Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

Article abstract of DOI:10.3762/bjoc.14.189

A synthetic approach to 1,4-imino-L-lyxitols with various modifications at the C-5 position is reported. These imino-L-lyxitol cores were used for the preparation of a series of N-(4-halobenzyl)polyhydroxypyrrolidines. An impact of the C-5 modification on

Full text of DOI:10.3762/bjoc.14.189

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their
evaluation as inhibitors of GH38 α-mannosidases
Maroš Bella1, Sergej Šesták1, Ján Moncoľ2, Miroslav Koóš1 and Monika Poláková*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2156–2162.
1Department of Glycochemistry, Institute of Chemistry, Slovak
Academy of Sciences, Dúbravská cesta 9, SK-845 38, Bratislava,
Slovakia and 2Department of Inorganic Chemistry, Faculty of
Chemical and Food Technology, Radlinského 9, SK-812 37
Bratislava, Slovakia
doi:10.3762/bjoc.14.189
Received: 21 May 2018
Accepted: 24 July 2018
Published: 17 August 2018
Email:
Associate Editor: S. Flitsch
Monika Poláková* - chemonca@savba.sk
© 2018 Bella et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
azasugars; hydrolases; inhibitors; pyrrolidines; synthesis
Abstract
A synthetic approach to 1,4-imino-L-lyxitols with various modifications at the C-5 position is reported. These imino-L-lyxitol cores
were used for the preparation of a series of N-(4-halobenzyl)polyhydroxypyrrolidines. An impact of the C-5 modification on the
inhibition and selectivity against GH38 α-mannosidases from Drosophila melanogaster, the Golgi (GMIIb) and lysosomal
(LManII) mannosidases and commercial jack bean α-mannosidase from Canavalia ensiformis was evaluated. The modification at
C-5 affected their inhibitory activity against the target GMIIb enzyme. In contrast, no inhibition effect of the pyrrolidines against
LManII was observed. The modification of the imino-L-lyxitol core is therefore a suitable motif for the design of inhibitors with
desired selectivity against the target GMIIb enzyme.
Introduction
Carbohydrates as chiral templates for a construction of bioac- During the years, many scaffolds based on monosaccharides
tive compounds are of steady interest in medicinal chemistry [4], disaccharides or higher oligosaccharides [5,6] as well as
[1-3]. The polyfunctional nature of carbohydrate units offers multivalent [7,8] carbohydrate units have been developed.
many possibilities for the design of a wide variety of new com- These glycomimetics and glycopeptides have also found appli-
pounds. Moreover, various desired substituents can be selec- cations as bioactive compounds [9,10].
tively appended to any required position of the carbohydrate
unit. This leads to a preparation of mimetics that meet the One group of the scaffolds includes iminosugars [11,12] as ana-
requirements of metabolically more stable bioactive com- logues of the monosaccharides wherein the endocyclic oxygen
pounds.
atom is replaced by a nitrogen atom. An additional feature of
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iminosugars, in comparison with their parent oxygen contain- membered imino-L-lyxitol core has been suggested. Indeed,
ing counterparts, is a protonation of the ring nitrogen under such N-benzyl-substituted polyhydroxypyrrolidines 1 (Figure 1)
physiological pH. The protonation of the amine is often impor- were found to be more potent and selective inhibitors of the
tant for the inhibition properties of these compounds [13,14]. target enzyme. Moreover, proposed N-benzyl substituent at the
Another advantage of the iminosugars is a possibility to intro- pyrrolidine core was also confirmed to be essential for selec-
duce a functional group onto the nitrogen atom. The impor- tivity [30].
tance of iminosugars is documented by a number of reports
dealing with the synthesis of polyhydroxylated piperidines,
pyrrolidines, pyrolizidines, indolizidines etc. which exhibited
remarkable biological activities and are highly interesting as
pharmaceutical agents [15-19]. In addition, iminosugars exhib-
ited a powerful inhibitory activity against a wide range of
glycoside hydrolases [20-22].
One naturally occurring iminosugar, alkaloid swainsonine,
interferes with the glycosylation pathway where it specifically
inhibits GH38 glycoside hydrolases [23,24]. Up to date, swain-
sonine is the most potent Golgi mannosidase II (GMII) inhibi-
tor. It is known that inhibition of the biosynthesis of complex
N-glycans in the Golgi apparatus influences progress of tumor
growth and metastasis. However, all potent GMII inhibitors, in-
cluding swainsonine, showed also an undesired co-inhibition of
lysosomal α-mannosidase (LM) that limits their use as thera-
Figure 1: Structures of GMIIb inhibitors.
peutic agents [25]. Since the discovery of swainsonine, new in-
hibitors of GMII that are based on its structure and related
pyrrolidines are of particular interest as potential candidates for In this study, we explored structure–activity relationships
cancer treatment [26,27].
