Potent chemical chaperone compounds for GM1-gangliosidosis: N-substituted (+)-conduramine F-4 derivatives

Article abstract of DOI:10.1039/c4md00270a

The development of second-generation valienamine-type chemical chaperones for G_M1-gangliosidosis is described. Several N-substituted (+)-conduramine F-4 derivatives were designed as novel chemical chaperones based on a lead chaperone compound, N-octyl-4-epi-β-valienamine, to decrease the inhibitory activity while increasing the enzyme enhancement activity. Among the derivatives synthesized during this study, a conduramine derivative with an N-cyclohexylmethyl group has demonstrated significant enhancement of R201C mutated β-galactosidase activity. This journal is

Full text of DOI:10.1039/c4md00270a

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Journal Name
RSCPublishing
ARTICLE
Potent chemical chaperone compounds for GM1-
gangliosidosis: N-substituted (+)-conduramine F-4
derivatives†
Cite this: DOI: 10.1039/x0xx00000x
Shinichi Kuno,*a Katsumi Higaki,*b Atsushi Takahashi,a Eiji Nanbab and Seiichiro
Ogawac
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
The development of secondꢀgeneration valienamineꢀtype chemical chaperones for GM1
ꢀ
gangliosidosis is described. Several
designed as novel chemical chaperones based on a lead chaperone compound,
ꢀvalienamine, to decrease the inhibitory activity while increasing the enzyme enhancement
activity. Among the derivatives synthesized during this study, a conduramine derivative with
an ꢀcyclohexylmethyl group has demonstrated significant enhancement of R201C mutated
ꢀgalactosidase activity.
N
ꢀsubstituted (+)ꢀconduramine Fꢀ4 derivatives were
www.rsc.org/
N
ꢀoctylꢀ4ꢀepi
ꢀ
β
N
β
ganglioside and its asialo derivative GA1 ganglioside are
accumulated in the central nervous system due to weak activity
of the enzyme. Unfortunately, enzyme replacement therapy,
which is available for some LSDs, may not provide benefit for
treatment of GM1ꢀgangliosidosis because intravenously injected
enzymes hardly penetrate the blood brain barrier. No effective
medical treatment is available for GM1ꢀgangliosidosis at this
time. Several research groups, including that of the authors,
have been engaged in developing pharmacological chaperone
reagents for GM1ꢀgangliosidosis, including NOEV and
derivatives of 1ꢀdeoxygalactonojirimycin6. NOEV possesses
Introduction
Small amounts of certain glycosidase inhibitors can benefit the
treatment of some genetic lysosomal storage disorders (LSDs);
this strategy is called pharmacological chaperone therapy1.
Stacking an inhibitor in the pocket of a mutated enzyme
stabilizes the threeꢀdimensional structure; this stabilization
prevents degradation during transport via endoplasmic
reticulum, enhancing the activity of the enzyme in the
lysosome2. Therefore, the development of 'suitable' glycosidase
inhibitors would generate novel pharmacological chaperones
(PCs) for LSDs. The design of PCs for various LSDs has been
based on mimicking the substrate structures or highꢀthroughput
screenings3. Interestingly, many of the former type of PCs
consist of pseudoꢀsugar moiety and long alkyl chain as
aglycone moiety. For example, the authors have developed PCs
with a transitionꢀstate analogue for the hydrolysis of sugars
remarkable enhancement activities for mutated lysosomal
βꢀ
galactosidase in vitro7 and in vivo with blood brain barrier
penetration for mice8.
Although NOEV is a potent chaperone drug candidate for
GM1ꢀgangliosidosis, we found that the mutated enzyme
enhancement activity of this compound decreased at higher
concentrations, as described later. The strong inhibitory action
of NOEV might disrupt its enhancement activity. In addition,
the nonꢀinhibitory chaperone reagents developed by Patnaik et
al9 and the allosteric chemical chaperone developed by Porto et
al10 were recently reported to have avoided inhibitory activity
relative to the previous PCs. In this paper, the chemical
structure of the lead chaperone compound was modified to
reveal the requirements for moderate inhibitory activity while
improving the enzyme enhancement activity. The chaperone
assays were carried out using mouse fibroblast cells with
(halfꢀchair conformation), valienamine structure, and
alkyl side chain: ꢀoctylꢀ
ꢀvalienamine (NOV)4 for Gaucher
disease, which results from glucocerebrosidase deficiency, and
nꢀoctyl
N
β
N
ꢀoctylꢀ4ꢀepi
ꢀ
β
ꢀvalienamine
(NOEV5,
1
)
for
GM1
ꢀ
gangliosidosis (Fig. 1).
