecules that have
monodisperse and highly branched structures with well-
SYNLETT 2013, 24, 1011–1015
Advanced online publication: 27.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318457; Art ID: ST-2013-W0060-L
© Georg Thieme Verlag Stuttgart · New York

1012
J. Pan et al.
LETTER
BnO
OBn
OBn
BnO
OBn
OBn
O
HN
O
O
OH
OBn
O
N
HN
H
HO
OH
BnO
OBn
O
HN
O
O
RO
HN
HN
O
a
OBn
OBn
ref. 20
RO
HN
BnO
O
OH
O
OH
OBn
OBn
BnO
BnO
O
3
BnO
c
NH
OBn
4
R = Me
OBn
O
b
OBn
5
R = H
OBn
6
7
R = Me
R = H
b
Scheme 1 Preparation of the dendritic gallic acid. Reagents and conditions: (a) L-lysine methyl ester hydrochloride, EDCI/HOBt, CH2Cl2, r.t.,
24 h (78%); (b) NaOH, MeOH–H2O, 100 °C, 2 h (98%); (c) L-lysine methyl ester hydrochloride, HOBt/HBTU, DIPEA, CH2Cl2, r.t., 24 h
(65%).
with benzyl-protected GA 3 in the presence of ED- nolysis for focal point activation to give dendrons 11 and
CI/HOBt (1-hydroxybenzotriazole) to afford [G1]-den- 12, respectively.19
dron 4.17 The methyl ester on the focal point of 4 was
The following spectroscopic data for 6 illustrates the char-
selectively deprotected in the presence of the benzyl
acterization of these dendrons. In the 1H NMR spectrum,
group, using 2N NaOH solution, affording dendron 5.
the structures can be confirmed by calculating the integra-
tion of the respective areas of the core protons (-OCH3
peak at δ = 3.6 ppm) and periphery protons (PhCH2 peak
at δ = 5.0 ppm) to ensure complete coupling. Moreover,
Subsequently, formation of [G2]-dendron 6 was achieved
by utilizing the more powerful coupling system
HOBt/HBTU (o-benzotriazol-1-yl-N,N,N′,N′-tetramethy-
luronium hexafluorophosphate) to overcome the in-
the mass spectrum showed molecular ion peaks [M+Na]+
creased steric hindrance.18 Dendron 7 was then obtained
+
at m/z 2127.825 (m/z calcd for C131H128N6NaO20
:
through removal of the methyl ester group under the same
conditions used for the preparation of 5. For the synthesis
of dendritic myristic acid (Scheme 2), [G1]-dendrons 9
and 10 were obtained according to our previous work.16
Subsequently, [G2]-dendrons were prepared through a
similar process that included use of EDCI/DMAP as the
coupling reagents for the growth and catalytic hydroge-
2127.908), which also confirmed the expected structure.
The key point of the synthesis of Janus dendrimers is the
coupling of two different dendrons. This process involves
the reaction of one dendron in a controlled manner with a
difunctional core, then a second dendron is grafted onto
the remaining functional group of the core.10 In this work
(Scheme 3), dendritic GA 5/7 (1.0 equiv) and EDCI/HOBt
(1.1 equiv) were added to a large excess (50 equiv) of eth-
O
O
O
O
O
N
N
O
O
O
OH
O
O
O
O
O
O
O
O
N
ref. 16
O
N
RO
N
O
RO
BnO
O
O
O
O
OH
O
8
O
9 R = Bn
10 R = H
a
11 R = Bn
12 R = H
b
Scheme 2 Preparation of the lipophilic dendrons. Reagents and conditions: (a) 8, EDCI /DMAP, CH2Cl2, r.t., 24 h, (70%). (b) H2, Pd/C (10
wt%), CH2Cl2–MeOH, r.t., 8 h (99%).