(SAR) of pyrrolidine derivatives 1 with different modifications
at position 5. The benzyl moiety was chosen to be
Our research interest has been focused on searching for effi- (4-halo)benzyl as the pyrrolidines 1 bearing these structural
cient inhibitors of α-mannosidases from the GH38 family. fragments were the most effective and selective against GMIIb
Another important feature required for such a potential inhibi- [30]. The synthesis of modified pyrrolidine derivatives 2–5
tor is its ability to inhibit only selected α-mannosidases, i.e., to (Figure 1) and GH38 α-mannosidases inhibition studies are re-
exhibit high inhibition activity and selectivity against the en- ported.
zymes within the GH38 family or even within the whole GH
Results and Discussion
family. These enzymes were represented by model GH38
α-mannosidases from Drosophila melanogaster Golgi Synthesis
α-mannosidase II (GMIIb, target enzyme) and lysosomal The synthesis of target compounds 2 and 3 started from imino-
α-mannosidase (LManII, enzyme not to be inhibited), and com- L-lyxitol 6 which was prepared in large quantity from D-ribose
mercial enzyme jack bean α-mannosidase (JBMan) from as described in our previous paper (Scheme 1) [30]. Conver-
Canavalia ensiformis.
sion of trityl ether 6 into the tosyl derivative 8 was achieved by
removal of the protecting trityl group under acidic conditions
In a series of our previous papers, it has been found that a com- followed by tosylation of the liberated hydroxy group with TsCl
bination of a saccharide core (D-mannose, D-mannose with in the presence of DMAP as a base. Thus, required tosyl deriva-
modification at C-6) and hydrophobic linker (benzyl, phenethyl) tive 8 was obtained in 76% yield in two steps. It should be em-
has an impact on the inhibition efficiency of the tested synthe- phasized that tosylation in the presence of commonly used
tic compound against the target GMIIb enzyme. Evaluation of bases such as pyridine or TEA was sluggish. Subsequent substi-
these derivatives revealed that benzyl is a suitable hydrophobic tution of the tosylate in 8 either with Super-hydride® (LiBHEt3)
linker. Some of them showed a weak inhibitory activity and or with a cuprate generated in situ from MeMgBr and CuI
selectivity against GMIIb [28,29]. Therefore, the structural afforded pyrrolidines 9 [31] and 12 in 68% and 44% yield, re-
design was further developed and a modification of the saccha- spectively (Scheme 1). In the course of tosylate substitution
ride core, i.e., a replacement of the D-mannose unit to five- with the cuprate, 3-methylpiperidine 11 was isolated as a by-
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Beilstein J. Org. Chem. 2018, 14, 2156–2162.
Scheme 1: Synthesis of pyrrolidines 2a and 3a.
product in 32% yield. A formation of the piperidine 11 proceeds The next series of target pyrrolidines 4 and 5 could be achieved
via opening of aziridinium intermediate 10 (Scheme 1) [32]. via nucleophilic addition of MeMgBr to an aldehyde obtained
Interestingly, a product of a ring expansion was not observed by the oxidation of alcohol 7. Despite this fact, we did not
during the tosylate substitution with LiBHEt3. Simple acidic manage the preparation of the aldehyde by the oxidation of
hydrolysis of acetonides 9 and 12 gave target compounds 2a alcohol 7 probably due to its instability [33]. However, similar
(64%) and 3a (68%, Scheme 1).
aldehyde 17 bearing a Cbz protecting group instead of the
benzyl moiety at the nitrogen atom was prepared as stable com-
As amines prepared by catalytic hydrogenolysis of pound by Trajkovic et al. [34]. Therefore, our attention was
N-benzylpyrrolidines 9 and 12 were extremely volatile they focused on preparation of aldehyde 17 starting from protected
were immediately subjected to acetonide hydrolysis without pyrrolidines 6 and 13 (Scheme 3). The exchange of the benzyl
isolation. So-obtained hydrochlorides were used directly to the group in 6 and 13 for a Cbz moiety was achieved by N-deben-
selective N-benzylation with the corresponding 4-halobenzyl zylation under catalytic hydrogenolysis conditions followed by
bromide under basic conditions to provide compounds 2b,c and protection of the liberated amines with CbzCl furnishing fully
3b,c. By this way, the final compounds 2b,c and 3b,c were protected pyrrolidines 14 [35] and 15. Exposure of 14 to a cata-
accessed in three steps in good yields (43–63%, Scheme 2). lytic amount of PTSA (0.04 equiv) in a mixture of CH2Cl2/
Scheme 2: Synthesis of pyrrolidines 2b,c and 3b,c.