Fig. 1. Pharmacological chaperone reagents,
valienamine (NOV) and ꢀoctylꢀ4ꢀepi
N
ꢀoctylꢀβ
ꢀ
N
ꢀ
β
ꢀvalienamine (NOEV).
human normal
βꢀgalactosidase or human mutant R201C βꢀ
galactosidase, which causes juvenile GM1ꢀgangliosidosis.
Among LSDs, GM1ꢀgangliosidosis is a very rare disease
caused by the mutation of lysosomal ꢀgalactosidase. GM1
β
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We have been interested in modifying the structure of Scheme 1. Synthesis of the
Nꢀsubstituted (+)ꢀconduramine Fꢀ4
NOEV to generate a novel pharmacological chaperone based on derivatives from (+)ꢀprotoꢀquercitol.
the strategy shown in Fig. 2. First, the pseudoꢀ ꢀgalactose
moiety of NOEV was simplified, which was expected to lower
its enzyme inhibitory activity and streamline its preparation. 2,2ꢀdimethoxypropane in the presence of an acid catalyst in
Therefore, the Cꢀ5 function of NOEV was modified to form the DMF afforded diacetonide at 90% yield. Afterwards, the
dehydroxy ( ) derivative, which is a previously reported 6ꢀ remaining hydroxyl group on was sulfonylated, providing
deoxy derivative of NOEV11, and the dehydroxymethyl (
mesylate (97%). Treating with excess DBU in refluxing
derivative, which is ꢀoctylꢀ(+)ꢀconduramine Fꢀ4. Some toluene produced cyclohexene
conduramines and their derivatives have shown moderate of two ring protons at
inhibitory activity toward glycosidases12. Moreover, to increase of
the enzyme enhancement activity, the ꢀsubstituent of was isopropylidene group of
modified. Because the space adjacent to the active site of using catalytic pyridiniumꢀ
galactosidase is hydrophobic6f, a functional group such as an methanol, giving diol
in high yield (91%). The subsequent
alkyl or aryl group is desirable for interactions in this region. epoxidation of was accomplished under conditions described
by Martin et al15; treatment with slight excess of Martin
sulfurane generated epoxide at 69% yield. Alternatively,
β
First, an
O
ꢀisopropylidenation14 of (+)ꢀprotoꢀquercitol with
4
2
4
3
)
5
5
N
6
at 76% yield. The appearance
δ
5.78 and 6.16 in the 1HꢀNMR spectrum
6
supported the assigned alkene structure. Next, the transꢀ
could be removed selectively by
ꢀtoluenesulfonate (PPTS) in
N
3
6
β
ꢀ
p
7
7
8
8
was also obtained in a moderate yield (59%) under Mitsunobu
conditions with PPh3 and diꢀisopropyl azodicarboxylate
(DIAD). Incorporating various amine functionalities into the Cꢀ
1 position of
8 was performed via simple addition reactions
with alkylamines. Because the allylic Cꢀ1 carbon atom of the
epoxide was more reactive, the amination reaction occurred in a
regioꢀ and stereoꢀselective fashion. After considering the
solubility of these compounds for successive biological assays,
we intended to isolate the pure amine hydrochlorides directly.
Silicaꢀgel column chromatography was followed by treatment
with hydrochloric acid/aqueous THF to afford the
(+)ꢀconduramine Fꢀ4 derivatives as the HCl salts (3aꢀn
to 100% yields.
N
ꢀsubstituted
Fig. 2. Strategy of modification of NOEV (1) to decrease the
inhibitory activity while increasing the enzyme enhancement
activity.
