Synthesis and biological evaluation of α-1-C-4′-arylbutyl-l- arabinoiminofuranoses, a new class of α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.06.001

A series of α-1-C-4′-arylbutyl-l-arabinoiminofuranoses 3 with functional groups attached to the phenyl ring, which are potential α-glycosidase inhibitors, was designed and synthesized by using a Negishi cross-coupling reaction as the key reaction. Arylbut

Full text of DOI:10.1016/j.bmcl.2014.06.001

Accepted Manuscript
Synthesis and biological evaluation of α-1-C-4’-arylbutyl-L-arabinoiminofura-
noses, a new class of α-glucosidase inhibitors
Yoshihiro Natori, Toshihiro Sakuma, Yuichi Yoshimura, Kyoko Kinami, Yuki
Hirokami, Kasumi Sato, Isao Adachi, Atsushi Kato, Hiroki Takahata
PII:
S0960-894X(14)00613-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.06.001
BMCL 21718
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
19 May 2014
29 May 2014
2 June 2014
Please cite this article as: Natori, Y., Sakuma, T., Yoshimura, Y., Kinami, K., Hirokami, Y., Sato, K., Adachi, I.,
Kato, A., Takahata, H., Synthesis and biological evaluation of α-1-C-4’-arylbutyl-L-arabinoiminofuranoses, a new
class of α-glucosidase inhibitors, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/
j.bmcl.2014.06.001
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Synthesis and biological evaluation of α-1-C-4’- Leave this area blank for abstract info.
arylbutyl-L-arabinoiminofuranoses, a new class of α-
glucosidase inhibitors
Yoshihiro Natoria, Toshihiro Sakumaa, Yuichi Yoshimuraa,*, Kyoko Kinamib, Yuki Hirokamib, Kasumi Satob,
Isao Adachib, Atsushi Katob,*, Hiroki Takahataa,§

Bioorganic & Medicinal Chemistry Letters
jour nal homepage: w ww.elsevier. com
Synthesis and biological evaluation of α-1-C-4’-arylbutyl-L-
arabinoiminofuranoses, a new class of α-glucosidase inhibitors
Yoshihiro Natoria, Toshihiro Sakumaa, Yuichi Yoshimuraa,*, Kyoko Kinamib, Yuki Hirokamib, Kasumi
Satob, Isao Adachib, Atsushi Katob,*, Hiroki Takahataa,§
aFaculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan
bDepartment of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan
§Deceased on 1st March, 2014
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of α-1-C-4’-arylbutyl-L-arabinoiminofuranoses 3 with functional groups attached to the
phenyl ring, which are potential α-glycosidase inhibitors, was designed and synthesized by
using a Negishi cross-coupling reaction as the key reaction. Arylbutyl derivatives 3a–e showed
potent inhibitory activities against intestinal maltase. Among them, difluorophenylbutyl
derivative 3e showed good inhibition activities against intestinal isomaltase and sucrase as
compared to those of 1 and commercial drugs.©
Revised
Accepted
Available online
Keywords
2009 Elsevier Ltd. All rights reserved
.
