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10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease
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326
Scheme 10.12 Synthesis of the N9 and N7 nucleosides 92 and 93, respectively. Reagents/
solvent and yield: (a) BSA, 2-acetamido-6-chloropurine, TMSOTf, (CH
Cl)2, 85 °C, 25% for 92
2
and 37% for 93. Source: Adapted from Marcelo etal.[88].
inhibitors, namely donepezil, rivastigmine, and galantamine, which help in controlling the symptoms of AD and do not treat the underlying disease or delay its progression[87]. In this perspective, Rauter and coworkers explored purine nucleosides as
ChE inhibitors. Marcelo etal.[88], developed the first synthesis of 2-acetamidopurine
nucleosides 92 and 93 starting from compound 91 incorporating a tetrahydrofuran
ring fused to the pyranose (Scheme10.12). The bicyclic sugar 94 was also modified to
generate the elongated carboxylic ester appendage bearing the azido group at position
6 (97a,b, Scheme 10.13). For the purpose, Swern oxidation followed by a Grignard
reaction afforded the allyl alcohols 95a,b. Ozonolysis followed by sodium chlorite oxi-
dation in tBuOH/H
O/2-methylbut-2-ene (2:2:1) afforded the corresponding car-
2
boxylic acids, which were esterified to give the benzyl esters 96a,b. Triflation and
Scheme 10.13 Synthesis of the (6′S)- and (6′R)-configurated N7 nucleosides 98a and 98b.
Reagents/solvent and yield: (a) 1. (COCl)
steps; (b) 1. O
(2:2:1); 3. BnBr, KHCO
NaN
, DMF, 72% for 97a, 86% for 97b both over two steps; (d) BSA, 2-acetamido-6-
3
chloropurine, TMSOTf, CH
, DMS, DCM; 2. NaClO2, NaH2PO4.H2O, tBuOH/H2O/2-methylbut-2-ene
3
, Bu4NI, DMF, 68% over three steps; (c) 1. Tf2O, pyridine, DCM; 2.
3
CN, 60% for 98a and 55% for 98b. Source: Adapted from Marcelo
3
, DMSO, Et3N; 2. CH2=CHMgBr, THF, 65% over two
2
etal.[88].
10.5 Cholinesterase Inhibitors
nucleophilic substitution with sodium azide afforded the diastereoisomers 97a and
97b in high yield. With these two bicyclic intermediates, coupling with silylated
9
2-acetamido-6-chloropurine catalyzed by TMSOTf afforded a mixture of N
- and N7-
linked (98a and 98b) nucleosides, which were screened for AChE and BChE inhibi-
7
tion. While none of the compounds tested inhibited AChE, the N
nucleosides showed
potent inhibition toward BChE (Table10.7). Nanomolar inhibition was obtained for
Table10.7 Inhibition (%) of BChE for different concentrations of the compounds tested
and IC
values.
50
327
Compound nr Concentration (μg ml−1) BChE inhibition (%) BChE IC50± SEM
92 100.00 48*** -----
10.00 11
93 100.00 84*** 0.76 ± 0.05
10.00 85***
1.00 70***
0.10 20***
97a 100.00 91*** 4.20 ± 0.05
10.00 64***
1.00 36***
0.10 15*
97b 100.00 98*** 13.40 ± 0.80
10.00 73***
1.00 14**
98a 100.00 81*** 22.00 ± 1.60
10.00 34***
1.00 9
98b 100 91*** 0.14 ± 0.01
10 79***
1 77***
0.1 63***
0.01 10
Rivastigmine
b
100 100*** 0.17 ± 0.01
10 100***
1 100***
0.1 76***
0.01 NI
a
a) IC50 compound concentration inhibiting 50% of enzyme activity; values are expressed as
mean ± standard error of the mean (SEM).
b) Rivastigmine is a drug to treat AD patients and was used as positive control.