) at 64
Inhibitory and chaperone activity
Results and discussion
The inhibitory and enhancement activities of the
compounds for normal human ꢀgalactosidase and R201C
mutated human ꢀgalactosidase, respectively, are shown in
Table 1. Regarding the enzyme enhancement activity, R201C is
often used to select pharmacological chaperone candidates for
Synthesis of N-substituted (+)-conduramine F-4 derivatives
β
β
The synthesis of various Nꢀsubstituted (+)ꢀconduramine Fꢀ4
derivatives is shown in detail in Scheme 1. Although the
synthesis of (+)ꢀconduramine Fꢀ4 was described previously13,
we report a more concise route toward (+)ꢀconduramine Fꢀ4
derivatives starting from (+)ꢀprotoꢀquercitol.
mutant human
IC50 = 1.7 M, while 6ꢀdeoxyꢀNOEV•HCl (2a) and
(+)ꢀconduramine Fꢀ4.•HCl (3a) have IC50 = 46 M and 120
β
ꢀgalactosidase. First, NOEV•HCl (1a) has an
ꢀoctylꢀ
M,
ꢀ
N
ꢀ
ꢀ
respectively. Therefore, the inhibitory activity was decreased
based on the functional groups at Cꢀ5, and the inhibitory
activity of 3a could be remarkably diminished to 1.4%
compared to 1a. The enhancement activity of the mutant
R201C
β
ꢀgalactosidase induced by treatment with both 1a (2
M) was almost identical, producing an
ꢀ
M) and 2a or 3a (20
ꢀ
approximately 5ꢀfold increase compared to the additiveꢀfree
system. However, the enzyme enhancement activity mediated
by 2a and 3a increased relative to their concentration at 0.2, 2
and 20
at 2
ꢀ
M, while for 1a, the concentration was nearly optimal
ꢀ
M and decreased at 20 M (Graph 1). The strong
ꢀ
inhibitory action of 1a may influence its enzyme enhancement
activity at the higher concentration, or the high concentration of
1a was participating in an unknown process that stabilized the
conformation of the R201C mutant through protein
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translocation. During the chemical modification of 1a
simplifying its pseudoꢀ ꢀgalactose moiety decreased its strong activity after adding several
inhibition activity to approximately oneꢀhundredth, preserving hydrochlorides at various concentrations (0.2, 2 and 20
the activity of the chaperone at concentrations up to 20 M. The enhancement activity of all of the conduramine derivatives
did not decrease up to 20 M, indicating that the desired
,
Graph 1 also shows the enhanced R201C
ꢀsubstituted (+)ꢀconduramine Fꢀ4
M).
βꢀgalactosidase
β
N
ꢀ
ꢀ
ꢀ
decrease in inhibitory activity after trimming the pseudoꢀsugar
moiety was successful; this decrease most likely occurred by
reducing the interaction between compounds and enzyme
through decreased mutual hydrogen bonding.
compd
1a
2a
3a
3b
3c
3d
3e
3f
R
IC50
(
ꢀ
M)a Enhancement (fold)b
Structureꢀactivity relationships for conduramine derivatives
summarized in Table 1 indicate that the enhancement activity
1.7
46
3.6 (4.6)c
5.2
increases relative to the length of the linear alkyl chain from
butyl (3b), ꢀpentyl (3c), ꢀhexyl (3d) to ꢀoctyl (3a), although
the ꢀdecyl derivative (3e) exhibited a poor enhancement.
Incorporating a hydroxyl group in the alkyl chain (3f
nꢀ
n
n
n
n
120
50
5.4
2.0
4.0
4.6
1.6
0.9
4.6
7.4
8.5
1.5
1.2
1.4
4.6
4.2
)
remarkably eliminated the inhibitory and enhancement
activities. This may suggest that the hydrophobic interactions
between the side chain part and the peripheral region around the
active site of the enzyme dominate the onset of both inhibitory
and enhancement activities and/or the hydrophobicity of the
side chain is essential for the cell membrane permeability. The
C4 isobutyl group (3g) induced better enhancement activity
19
56
43
than the C4
nꢀbutyl group (3b). In addition, elongating the
terminus of the side chain from C4 isobutyl (3g) to C6 2ꢀ
ethylbutyl (3h) increased the enhancement activity from 4.6ꢀ
>1000
41
3g
3h
3i
fold to 7.4ꢀfold, surpassing that of
nꢀoctyl conduramine 3a.