Synlett 2013, 24, 1011–1015
© Georg Thieme Verlag Stuttgart · New York

LETTER
Janus Dendrimers as Lipophilized Antioxidants
1013
1
ylenediamine (the difunctional core) in CH2Cl2 dropwise Quantitative coupling was demonstrated by H NMR
to make sure only one of the amino groups of ethylenedi- spectroscopy, with the characteristic resonance signals
amine was connected with the GA dendron while the sec- being assigned to the two opposite sides. For dendrimers
ond amino group was available for the next dendron 1 and 2, the peaks at δ = 6.80–6.88 ppm (PhH of GA) were
(excess ethylenediamine can be removed easily by extrac- used to compare with the peaks at δ = 0.86 ppm (CH3 of
tion without further purification). Dendrons 10 and 12 myristic acid), which confirmed the perfect joining.
were introduced into the difunctional core by coupling 13 Moreover, the well-defined nature of the dendrimers were
and 15 with HBTU/HOBt to obtain Janus dendrimers 14 further verified by ESI MS, which showed the molecular
and 16, respectively. Finally, after removal of the benzyl ion peak [M+H]+ at m/z 1100.6746 (1; m/z calcd for
protecting groups by catalytic hydrogenolysis, the target C58H94N5O15+: 1100.6741) and [M+Na]+ at m/z 2477.4323
molecules 1 and 2 were obtained.
(2; m/z calcd for C128H203N11NaO35+: 2477.4335), respec-
BnO
BnO
OBn
RO
OR
RO
O
O
NH
O
NH HN
O
NH
O
O
R1
O
O
NH
O
N
O
N
BnO
BnO
5 R1 = OH
13 R1 = NHCH2CH2NH2
H
O
RO
O
OBn
b
RO
OR
14 R = Bn
1 R = H
a
d
BnO
BnO
OBn
O
NH
O
O
O
N
NH
H
O
R1
NH
NH
BnO
BnO
OBn
OBn
OBn
O
HN
OBn
BnO
O
BnO
OBn
7 R1 = OH
15 R1 = NHCH2CH2NH2
a
c
RO
OR
O
RO
O
O
NH
O
O
O
N
N
O
O
N
O
O
NH
H
O
O
O
O
O
O
NH HN
NH
N
RO
O
O
N
H
O
RO
OR
OR
OR
O
O
O
HN
OR
RO
O
16 R = Bn
2 R = H
d
RO
OR
Scheme 3 Preparation of the Janus dendrimers. Reagents and conditions: (a) ethylenediamine, EDCI/HOBt, DIPEA, CH2Cl2, r.t., 24 h (92%
for 13, 86% for 15); (b) 10, HBTU/HOBt, DIPEA, CH2Cl2, r.t., 24 h (83%); (c) 12, HBTU/HOBt, DIPEA, CH2Cl2, r.t., 24 h (72%); (d) H2,
Pd/C (10 wt%), CH2Cl2–MeOH, r.t., 5 h (92% for 1, 90% for 2).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1011–1015

1014
J. Pan et al.
LETTER
tively. The polydispersity values (Mn/Mw) of dendrimers kinds of functional groups placed precisely on opposite
1 and 2 were measured to be 1.01 and 1.02, respectively, dendrons. Consequently, the resulting dendrimers showed
which indicated high purity.21
simultaneously satisfactory lipophilicity and improved
antioxidant activity. The result indicates that Janus den-
drimers are promising molecular scaffolds for the design
of more potent and lipophilized antioxidants. Further bio-
logical evaluations, such as on the antioxidant activity of
the Janus dendrimers in oils or oil-in-water emulsions, are
ongoing.
Table 1 LogP Values and Antioxidant Activity of GA and the Janus
Dendrimers
Compound
LogPa
0.733
DPPH EC50 (μM)
1.952±0.049
GA
1
10.608
21.445
1.177±0.034
Supporting Information for this article is available online at
2
0.727±0.038
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
a Determined by using the atom-based method published by Ghose
and Crippen22 to calculate the n-octanol/water partition coefficient
(LogP).
