Synthetic N-alkylated iminosugars as new potential immunosuppressive agents

Article abstract of DOI:10.1021/ml2000998

The new emerging immunosuppressive effects displayed by iminosugars have not been much investigated so far. Several new N-alkyl dideoxy iminoalditols were designed and synthesized to explore their immunosuppressive effects. These iminosugars inhibited the

Full text of DOI:10.1021/ml2000998

LETTER
pubs.acs.org/acsmedchemlett
Synthetic N-Alkylated Iminosugars as New Potential
Immunosuppressive Agents
Guan-Nan Wang, Yulan Xiong, Jia Ye, Li-He Zhang, and Xin-Shan Ye*
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University,
Xue Yuan Road No. 38, Beijing 100191, China
S Supporting Information
b
ABSTRACT: The new emerging immunosuppressive effects
displayed by iminosugars have not been much investigated so
far. Several new N-alkyl dideoxy iminoalditols were designed
and synthesized to explore their immunosuppressive effects.
These iminosugars inhibited the proliferation of mouse sple-
nocytes and the secretion of both IFN-γ and IL-4, which are the hallmark cytokines of Th1 and Th2 cells, respectively. Some
compounds exerted good inhibitory effects. More importantly, the synthetic iminosugars prolonged the allograft survival in the
mouse skin transplantation experiment. Our results provide a lead for further elucidation of the structureÀactivity relationships and
modifications of iminosugars for better immunosuppressive agents.
KEYWORDS: Iminosugar, immunosuppressive agent, mouse skin allograft, synthesis
he search to find better immunosuppressants has been
stimulated by the need to improve transplant survival and
T
to decrease the toxicity of current agents. The main clinically
used immunosuppressive drugs, such as cyclosporin A (CsA),
sirolimus, tacrolimus, and mycophenolate mofetil, have signifi-
cant side effects including hypertension, dyslipidemia, hypergly-
cemia, and neurotoxicity and may lead to liver and kidney
injury.1À3 So, more effective and safer immunosuppressants are
in great demand.
Figure 1. 1,5-Dideoxy-l,5-iminopentitols isolated from E. fortunei
TURZ.
1À3 (Figure 1) were isolated from Eupatorium fortunei TURZ by
Kusano and co-workers in 1995 and have been shown to be the
active components of the extracts of this plant, which are
traditionally used in Chinese and Japanese folk medicine as
diuretic, antipyretic, emmenagogue, and antidiabetic agents.16
Since then, a number of new derivatives of compounds 1À3 have
been synthesized and have been displayed to be good inhibitors
of glycosidases.17À21
Previously, a one-pot tandem reaction to construct N-sub-
stituted δ-lactams was reported by us.22 On the basis of this
reaction, a new and expeditious approach to the synthesis of
N-alkylated dideoxy-iminoalditols was developed. As shown in
Scheme 1, the exoglucal 4 was easily prepared from methyl R-D-
glucopyranoside through short three steps23 or five steps in high
overall yield (77%).12 The ozonolysis of compound 4 at À78 °C
gave the methoxyl acetal lactone 5, which was then subjected to
the one-pot amination and cyclization tandem reaction providing
N-substituted δ-lactams in high yield. The N-substituted δ-
lactams were subsequently reduced by BH3-THF, which was
followed by catalytic hydrogenolysis to afford N-alkylated 1,5-
dideoxy-l,5-iminoxylitols 8a and 8b in excellent yield.
Iminosugars, widespread in plants and microorganisms, are
carbohydrate mimetics in which the endocyclic oxygen is re-
placed by nitrogen.4 These kinds of compounds raise many
synthetic challenges, and as inhibitors or chaperones of carbohy-
drate-processing enzymes,5 they open the way to treat a wide
range of diseases including diabetes,6 viral infections,7 tumor
metastasis,8 and lysosomal storage disorders.9 However, the use
of iminosugar derivatives as immunosuppressive agents is an area
that is less explored. To date, only castanospermine, a naturally
occurring indolizidine alkaloid (bicyclic polyhydroxylated imi-
nosugar), has been found to exhibit some immunosuppressive
activity.10,11 Our recent investigation disclosed that some syn-
thetic iminosugars, especially N-alkylated derivatives, displayed
immunosuppressive activity in vitro.12À14 On the basis of the
previous studies in our group, in this report, new N-alkylated 1,5-
dideoxy-l,5-iminopentitols and N-alkylated 1,4-dideoxy-l,4-imi-
notetritol have been synthesized. These iminosugars show
inhibitory effects on proliferation of mouse splenocytes induced
by concanavalin A (Con A) as well as the secretion of cytokines
from the mouse splenocytes. More importantly, the inhibitory
effects of these iminosugars have been confirmed in the mouse
skin transplantation model.