Thus, in this case, ꢀCH2ꢀbranched alkyl chains contributed
N
15
strongly to the enzyme enhancement activities. Furthermore,
bridging the branched chains of 3h to form a cyclohexylmethyl
60
group (3i) enhanced the R201C mutated
βꢀgalactosidase
activity in cell lysates 8.5ꢀfold, attaining the highest increase.
When assuming that compound 3i possesses the optimal
structure within the present series, 3a and 3d should exert a
strong activity enhancement toward the mutant enzyme when
3j
180
>1000
490
28
3k
3l
the
conformation that resembles the cyclohexylmethyl function of
3i. Moreover, 3i showed moderate IC50 values (60 M) against
normal human ꢀgalactosidase compared to that of 1a (1.7 M).
Replacing the cyclohexyl group with a phenyl group (3i 3j
decreased both the inhibitory and enhancement activities. The
predominance of the ꢀCH2ꢀstructure in the side chains was
confirmed because the activity of the 1ꢀethylpropylamino (3k
and cyclohexylamino (3l) compounds decreased drastically.
NꢀC6 and C8 aliphatic chains undulate and adopt a
ꢀ
3m
3n
β
ꢀ
ꢀ
)
86
aIC50 for normal human
bComparison between the addition of 20
additiveꢀfree system. cFor the addition of 2
βꢀgalactosidase determined at pH 4.5.
N
)
ꢀ
M of compounds and the
ꢀM of 1a
.
Elongating the alkyl chains (3g
remarkable
ꢀ
3m) further induced no
Table 1. Structureꢀactivity relationships for NOEV•HCl (1a),
6ꢀdeoxyꢀNOEV•HCl (2a), and ꢀsubstituted (+)ꢀconduramine
derivatives (3a ).
N
ꢀ
n
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n: normal human
Graph 1. Enzyme enhancement activity of NOEV•HCl (1a), 6ꢀdeoxyꢀNOEV•HCl (2a), and
derivatives (3a ) with mutated R201C human ꢀgalactosidase. Each bar represents the means±S.E.M. of three independent assays
performed in triplicate.
βꢀgalactosidase. na: no added compounds.
Nꢀsubstituted (+)ꢀconduramine Fꢀ4
ꢀ
n
β
effects on the enhancement activity, but phenethylamine (3n
)
showed modest activity (24%). The cytotoxicity decreased as
was superior to benzylamine (3j).
the length of aliphatic chain shortened;
demonstrated modest activity (25%) at 200
The inhibitory activity of a compound against an enzyme hexyl (3d), ꢀpentyl (3c), and
does not correlate directly with its chaperone activity. However, (<10%) at 200 M. This suggested that strong amphiphilic
the IC50 values of the derivatives showing good enhancement properties of the compounds with long alkyl chains caused
activity ranged from approximately 10 M to 100 M. Future cytotoxic effect on human fibroblasts. The LDH activities of
in vivo studies will determine whether IC50 values ranging from other derivatives with ꢀbranched chains at 200 M were low
10~100 M are acceptable. In addition, most of the derivatives (<10%). In addition, except 3e, almost all of the derivatives
3a ) showed inhibitory activities against bovine liver
galactosidase in a similar fashion to those for human
n
ꢀoctyl derivative (3a
)
ꢀ
ꢀ
M whereas
n
n
nꢀbutyl (3b) showed low activity
ꢀ
ꢀ
ꢀ
N
ꢀ
ꢀ
(
ꢀ
n
β
β
ꢀ
ꢀ
showed very small cytotoxicity at 20
the most effective chaperone compound 3i was 3.8% at 200
M, smaller than that of parent 1a (7.5% at 200
M and 1.1% at 20 M).
ꢀM. The LDH activity of
ꢀ
M
galactosidase while also demonstrating crossꢀinhibition for and 0.7% at 20
almond ꢀglucosidase (Supplementary Information, Table S1).
ꢀ
β
ꢀ
ꢀ
However, this crossꢀinhibition was probably resulted from the
loose substrate specificity of the almond glucosidase. We tested
Conclusions
the inhibition of human
galactosidase by the derivatives. As a result, all of the
conduramine derivatives (3a ) and also 1a and 2a did not
βꢀglucosidase and human αꢀ
In summary, we have studied
conduramine Fꢀ4 derivatives as novel PCs for GM1
Nꢀsubstituted (+)ꢀ
ꢀ
n
ꢀ
inhibit those glycosidases (IC50 >1 mM). Thus, both of the
conduramine and valienamine derivatives showed high
specificity to human βꢀgalactosidase.
gangliosidosis. Conduramine was derived from the lead
chaperone NOEV based on intentional structural modification.