References and Notes
(1) For a review, see: Khadem, S.; Marles, R. J. Molecules 2010,
15, 7985.
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J. Microbiol. 2008, 46, 744.
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R. J.; Yunes, R. A.; Trybala, E.; Bergstrom, T.; Barardi, C.
R. M.; Simoes, C. M. O. Biol. Pharm. Bull. 2008, 31, 903.
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Neurochem. Int. 2006, 48, 263.
(6) For a review, see: Figueroa-Espinoza, M. C.; Villeneuve, P.
J. Agric. Food Chem. 2005, 53, 2779.
(7) (a) Buisman, G. J. H.; van Helteren, C. T. W.; Kramer, G. F.
H.; Veldsink, J. W.; Derksen, J. T. P.; Cuperus, F. P.
Biotechnol. Lett. 1998, 20, 131. (b) Ha, T. J.; Nihei, K. I.;
Kubo, I. J. Agric. Food Chem. 2004, 52, 3177. (c) Yu, X.
W.; Li, Y. Q.; Wu, D. J. Mol. Catal. B: Enzym. 2004, 30, 69.
(d) Medina, I.; Lois, S.; Alcantara, D.; Lucas, R.; Morales, J.
C. J. Agric. Food Chem. 2009, 57, 9773.
Lipophilization is the method of introducing a lipophilic
moiety on hydrophilic substrates, resulting in new mole-
cules with a modified hydrophilic/lipophilic balance.
Generally, logP values, which represent the partitioning
of a compound in an n-octanol/water system, is an appro-
priate parameter to describe the hydrophilicity/hydropho-
bicity of compounds. In this work, the logP values of both
GA and the Janus dendrimers were determined by using
Discovery Studio 3.1 software (Accelrys Inc., San Diego;
Table 1). First, whereas GA was a typical hydrophilic
molecule, Janus dendrimers 1 and 2 showed remarkably
hydrophobic properties. With logP values of 10.608 and
21.445, respectively, the logP value of [G2] dendrimer 2
was about two times as much as that of [G1] dendrimer 1,
which is presumably because the [G2] molecules have
more and condensed lipophilic groups at the surface area.
The synthesized dendrimers were allowed to react with
1,1-diphenyl-2-picrylhydrazyl (DPPH), with GA being
included as a control.23 For phenolic antioxidants, the phe-
nolic hydroxyl worked as the hydrogen donor, so the num-
ber of Ph-OH groups affected the antioxidant activity
prominently. Therefore, it is an effective approach to at-
tach several GA moieties to a multivalent scaffold, such as
a dendrimer,9a gelatin,24 or chitosan,25 to obtain conju-
gates as more powerful antioxidants. In this work, the re-
sults showed the following radical scavenging efficiency:
dendrimer 2 > dendrimer 1 > GA (Table 1). As a result,
the Janus dendrimers showed better antioxidant activity
than the GA monomer, and [G2] dendrimer 2, with more
GA moieties on the surface, exhibited better antioxidant
activity than [G1] 1, as expected. However, the antioxi-
dant activities of 1 and 2 were not 2- and 4-fold higher
than that of the GA monomer, respectively, presumably
because extensive steric crowding suppressed the valency
effect of the surface units.8b
(8) (a) Mammen, M.; Choi, S. K.; Whitesides, G. M. Angew.
Chem. Int. Ed. 1998, 37, 2755. (b) Tomalia, D. A. New J.
Chem. 2012, 36, 264.
(9) (a) Halkes, S. B. A.; Vrasidas, I.; Rooijer, G. R.; van den
Berg, A. J. J.; Liskamp, R. M. J.; Pieters, R. J. Bioorg. Med.
Chem. Lett. 2002, 12, 1567. (b) Nakazono, M.; Ma, L.;
Zaitsu, K. Tetrahedron Lett. 2002, 43, 9185.
(10) For a review, see: Caminade, A. M.; Laurent, R.; Delavaux-
Nicot, B.; Majoral, J. P. New J. Chem. 2012, 36, 217.