Iminosugars
1-C-4’-Arylbutyl-L-arabinoiminofuranoses
α-Glucosidase inhibitor
Type-2 diabetes
Structure-activity relationship
Iminosugars are sugar mimics with nitrogen atoms instead
oxygen atoms in the monosaccharides, and they inhibit various
glycosidases in a reversible and competitive manner. These
inhibitors are currently of great interest as potential therapeutic
agents.1 α-Glucosidase inhibitors are used in the treatment of
type-2 diabetes because they delay the absorption of
carbohydrates, which allows beta cells to increase insulin
secretion, thus reducing the glucose levels during circulation and
especially during the postprandial period. On the basis of the
benefits of α-glucosidase inhibitors, three drugs for the treatment
of type-2 diabetes, acarbose (GlucobayTM), voglibose (BasenTM),
and miglitol (GlysetTM), have been approved for use and are
currently on the market.2,3 However, the carbasugar-based drugs,
such as acarbose and voglibose, have been associated with a high
frequency of side effects, such as flatulence, diarrhea, and
hypoglycemia, because the drugs stay in the intestine and colon
for long periods of time.4 In the worst case, it has been reported
that they cause fulminant hepatitis.5 In contrast, the iminosugar-
based drug miglitol has been designed to be absorbed almost
completely from the intestinal tract. However, it may cause
systemic effects in addition to affecting the intestinal border.6
Moreover, an absorbable inhibitor, such as miglitol, may exert an
inhibitory effect on nonintestinal α-glucosidases present in the
various cell types of the body as a side-effect.7 Therefore, our
strategy has been to design effective iminosugar-type α-
glucosidase inhibitors that affect postprandial hyperglycemia
while showing strong inhibitory effects against maltase,
isomaltase, and sucrase and that do not interfere with the
processing of glycoproteins. As part of our research program
aimed at developing new potent and selective α-glucosidase
inhibitors ,8 we have recently reported the synthesis and
biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-
1,4-imino-L-arabinitol (LAB) derivatives as a new class of
promising compounds that can be used to treat postprandial
hyperglycemia.9 Among them, α-1-C-butyl-LAB 1 strongly
suppresses postprandial hyperglycemia during early stages,
similar to miglitol in vivo, with an effective dose about 10-fold
lower than that for miglitol. In addition, α-1-C-4’-phenybutyl-L-
arabinoiminofuranose 2 shows inhibitory activities against
intestinal maltase and isomaltase similar to those of 1, although
the inhibitory potency of 2 against intestinal sucrase is lower than
that of 1.9a Therefore, we focused on the effects of the
substituents on the phenyl ring of 2 on the inhibitory activities
against α-glucosidases.
Herein we report the synthesis of α-1-C-4’-arylbutyl-
L-
arabinoiminofuranoses 3 with different functional groups
attached to the phenyl ring and their inhibitory activities against
intestinal α-glucosidases.

Finally, oxazolinones 8a,c–e were transformed into the desired
iminosugars 3a,c–e by using basic hydrolysis (Scheme 2 and
Table 2).
In addition, iminosugar 3b was obtained by methylation of 8c
with trimethylsilyldiazomethane, followed by treatment with
NaOH, in two-steps in 41% yield (Scheme 3).
Figure 1. Structures of 1-substituted L-arabinoiminofuranoses.
Next the abilities of 3a–e to act as inhibitors against intestinal α-
glucosidases (maltase, isomaltase, and sucrase) were examined12
since they could be of value in managing type-2 diabetes, as
demonstrated by similar commercially available drugs (acarbose
(GlucobayTM), voglibose (BasenTM), and miglitol (GlysetTM)).
The results are summarized in Table 3.
An iodomethyl derivative 4 was prepared by using a modified
Trost procedure10 with asymmetric allylic alkylation (AAA) and
ring closing metathesis (RCM) as the key reactions, as reported
previously.9 A Csp3–Csp3 bond formation reaction using a nickel-
catalyzed Negishi cross-coupling reaction11 of 4 with 3-
arylpropylzinc bromides 5a–e gave 4-arylbutylated bicyclic 2,5-
dihydropyrroles 6a–e in good yields (Scheme 1 and Table 1).
We have previously reported that α-1-C-butyl-LAB 1 is an
excellent inhibitor against intestinal maltase, isomaltase, and
sucrase with IC50 values of 0.13, 4.7, and 0.032 µM,
respectively.9(a) On the basis of these finding, we first
investigated whether or not adding a phenyl group to the 1-C-
butyl terminal position affected the inhibition activities of 1.
However, as shown in Table 3, the phenyl substituent did not
enhance intestinal maltase inhibition (2: IC50 = 0.22 µM). For
comparison, we investigated whether the introduction of
substituents on the phenyl ring had an effect on the inhibition of
these enzymes. The inhibition potencies of compounds 3a–e
against maltase were similar to that of 1 (IC50 = 0.11–0.34 µM).
Thus, it was concluded that electronic factors did not affect the
inhibition against maltase. On the other hand, 3a and 3e showed
much better inhibition against isomaltase than that of 1 with IC50
values of 0.63 and 0.22 µM, respectively. In addition, both 3a
and 3e showed excellent inhibitory activities against sucrase (IC50
= 0.045 and 0.026 µM, respectively), which are comparable to
that of 1 (IC50 = 0.032 µM). In contrast, 3b–d and 2 are 3–10-
fold weaker sucrase inhibitors than 1 is. Moreover, no significant
electronic effects of the substituents were observed.