Iminosugars continue to be of great synthetic interest because
of the intrinsically pharmacological potential and the need for more
potent and selective compounds.15 1,5-Dideoxy-l,5-iminopentitols
Received: April 17, 2011
Accepted: July 5, 2011
Published: July 05, 2011
r
2011 American Chemical Society
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|

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LETTER
Scheme 1. Synthesis of N-Alkylated 1,5-Dideoxy-l,5-iminoxylitolsa
a Reagents and conditions: (a) O3, MeOH, À78 °C, 100%. (b) NaCNBH3, ZnCl2, RNH2, MeOH, reflux, 88% for 6a, 82% for 6b. (c) BH3-THF, THF,
reflux, 95% for 7a, 93% for 7b. (d) Pd/C, H2, THF/H2O/HOAc, 97% for 8a, 100% for 8b.
Scheme 2. Synthesis of Compounds 12 and 16a
a Reagents and conditions: (a) O3, MeOH, À78 °C. (b) NaCNBH3, ZnCl2, RNH2, MeOH, reflux, 88% for 10, 91% for 14. (c) BH3-THF, THF, reflux,
96% for 11, 93% for 15. (d) Pd/C, H2, THF/H2O/HOAc, 98% for 12, 98% for 16.
Scheme 3. Synthesis of N-Decyl 1,4-Dideoxy-l,4-
iminotetritola
Figure 2. N-Decyl lactams used in the immunosuppressive assay.
and 6b; however, LiAlH4 was not a good reductant for galactose
type δ-lactam 10 and mannose type δ-lactam 14. The yield for
the reduction of compound 10 was poor (20%), and LiAlH4 did
not reduce the compound 14 at all. Although the LiAlH4
reductive reaction could be influenced by many factors, it is
proposed that the steric hindrance around the carbonyl group
and the chelation of cis-benzylether with aluminum preventing
the delivery of hydride are possible reasons for this phenomenon,
since there are axial bonds with benzyloxy groups on them in
both compound 10 and compound 14. BH3-THF was finally
used to reduce different type lactams 10 and 14, and both worked
very smoothly. Although it was reported that in some circum-
stances the adduct of BH3 product was too tight to release the
free iminosugar,24 BH3-iminosugar was successfully dissociated
by 6 N HCl during the workup operation.
a Reagents and conditions: (a) BnBr, NaH, DMF, 72%. (b) (i) O3,
MeOH, À78 °C; (ii) NaCNBH3, ZnCl2, CH3(CH2)9NH2, MeOH,
reflux, 90% for two steps. (c) BH3-THF, THF, reflux, 95%. (d) Pd/C,
H2, THF/H2O/HOAc, 98%.
Compounds 8a and 8b can be regarded as N-alkylated 5-de-
(hydroxymethyl)-1-deoxynojirimycin. Our synthetic strategy
was then extended to prepare N-decyl 5-de(hydroxymethyl)-
1-deoxygalactonojirimycin (12) and N-decyl 5-de(hydro-
xymethyl)-1-deoxymannonojirimycin (16) by a similar pro-
cedure starting from exogalactose and exomannose alkenes,
respectively (Scheme 2). The reduction of lactams needs more
explanation. It is known that lactams are generally reduced by
reducing agents such as lithium aluminum hydride (LiAlH4) and
sodium borohydride. When LiAlH4 was chosen as the reductant,
it worked very well for the reduction of glucose type δ-lactams 6a
Besides N-alkylated 1,5-dideoxy-l,5-iminopentitols, the N-al-
kylated 1,4-dideoxy-l,4-iminotetritol 21 was also designed since
these kinds of structures have been rarely reported on both
chemistry and biological activity. Our one-pot tandem procedure
provides an expeditious access to this type of compounds. As
shown in Scheme 3, the exoglycal 18 was prepared from the
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Figure 5. Effects of iminoalditols on the secretion of IFN-γ from mouse
splenocytes induced by Con A. Values are means ( SEMs; ***p < 0.001
vs control.
Figure 3. Effects of iminoalditols on Con A-induced mouse splenocytes
proliferation were assessed by the MTT assay. Values are means (
SEMs; **p < 0.01, and ***p < 0.001 vs control.
A-treated splenocytes as the experimental control and CsA
(1 μM, 58.3% inhibitory rate) as the positive control.
None of the lactams 22À25 exhibited inhibitory effects of
more than 40% on mouse splenocyte proliferation induced by
Con A. However, most of the iminoalditols, as shown in Figure 3,
displayed good inhibitory effects on splenocyte proliferation.