(11) Feng, X. S.; Pinaud, J.; Chaikof, E. L.; Taton, D.; Gnanou,
Y. J. Polym. Sci., Part A: Polym. Chem. 2011, 49, 2839.
(12) Guillot, M.; Eisler, S.; Weller, K.; Merkle, H. P.; Gallani, J.
L.; Diederich, F. Org. Biomol. Chem. 2006, 4, 766.
(13) Fuchs, S.; Pla-Quintana, A.; Mazeres, S.; Caminade, A. M.;
Majoral, J. P. Org. Lett. 2008, 10, 4751.
(14) (a) Wang, Y.; Grayson, S. M. Adv. Drug Delivery Rev. 2012,
64, 852. (b) Cho, B. K.; Jain, A.; Nieberle, J.; Mahajan, S.;
Wiesner, U.; Gruner, S. M.; Turk, S.; Rader, H. J.
Macromolecules 2004, 37, 4227. (c) Choy, L. S.; Chow, H.
F. Synlett 2013, 24, 201.
(15) Pan, J. Z.; Wen, M.; Yin, D. Q.; Jiang, B.; He, D. S.; Guo, L.
Tetrahedron 2012, 68, 2943.
(16) Pan, J. Z.; Guo, L.; Ouyang, L.; Yin, D. Q.; Zhao, Y. Synlett
2012, 1937.
(17) Convergent Synthesis of Dendrons; Typical Procedure
for 4: L-Lysine methyl ester hydrochloride (0.91 g, 5 mmol),
3 (4.62 g, 10.5 mmol), EDCI (10.5 mmol), and HOBt (10.5
mmol) were dissolved in CH2Cl2 (50 mL). The reaction
mixture was stirred at room temperature for 24 h, then the
In summary, a series of Janus dendrimers consisting of
GA and alkyl chains as the peripheral groups, were syn-
thesized by a convergent approach and well characterized.
The structure of these Janus dendrimers had the distinc-
tive feature that both multi-bioactive and multi-lipophilic
moieties were attached to the dendrimer, with the two
Synlett 2013, 24, 1011–1015
© Georg Thieme Verlag Stuttgart · New York

LETTER
solution was washed with 1 M HCl (10 mL), 1 M NaHCO3
Janus Dendrimers as Lipophilized Antioxidants
1015
as a white waxy solid. 10% Pd/C (100 mg) was added to a
solution of 14 in MeOH–CH2Cl2 (3:1 v/v, 30 mL) and the
reaction mixture was stirred under a hydrogen atmosphere
for 24 h in the dark, filtered through a membrane filter, and
concentrated under reduced pressure. The residue was
purified by flash chromatography to afford 1 (76%, two
steps from 13) as a white foam. 1H NMR (400 MHz, DMSO-
d6): δ = 0.83–0.86 (m, 6 H, 2 × CH3), 1.23 (br s, 42 H,
20 × myristic acid CH2+Lys-γ-CH2), 1.45–1.49 (m, 6 H,
2 × myristic acid-β-CH2+Lys-β-CH2), 1.70 (br s, 2 H, Lys-
δ-CH2), 2.23–2.31 (m, 4 H, 2 × myristic acid-α-CH2), 2.50–
2.57 (m, 4 H, 2 × succinic acid CH2), 3.08–3.17 (m, 6 H,
Lys-ω-CH2+NHCH2CH2NH), 3.47–3.60 (m, 4 H,
(10 mL), and brine (10 mL), and the organic layer was dried
over anhydrous Na2SO4. After concentration, the crude
product was recrystallized by EtOAc to obtain 4 (78%) as a
white solid; mp 160–161 °C. 1H NMR (400 MHz, CDCl3): δ
= 1.46–1.54 (m, 2 H, Lys-γ-CH2), 1.61–1.70 (m, 2 H, Lys-β-
CH2), 1.83–2.00 (m, 2 H, Lys-δ-CH2), 3.42–3.46 (m, 2 H,
Lys-ω-CH2), 3.78 (s, 3 H, OCH3), 4.75–4.78 (m, 1 H, Lys-α-
H), 5.01–5.07 (m, 12 H, 6 × Ph-CH2), 6.27 (br s, 1 H,
CONH), 6.83 (br s, 1 H, CONH), 7.10 (s, 2 H, GA-Ph-H),
7.17 (s, 2 H, GA-Ph-H), 7.20–7.37 (m, 30 H, OBn-Ph-H).