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Beilstein J. Org. Chem. 2018, 14, 2156–2162.
Scheme 3: Synthesis of pyrrolidines 4.
MeOH 30:1 (v/v) resulted in rapid cleavage of the trityl ether corresponding benzyl bromides to yield pyrrolidines 22. Final
providing known alcohol 16 [34]. Treatment of 15 with TBAF hydrolysis of acetonides 22 in highly acidic media provided
yielded identical alcohol 16 in good yield. As described by target compounds 5 (Scheme 4).
Trajkovic et al. [34], oxidation of alcohol 16 with DMP led
cleanly to the desired aldehyde 17. As some decomposition
products were formed during flash chromatography on silica
gel, the sensitive aldehyde 17 was used in the next step without
further purification and characterization. Diastereoselective ad-
dition of MeMgBr to the aldehyde group of 17 gave alcohol 18
as single diastereoisomer in 69% yield. Removal of the Cbz
protecting group of 18 under catalytic hydrogenolysis condi-
tions furnished the free amine which was subsequently subject-
ed to N-benzylation with the corresponding (4-halo)benzyl bro-
mide to afford N-(4-halo)benzylpyrrolidines 19a–c. Acidic
hydrolysis of the acetonide protecting group in 19a–c provided
target compounds 4a–c in good yields (Scheme 3).
Figure 2: Molecular structure (OLEX2 drawing with adjacent Chem-
Draw image) of compound 20. Atomic displacement ellipsoids are
drawn at 50% probability level.
In order to obtain final compounds 5, a configurational inver-
sion of the stereocenter at C-5 in 18 was necessary. The inver- Biochemical evaluation
sion of the configuration was first attempted by a modified N-(4-Halo)benzylpyrrolidines 2–5 were evaluated against the
Mitsunobu reaction or activation of the hydroxy group by mesy- class II α-mannosidases GMIIb, LManII and JBMan from the
lation according to Trajkovic et al. [34]. However, these GH38 family to investigate their ability to inhibit only selected
attempts resulted in either no reaction or formation of an enzyme. All pyrrolidines 2–5 demonstrated inhibitory activity
unstable mesylate. For this reason, the inversion of configura- against the target enzyme (GMIIb) with IC50 values in the range
tion was performed by the activation of the hydroxy group in 18 of 0.30 mM to 2.95 mM (Table 1). On the other hand, none of
with triflic anhydride in the presence of pyridine at 0 °C to form them was effective against LManII at 2 mM concentration.
carbamate 20 in 72% yield (Scheme 4). The structure and Therefore in this panel of tested enzymes the pyrrolidines 2–5
absolute configuration of carbamate 20 was confirmed by are selective inhibitors for GMIIb.
single-crystal X-ray analysis (Figure 2) [36]. Basic hydrolysis
of carbamate 20 with 10% NaOH in refluxing EtOH provided The inhibitory activity of the tested pyrrolidines against GMIIb
aminoalcohol 21 which was subsequently N-benzylated with the was affected by modification at C-5 of the imino-L-lyxitol core.
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Beilstein J. Org. Chem. 2018, 14, 2156–2162.
Scheme 4: Synthesis of pyrrolidines 5.
of a halogen atom to the para position of the benzyl substituent
had a certain effect. While the inhibitory activity of 4b and 4c
was very similar to 4a, the halogenated counterparts of 5a, 5b
and 5c showed slightly reduced inhibitions of GMIIb. Some
differences were also observed in their effects on JBMan.
Pyrrolidine 4c showed moderate inhibitory activity comparable
with 5a, while 5b,c were the most active, but still poor (40%
inhibition at 2 mM concentration) inhibitors of this enzyme
among all tested pyrrolidines. Structural modifications in
pyrrolidines 4a and 4b showed negligible influence on the ac-
tivity against JBMan.
Table 1: Inhibitory activity of pyrrolidines 2–5 against the class II
α-mannosidases GMIIb, LManII and JBMan from GH38 family en-
zymes.