Especially, the inhibitory rates of compounds 12 (57.2%), 16
(59.0%), and 21 (61.0%) were more than 50%. The inhibitory
rate of compound 8a (45.9%) was a little lower than that of
compounds 12, 16, and 21 but much better than compound 8b
(27.1%). The only difference between compound 8a and com-
pound 8b is the substituent group on the nitrogen atom, so it
seems that N-decyl chain is much better than N-octyl chain on
the behavior of inhibition. Moreover, the activity difference
between lactams and iminoalditols indicates that some structural
features are essential for inhibition, although there is a certain
redundancy around the six- or five-membered iminosugars.
Next, we tested the effects of the N-alkylated dideoxy imi-
noalditols on the secretion of cytokines from mouse splenocytes.
The spleen cells induced by 2.5 μg/mL of Con A were incubated
with each compound at 37 °C and 5% CO2 for 48 h. The amount
of cytokines was measured with enzyme-linked immunosorbent
assay. All of these five compounds showed inhibitory ability to
the interleukin (IL)-4 secretion. As compared to the control, the
levels of IL-4 secretion were reduced by 60.9, 8.7, 95.7, 85.6, and
88.6% when including 30 μM compounds 8a, 8b, 12, 16, and 21,
respectively (Figure 4, 96.8% for CsA at 1 μM). It was found that
among the five dideoxy iminoalditols, compound 12 displayed the
strongest inhibitory effects on the release of the cytokine IL-4.
The assay on secretion of interferon (IFN)-γ from spleno-
cytes was similar to the assay of IL-4. The supernatant of the
spleen cells was detected by mice IFN-γ ELISA kit. All of these
five compounds showed inhibition to the IFN-γ secretion. The
levels of IFN-γ secretion were reduced by 89.1, 40.3, 78.1, 75.0,
and 94.7% when including 30 μM compounds 8a, 8b, 12, 16, and
21, respectively (Figure 5, 97.1% for CsA at 1 μM). The
inhibition efficiency of iminosugar 21 was the strongest out of
the five compounds.
Figure 4. Effects of iminoalditols on the secretion of IL-4 from mouse
splenocytes induced by Con A. Values are means ( SEMs; ***p < 0.001
vs control.
corresponding 5-iodo-ribofuranoside 1725 through a one-step
elimination and benzylation process. Ozonolysis of compound
18 followed by the tandem reaction gave N-decyl γ-lactam 19.
The lactam was subsequently reduced by using BH3-THF to
yield compound 20, which was deprotected to afford the target
compound 21. On the other hand, to make comparison, N-decyl
δ-lactams 6a, 10, and 14 and N-decyl γ-lactam 19 were also
deprotected to provide compounds 22, 23, 24, and 25, respec-
tively (Figure 2).22
With five iminoalditols 8a, 8b, 12, 16, and 21 and four lactams
22À25 in hand, their effects on mouse splenocyte proliferation
induced by Con A were evaluated by 3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which mea-
sured the mitochondrial dehydrogenase activity of surviving cells
(Figure 3). The mouse splenocytes were induced by 2.5 μg/mL
of Con A with 30 μM concentration of each compound at 37 °C
and 5% CO2 for 48 h. The assays were conducted using the Con
The T cells contain two classes of T lymphocytes, T helper
cells (Th), and T cytotoxicity (Tc) cells. The Th cells are generally
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Table 1. Effects of Compounds 8a, 12, 16, and 21 on Mouse
Skin Allografta (MST ( SE, Days)
On the basis of the results of the mouse skin allograft together
with the splenocyte proliferation and cytokine assays, iminote-
tritol 21 was better than the others, although it is hard to further
tell the suppression difference between compounds 8a, 12, and
16. It seems that the long hydrophobic N-decyl group is more
favored for the immunosuppressive activity, indicating that there
might be a lipophilic pocket in the binding site of the target
biomacromolecule. Moreover, the activity difference between
lactams 22À25 and iminoalditols 8a, 12, 16, and 21 in prolifera-
tion assays indicates that dideoxy iminoalditol scaffolds are good
for inhibition. These N-decyl dideoxy iminoalditols not only
showed good inhibition in the splenocyte proliferation and
cytokine assays but also improved the mouse skin allograft
survival by 3À5 days.
compound
MST ( SEb
Vel
8a
11.25 ( 1.83
14.71 ( 1.70**c
14.14 ( 2.54*
15.20 ( 2.39**
15.60 ( 0.55**
12
16
21d
a Grafts were inspected daily and were considered to be rejected when no
viable donor epidermis remained. b MST in days. Each group consisted
of eight mice with half males and half females (body weight, 18À22 g).
c *P < 0.05, and **P < 0.01 vs Vel group. d The subcutaneous LD50 of
compound 21 is 392.1 mg/kg in mouse.