MS (ESI): m/z [M+Na]+ calcd for C63H60N2NaO10+: 1027.41;
found: 1027.36. Anal. Calcd for C63H60N2O10: C, 75.28; H,
6.02; N, 2.79; O, 15.92. Found: C, 75.14; H, 5.97; N, 2.69;
O, 15.88.
2 × NCH2), 4.04–4.17 (m, 4 H, 2 × NCH2CH2), 4.26–4.28
(m, 1 H, Lys-α-H), 6.80 (s, 2 H, Ph-H), 6.88 (s, 2 H, Ph-H),
7.84 (br s, 1 H, CONH), 7.93 (br s, 1 H, CONH), 7.95 (br s,
1 H, CONH), 8.06 (br s, 1 H, CONH), 8.65 (br s, 2 H,
(18) Data of dendron 6: Yield: 65%; white solid; mp 170–172 °C.
1H NMR (400 MHz, CDCl3): δ = 1.16–1.77 (m, 18 H,
3 × Lys-γ-CH2+3 × Lys-β-CH2+3 × Lys-δ-CH2), 3.33–3.41
(m, 6 H, 3 × Lys-ω-CH2), 3.60 (s, 3 H, OCH3), 4.67–4.69
(m, 3 H, 3 × Lys-α-H), 4.89–5.02 (m, 24 H, 12 × Ph-CH2),
6.80–7.50 (m, 68 H, Ph-H). ESI-TOF-MS: m/z [M+Na]+
calcd for C131H128N6NaO20+: 2127.908; found: 2127.825.
Anal. Calcd for C131H128N6O20: C, 74.69; H, 6.12; N, 3.99;
O, 15.19. Found: C, 74.58; H, 6.07; N, 3.93; O, 15.11.
(19) Data of dendron 11: Yield: 70%; colorless oil. 1H NMR (400
MHz, CDCl3): δ = 0.86–0.90 (t, J = 6.4 Hz, 12 H, 4 × CH3),
1.25 (br s, 80 H, 40 × myristic acid CH2), 1.58–1.60 (m, 8 H,
4 × myristic acid-β-CH2), 2.27–2.34 (m, 8 H, 4 × myristic
acid-α-CH2), 2.63–2.72 (m, 12 H, 6 × succinic acid CH2),
3.60–3.69 (m, 12 H, 6 × NCH2), 4.17–4.23 (m, 12 H,
6 × NCH2CH2), 5.12 (s, 2 H, Ph-CH2), 7.35–7.36 (m, 5 H,
Ph-H). ESI-TOF-MS: m/z [M+Na]+ calcd for
2 × Ph-OH), 8.98 (br s, 2 H, 2 × Ph-OH), 9.03 (br s, 2 H,
+
2 × Ph-OH). MS (ESI): m/z [M+H]+ calcd for C58H94N5O15
1100.6741; found: 1100.6746. GPC: PDI(Mw/Mn) = 1.01.