Scheme 1 and Table 1. Csp3–Csp3 bond formation reactions using a nickel-
catalyzed cross-coupling reaction.
yield
entry
1
X
4-Me (5a)
(%)a
81
O
O
N
2
3
4
5
4-MeO (5b)
4-AcO(5c)
4-F (5d)
65
64
79
80
N
N
iPr
iPr
Ligand
{(R,R)-2,6-bis(4-isopropyl-
2-oxazoline-2-yl)}pyridine
3,5-diF (5e)
a Isolated yield.
(DMA = N,N-dimethylacetamide)
However, there was a striking difference between 3d and 3e with
fluoro substituents, which are strong withdrawing groups, toward
the inhibitions of isomaltase and sucrase. Namely, difluoro 3e
was found to be a much stronger inhibitor against both isomaltase
and sucrase than monofluoro derivative 3d was, whereas a slight
reduction in the inhibitory activities of 3e against maltase was
observed. In addition, 3a and 3e were found to be 62-fold and
163-fold stronger inhibitors, respectively, against every α-
glucosidases than miglitol was. Moreover, 3a and
The epoxidation of the olefin moiety in 6a–e with dioxirane,
which was generated in situ from the reaction of OxoneTM with
1,1,1-trifluoroacetone, stereoselectively afforded epoxides 7a,c–
e, whereas 7b was not detected because the reaction involving 6b
resulted in the oxidation of the anisyl ring to give a complex
mixture. Ring-opening of the epoxide moieties in 7a,c–e with
aqueous trifluoroacetic acid stereoselectively proceeded to afford
diols 8a,d,e.9,10 Under the conditions used, in the case of 7c,
hydrolysis of the acetate group occurred, affording phenol 8c.
Scheme 2. Reagents and conditions: (a) CF3COCH3, OxoneTM, NaHCO3, CH3CN-aq. Na2EDTA (3:2), 0 °C (b) CF3CO2H, THF-H2O (3:2), 80 °C (c) NaOH,
EtOH-H2O (2:1), 100 °C.
Table 2. Summary of syntheses of 3 from 6
procedure (a) (6 → 7)
X
procedure (b) (7 → 8)
Y
procedure (c) (8 → 3)
Y
entry
yield (%)a
yield (%)a
yield (%)a
1
2
3
4-Me (7a)
4-MeO (7b)
4-AcO(7c)
90
not detected
99
4-Me (8a)
77
4-Me (3a)
58
4-HO(8c)
76
4-HO(3c)
61
4
4-F (7d)
3,5-diF (7e)
88
92
4-F (8d)
3,5-diF (8e)
96
90
4-F (3d)
3,5-diF (3e)
53
63
5
a Isolated yield.

Scheme 3. Reagents and conditions: (a) TMSCHN2 (2.0 M in Et2O) CH2Cl2-MeOH (2:1), 0 °C (b) NaOH, EtOH-H2O (2:1), 100 °C.
Table 3. Inhibitory activities of 3a–e toward α-glucosidases
IC50 (µM)
Compounds
α-1-C-butyl-LAB (1)
α-1-C-(4-phenyl)butyl-LAB (2)
3a (Y = 4-Me)
Maltase
0.13
Isomaltase
4.7
Sucrase
0.032
0.31
0.22
14
0.28
0.63
0.045
3b (Y = 4-MeO)
3c (Y = 4-HO)
3d (Y = 4-F)
3e (Y = 3,5-diF)
acarbose
0.11
0.17
0.18
0.34
0.18
0.12
1.3
1.8
6.0
3.0
0.22
NI
0.13
0.11
0.17
0.026
2.9
voglibose
miglitol
5.2
39
0.37
1.0
NI: less than 50% inhibition at 1000 µM
Acknowledgements
3e and 1 showed comparable inhibitory activities against maltase
and sucrase. In sharp contrast, 3a and 3e are 7-fold and 21-fold
greater inhibitors, respectively, against isomaltase than 1 is. We
found that changing the butyl and 4-phenyl groups to a 4-(4-
This work was supported in part by a Grant-in-Aid for Young
Scientists (B) (No. 23790138) (Y.N.) from JSPS and by a Grant
of Strategic Research Foundation Grant-aided Project for Private
Universities from Ministry of Education, Culture, Sport, Science,
and Technology, Japan (MEXT), 2010–2014.