Generally, iminosugars are potent inhibitors of many carbo-
hydrate-processing enzymes. All cytokines are N-glycoproteins.
The immunosuppressive activities by these dideoxy iminoalditols
may come from the N-glycoprotein-processing inhibition effects
on these glycoproteins. However, there are other possibilities for
the immunosuppressive effects of these iminoalditols with a long
hydrophobic chain. These N-alkylated iminoalditols might bind
to some lipophilic sites of proteins by the alkyl group. The
mechanism of this kind of iminosugars working on immune
system needs to be further explored.
subdivided into Th1 and Th2 cells, which are distinguished by
the cytokines that they produce and the immune responses that
they promote. Th1 cells produce pro-inflammatory cytokines
like IFN-γ, TNF-β, and IL-2, while Th2 cells produce the
cytokines such as IL-4, IL-5, IL-6, and IL-13. Th1 responses
predominate in organ-specific autoimmune disorders, acute
allograft rejection, and in some chronic inflammatory disorders.
In contrast, Th2 responses predominate in chronic graft versus
host disease, progressive systemic sclerosis, systemic lupus
erythematosus, and allergic diseases. The cytokines (e.g., IFN-
γ) secreted by the Th1 subset act primarily in cell-mediated
response, whereas those (e.g., IL-4) secreted by the Th2 subset
function mostly in B-cell activation and humoral response.26 In
the cytokine assay, we chose IFN-γ and IL-4, which are the
hallmark cytokines for Th1 and Th2 cells, respectively.27 From
the assay of the cytokine secretion, it seems that compounds 8a,
12, 16, and 21 suppress both Th1 and Th2 cells, whereas
compound 8b has a moderate inhibition toward Th1 cells
selectively. Therefore, compounds 8a, 12, 16, and 21 might
show inhibition activity toward both humoral responses and cell-
mediated immune responses, holding the potential to treat
different kinds of immune diseases.
CsA is one of the strongest immunosuppressants, and it
selectively inhibits the lymphocytes especially the Th cells.28,29
The suppressive effects of compounds 8a, 12, 16, and 21 on
splenocyte proliferation and secretion of cytokines (IFN-γ and
IL-4) are similar to CsA and better than any other synthetic
iminosugars previously reported by our group.30 Encouraged by
the immunosuppressive results in vitro, compounds 8a, 12, 16,
and 21 were further tested on the mouse skin transplantation
model. The BALB/c mouse was used as the donor, and the
C57BL/6 mouse was used as the recipient. In this experiment,
the compounds (50 μmoL/kg) or vehicle were subcutaneously
injected in mice daily, starting from the day of transplant surgery
until the time of rejection. The mean survival time (MST) of
vehicle-treated grafts was 11 days. Compounds 8a, 12, 16, and 21
prolonged the mouse skin allograft survival to 14À16 days, which
means that the skin survived 3À5 days longer than vehicle-
treated grafts (Table 1). None of the allograft mice died during
administration. As the control, the mice with injection of CsA
(20 μmoL/kg) did not show skin rejection within 19 days.
Therefore, as compared with the vehicle, iminosugars 8a, 12, 16,
and 21 did prolong the mouse skin allograft survival, although the
survival time resulted from these iminosugars was shorter than
that of CsA.
In summary, we report herein the synthesis of hitherto
unknown N-alkylated 1,5-dideoxy-l,5-iminopentitols and N-al-
kylated 1,4-dideoxy-l,4-iminotetritol by an expeditious strategy.
These iminosugars inhibit the mouse splenocyte proliferation
induced by Con A. Further studies revealed that the inhibitory
effects on splenocyte proliferation may come from the suppres-
sion of both IFN-γ and IL-4 cytokines, which are the hallmark
cytokines for Th1 and Th2 cells, respectively. Importantly, these
iminosugars can prolong the allograft survival on the mouse skin
transplantation model. Although the effects are not as good as
CsA in mouse skin allograft at the current stage, to our knowl-
edge, they are the first synthetic iminosugars that show immu-
nosuppressive activities in animal model. It is a forward step for
investigating immunosuppressive effects of iminosugars. Our
results provide a lead for further elucidation of the structure
Àactivity relationships on iminosugars and modifications for
better immunosuppressive agents.
’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental procedures
b
and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: +(86)10-82805736. E-mail: xinshan@bjmu.edu.cn.
Funding Sources
This work was financially supported by the National Natural
Science Foundation of China (Grant Nos. 21072014 and
20732001).
’ ABBREVIATIONS
CsA, cyclosporin A;Con A, concanavalin A;Th, T helper cells; Tc,
T cytotoxicity cell; MST, mean survival time; LD50, median
lethal dose
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