Data of dendrimer 2: Yield: 65% (two steps from 15). 1H
NMR (400 MHz, DMSO-d6): δ = 0.76–0.86 (m, 12 H,
:
4 × CH3), 1.22 (br s, 86 H, 40 × myristic acid CH2+3 × Lys-
γ-CH2), 1.36–1.48 (m, 14 H, 4 × myristic acid-β-
CH2+3 × Lys-β-CH2), 1.69 (br s, 6 H, 3 × Lys-δ-CH2),
2.22–2.31 (m, 8 H, 2 × myristic acid-α-CH2), 2.47–2.61 (m,
12 H, 6 × succinic acid CH2), 3.00–3.13 (m, 10 H, 3 × Lys-
ω-CH2+NHCH2CH2NH), 3.48–3.59 (m, 12 H, 6 × NCH2),
4.05–4.16 (m, 12 H, 6 × NCH2CH2), 4.28–4.30 (m, 3 × Lys-
α-H), 6.80–6.89 (m, 8 H, Ph-H), 7.81–7.95 (br s, 4 H,
CONH), 8.07 (br s, 3 H, CONH), 8.17 (br s, 1 H, CONH),
8.66 (br s, 4 H, 4 × Ph-OH), 8.99 (br s, 4 H, 4 × Ph-OH),
9.04 (br s, 4 H, 4 × Ph-OH). ESI-TOF-MS: m/z [M+Na]+
calcd forC128H203N11NaO35+: 2477.4335; found: 2477.4323.
GPC: PDI(Mw/Mn) = 1.02.
C87H151N3NaO17+: 1533.094; found: 1533.074. Anal. Calcd
for C87H151N3O17: C, 69.15; H, 10.07; N, 2.78; O, 18.00.
Found: C, 69.08; H, 10.02; N, 2.71; O, 17.93.
(20) Dodo, K.; Minato, T.; Noguchi-Yachide, T.; Suganuma, M.;
Hashimoto, Y. Bioorg. Med. Chem. 2008, 16, 7975.
(21) Synthesis of Janus Dendrimers; Typical Procedure for 1:
Dendron 5 (0.99 g, 1 mmol), HOBt (1.1 mmol), HBTU (1.1
mmol), DIPEA (2 mmol) were dissolved in CH2Cl2 (30 mL)
and the reaction mixture was stirred at room temperature for
30 min. The above solution was added dropwise into
ethylenediamine (3 g, 50 mmol) in CH2Cl2 (30 mL). After
stirring at room temperature for 24 h, the solution was
washed with 10% citric acid (10 mL), 1 M NaHCO3 (10
mL), and brine (10 mL), and the organic layer was dried over
anhydrous Na2SO4. After concentration, 13 (1.01 g, 98%)
was obtained for the next step without further purification.
Dendron 13 (516 mg, 0.5 mmol), 10 (312 mg, 0.5 mmol),
HBTU (0.6 mmol), HOBt (0.6 mmol), and DIPEA (1 mmol)
were dissolved in CH2Cl2 (30 mL) and the reaction mixture
was stirred at room temperature for 24 h. The solution was
then concentrated under vacuum and the residue was
purified by silica-gel column chromatography to obtain 14
(22) Ghose, A. K.; Crippen, G. M. J. Comput. Chem. 1986, 7,
565.
(23) Evaluation of the Antioxidant Activity by DPPH Assay:
Briefly, 2,2-diphenyl-1-picrylhydrazyl (DPPH) in ethanol
(200 μM, 2 mL) was added to the test compound (2 mL) at
different concentrations in ethanol. In the reaction mixtures,
the final concentration of DPPH was 100 μM, and the
concentrations of the test compounds were 0.1–10 μM. Each
mixture was then shaken vigorously and held for 30 min at
room temperature in the dark. The decrease in absorbance of
DPPH at 517 nm was measured. All tests were performed in
triplicate. EC50 corresponds to effective concentration of test
compounds resulting in 50% decolorization of initial DPPH.
(24) Spizzirri, U. G.; Iemma, F.; Puoci, F.; Cirillo, G.; Curcio,
M.; Parisi, O. I.; Picci, N. Biomacromolecules 2009, 10,
1923.
(25) Cho, Y. S.; Kim, S. K.; Ahn, C. B.; Je, J. Y. Carbohydr.
Polym. 2011, 83, 1617.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1011–1015

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