Compound GMIIb
[IC50 (M)]
LmanII
[IC50 (M)]
JBMana
(%)
1a [30]
2a
(8.8 ± 0.06) × 10−5
(3.6 ± 0.20) × 10−4
(3.5 ± 0.17) × 10−4
(3.0 ± 0.18) × 10−4
(7.5 ± 0.35) × 10−4
(9.5 ± 0.33) × 10−4
(4.5 ± 0.14) × 10−4
7.0 × 10−3
n.i.a
1
n.i.
n.i.
n.i.
3
2b
2c
n.i.a
n.i.a
3a
n.i.a
3b
3c
n.i.a
14
39
2
n.i.a
4a
(18.0 ± 0.40) × 10−4 n.i.a
(16.0 ± 0.40) × 10−4 n.i.a
(19.0 ± 0.46) × 10−4 n.i.a
(19.5 ± 0.41) × 10−4 n.i.a
(26.5 ± 0.51) × 10−4 n.i.a
(29.5± 0.56) × 10−4 n.i.a
Pyrrolidines 3 represent deoxygenated analogs of 4 and 5, and
their efficiencies against JBMan were similar. In comparison
with the latter compounds, inhibition capacity of 3 against
GMIIb was improved, each showing an IC50 value lower than
1 mM, in case of the most efficient 3c even below 0.5 mM.
4b
4c
4
17
21
40
38
5a
5b
5c
aInhibition in the presence of 2 mM inhibitor concentration; n.i. no inhi-
bition.
Further improvement of the GMIIb inhibition was achieved by
the removal of the primary hydroxy group from C-5 position in
1 leading to deoxygenated analogs 2. In series of compound 2
Elongation of the C-5 position in pyrrolidine 1a by a methyl only a weak impact of the halogen substituent at the aromatic
group led to a pair of diastereoisomers 4a and 5a which differ in unit on the efficiency of the inhibition was observed. Pyrrol-
the configuration at the new C-5 stereocenter. This elongation idine 2a, as well as its N-(4-halobenzyl) derivatives 2b and 2c,
led to about 25-fold decrease in inhibition activity against exhibited similar IC50 values in the range of 0.30–0.36 mM.
GMIIb in comparison with 1a. It is interesting that the increase The most potent was N-(4-iodobenzyl)pyrrolidine 2c (IC50
of IC50 values was essentially not influenced by the stereo- 0.30 mM). In regard to the inhibition pattern against GMIIb, the
chemistry at C-5 in 4a and 5a. On the contrary, the introduction results are in agreement with our previous study for
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Beilstein J. Org. Chem. 2018, 14, 2156–2162.
(4-halo)benzylpyrrolidines 1 with retained primary hydroxy- Acknowledgements
methyl function [30]. In both series of pyrrolidines 1 and 2, the The financial support received from the Slovak Research and
presence of a halogen substituent at the aromatic unit slightly Development Agency (Grant no. APVV-0484-12) and Scien-
improved efficiency of the GMIIb inhibition. However, the tific Grant Agency (Grant no. VEGA 2/0064/15) is gratefully
deoxygenation of the hydroxymethyl function to a methyl group acknowledged. This contribution is the result of the project
(compounds 2) led to approximately 4-fold decrease in potency implementation: Centre of Excellence for Glycomics,
(benzylpyrrolidine 1a was used as a reference compound in this ITMS26240120031, supported by the Research & Develop-
assay, IC50 0.088 mM). None of the pyrrolidines 2 affected ment Operational Program funded by the ERDF. The crystal
JBMan at 2mM concentration.
structure determination was made with the support of the proj-
ect "University Science Park of STU Bratislava", ITMS
In summary, taking into account no significant influence on 26240220084, supported by the Research & Development
other tested GH38 mannosidases (LManII and JBMan), all syn- Operational Program funded by the ERDF.
thesized derivatives 2–5 having C-5 modified pyrrolidine core
ORCID® iDs
Maroš Bella - https://orcid.org/0000-0001-6556-1579
were identified as selective inhibitors of the target GMIIb en-
zyme. Nature and size of the functional group at position 5 of
Miroslav Koóš - https://orcid.org/0000-0002-9867-0015
the pyrrolidine core has a limited impact on the activity against
Monika Poláková - https://orcid.org/0000-0002-1125-4482
the GMIIb which was decreasing with increasing size of this
functional group, suggesting a certain role of steric effect. An
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