methylphenyl)butyl or
a 4-(3,5-difluorophenyl)butyl group
resulted in a greater specificity for inhibiting isomaltase. In other
words, we observed that the substituent on the phenyl ring of 2
dramatically affected the inhibition abilities against certain α-
glucosidases. Since intestinal absorption of dietary disaccharides
is mediated by a group of α-glucosidases, which include
intestinal maltase, isomaltase, and sucrase, inhibition of these
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://@@
enzymes
can
significantly
decrease
postprandial
hyperglycemia.9(a),12 Among these intestinal α-glucosidases,
isomaltase cleaves the α-1-6 bonds linking the saccharides,
which cannot be broken by amylase or maltase. This study
revealed that, of the prepared α-1-C-4’-arylbutyl-L-
arabinoiminofuranoses, 3e was the most potent and selective
inhibitor against intestinal isomaltase. In addition, 3e is 4500-fold
and 570-fold more potent against isomaltase than acarbose and
miglitol, respectively, are. In other words, 3e will be an excellent
α-glucosidase inhibitor for treating postprandial hyperglycemia.
References and notes
1.
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England, 2007. (b) Asano, N.; Oseki, K.; Tomioka, E.; Kizu, H.; Matsui,
K. Carbohydr. Res. 1994, 259, 243.
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Nash, R. J.; Kato, A.; Yu, C.-Y.; Fleet, G. W. J. Future, Med. Chem.
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4.
Horne, G.; Wilson, F. X. Prog, in Med. Chem. 2011, 50, 135.
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R. C. Diabetes Care., 1999, 22, 960.
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Carrascosa, M.; Pascual, F.; Aresti, S. Lancet 1997, 349, 698.
(a) Joubert, P. H.; Venter, H. L.; Foukaridis, G. N. Br. J. Clin.
Pharmacol. 1990, 30, 391. (b) Bischoff, H. Eur. J. Clin. Invest. 1994,
24 Suppl 3, 3.
In summary, we synthesized a series of α-1-C-4’-arylbutyl-L-
arabinoiminofuranoses with functional groups on the phenyl ring
(3) for use as AGIs by using a Negishi cross-coupling reaction as
the key reaction. The inhibitory activities of arylbutyl derivatives
3a–e against intestinal maltase were comparable to that of the
original butyl derivative 1. Among them, difluorophenylbutyl
derivative 3e showed a greater inhibitory activity against
intestinal isomaltase than 1 and commercial drugs did. In
addition, the inhibitory potency of 3e (IC50 = 0.026 µM) against
intestinal sucrase was the same as that of 1 (IC50 = 0.032 µM).
We are currently studying the effects of a wide variety of
substituents on the phenyl ring of 3 on their inhibition activities.
7.
8.
Reuser, A. J.; Wisselaar, H. A. Eur. J. Clin. Invest. 1994, 24 Suppl 3, 19.
(a) Asano, N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.; Adachi, I.;
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13. Experimental procedure: Male Wistar rats with a body mass of 130 g
were obtained from Japan SLC, Inc. (Hamamatsu, Japan). Brush border
membranes were prepared from the rat small intestines according to the
method of Kessler et al.,14 and were assayed at a pH of 6.8 for rat
intestinal maltase, isomaltase, and sucrase using the appropriate
disaccharides as substrates. The reaction mixture contained substrate
(25 mM) and an appropriate amount of enzyme, and incubation was
performed for 30 min at 37 °C. The reaction was stopped by heating at
100 °C for 3 min. After centrifugation (600 xg; 10 min), the resulting
reaction mixtures were added to Glucose CII-test Wako (Wako Pure
Chemical Ind., Osaka, Japan). The absorbance at 505 nm was measured
to determine the amount of D-glucose released.
14. Kessler, M.; Acuto, O.; Strelli, C.; Murer, H.; Semenza, G. A. Biochem.
Biophys. Acta, 1978, 506, 136.