Removing the 5ꢀhydroxymethyl group from NOEV could
reduce its strong inhibitory activity, which should mask the
enzyme enhancement. The search for a suitable side chain
demonstrated that the 2ꢀbranched alkylamino group was a
Cytotoxicity
Considering therapeutic application of the conduramine
derivatives, their cytotoxic effects on human fibroblasts were
investigated by lactate dehydrogenase (LDH) assay
(Supplementary Information, Graph S1). The highest LDH
preferable chaperone compound for the R201C mutant
βꢀ
galactosidase. This initial study presented here provided the
evidence, at least in part, that these series of compounds as
novel potential chaperones for human βꢀgalactosidase
deficiency. Further therapeutic study with animal models would
be necessary to explore the ability of the compounds to restore
activity (54%), namely cytotoxicity, was shown by
conduramine derivative (3e) at 200 M, and 3e at 20
n
ꢀdecyl
ꢀ
ꢀM also
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trafficking the mutant protein into the lysosome, to reduce the
substrate burden and to prevent neurological deterioration in the
next study. Moreover, the present structural modification
strategy could also help the development of novel and potent
chaperones for other lysosomal storage diseases.
6
(a) K. Fantur, D. Hofer, G. Schitter, A. J. Steiner, B. M. Pabst, T. M.
Wrodnigg, A. E. Stütz and E. Paschke, Mol. Genet. Metab., 2010,
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Martin and D. J. Mahuran, Mol. Genet. Metab., 2012, 107, 203; (d)
M. AguilarꢀMoncayo, T. Takai, K. Higaki, T. MenaꢀBarragán, Y.
Hirano, K. Yura, L. Li, Y. Yu, H. Ninomiya, M. I. GarcíaꢀMoreno, S.
Ishii, Y. Sakakibara, K. Ohno, E. Nanba, C. Ortiz Mellet, J. M.
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Sakakibara, K. Ohno, E. Nanba, C. Ortiz Mellet, J. M. García
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Currently, the parent NOEV might be replaced by potent Nꢀ
substituted conduramine Fꢀ4 derivatives, which are
conveniently synthesized from (+)ꢀprotoꢀquercitol. Further
studies utilizing chiral conduramine derivatives would deepen
our insight into biochemically interesting aminocyclitols. In
addition, our initial studies suggested that the chaperone effects
were mutation specific6e,7 and many mutants including common
mutations such as R201C are currently listed in βꢀgalactosidase
for GM1ꢀgangliosidosis. Therefore, examining the enhanced
activity spectrum of 3i is particularly important for future
studies. Additional computational calculations and Xꢀray
structure analyses of coꢀcrystallized species will reveal the fine
interactions between the enzyme and the compounds with
atomic precision. We are also interested in preparing and
7
8
9
K. Higaki, L. Li, S. Okuzawa, A. Takamuram, K. Yamamoto, K.
Adachi, R. C. Paraquison, T. Takai, H. Ikehata, L. Tominaga, I.
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32, 843.
evaluating the Nꢀcyclohexylmethyl derivatives of valienamines.
Acknowledgements
This study was supported by a MEXT/JPSP KAKENHI grant
and the Takeda Science Foundation. We wish to thank Drs. R.
Sawa and Y. Umezawa at the Institute of Microbial Chemistry
for HRMS analyses.
J. Matsuda, O. Suzuki, A. Oshima, Y. Yamamoto, A. Noguchi, K.
Takimoto, M. Itoh, Y. Matsuzaki, Y. Yasuda, S. Ogawa, Y. Sakata,
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H. Watanabe, R. O. Brady and Y. Suzuki, Proc. Natl. Acad. Sci.
USA., 2003, 100, 15912.
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Medicinal Chemistry Communications
Page 6 of 6
The development of chemical chaperones to decrease the inhibitory activity
while increasing the enzyme enhancement activity.