***P< 0.001, **P< 0.01, *P< 0.05, NI: no inhibition. Source: Adapted from Marcelo etal.[88].
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328
Scheme 10.14 Synthesis of the N9 and N7 nucleosides 99 to 122 as reported by Schwarz
etal.[89] Reagents/solvent and yield: (a) BSA, 6-chloropurine (CP) or 2-acetamido-6chloropurine (ACP), TMSOTf, CH
R
=βN7CP, 20%; 100: d-Glc, R1=Ac, R2=βN9CP, 41%; 101: d-Glc, R1=Bn, R2=αN7CP, 6%; 102:
2
d-Glc, R
=Bn, R2=βN7CP, 17%; 103: d-Glc, R1=Bn, R2=αN9CP, 10%; 104: d-Glc, R1=Bn, R2=βN9C P,
1
45%; 105:
R
2
110:
R
2
d-Gal, R
R
2
120:
R
1
d-Gal, R
=Bn, R2=β-N7CP, 12%; 106: d-Gal, R1=Bn, R2=αN9CP, 7%; 107: d-Gal, R1=Bn,
1
=β-N9CP, 43%; 108: d-Man, R1=Bn, R2=αN7CP, 17%; 109: d-Man, R1=Bn, R2=βN7CP, 14%;
d-Man, R
=Bn, R2=αN9CP, 27%; 111: d-Man, R1=Bn, R2=βN9CP, 10%; 112: d-Glc, R1=Bn,
1
=αN7ACP, 7%; 113: d-Glc, R1=Bn, R2=βN7ACP, 34%; 114: d-Glc, R1=Bn, R2=βN9ACP, 29%; 115:
=Bn, R2=αN7ACP, 3%; 116: d-Gal, R1=Bn, R2=βN7ACP, 44%; 117: d-Gal, R1=Bn,
1
=αN9ACP, 10%; 118: d-Gal, R1=Bn, R2=βN9ACP, 41%; 119: d-Man, R1=Bn, R2=αN7ACP, 8%;
d-Man, R
=Bn, R2=βN7ACP, 28%; 121: d-Man, R1=Bn, R2=αN9ACP, 24%; 122: d-Man,
1
=Bn, R2=βN9ACP, 3%. Source: Adapted from Schwarz etal.[89].
CN, microwave irradiation (150 W); 99: d-Glc, R1=A c ,
3
compound 98b competing well with rivastigmine, a drug currently in use for the treatment of AD[88]. Experimental results showed that the presence of benzyl groups on
7
the carbohydrate scaffold and the N
-linked purine nucleobase were required for the
strong BChE inhibition[84]. The preliminary evaluation of the acute cytotoxicity of
the elongated bicyclic sugar precursors and nucleosides was also performed indicating low values, in the same order of magnitude as those of rivastigmine[88].
In 2014, Rauter and coworkers[89] presented a novel microwave-assisted synthesis
and anticholinesterase activity of a series of 24new purine nucleosides incorporating
6-chloropurine or 2-acetamido-6-chloropurine linked to -glucosyl, -galactosyl and
-mannosyl residues, with very interesting results compared to those previously
obtained by Marcelo etal.[88]. Optimization of the reaction conditions adapted to
formation of the new nucleoside structures was achieved by the use of microwave
irradiation (150 W, 65 °C), reducing the reaction time from 2 hours to 15 minutes
(Scheme10.14)[89]. Compound structure was designed aiming at ChE (AChE and
BChE) inhibition efficiency and selectivity by investigating sugar stereochemistry,
7
purine structure, and N
or N9-linked purine ligation to the sugar (Table10.8). The
outcome of this work showed that α-anomers were the most active compounds.
Regarding BChE inhibition, the nucleosides 110, 112, 119, and 120 were noticeably
more potent than the drug galantamine, and the most promising competitive and
7
selective BChE inhibitor, the N
showed a K
of 50 nM and a selectivity factor of 340-fold for BChE over AChE[89]. To
i
the best of our knowledge, compound 119 shows the lowest K
-linked 2-acetamido-α--mannosylpurine 119,
for BChE, being one of
i
the best candidates toward the study of BChE selective inhibition against AD, when
compared to other newly reported carbohydrate-based[90, 91] and noncarbohydratebased compounds[82]. Interestingly, selectivity over AChE or BChE can be tuned by
10.5 Cholinesterase Inhibitors
Table10.8 Inhibitory constant Ki for nucleosides 99–123 as determined by Elman's assay
with BChE and AChE in comparison to galantamine hydrobromide.
329
Compound
BChE Ki
(μM)
AChE Ki
(μM) Compound BChE Ki (μM)
AChE Ki
(μM)
99 β-Glc-N7CP >100 28.9 ± 2.1 111 β-Man-N9CP >20 >20
100 β-Glc-N
101 α-Glc-N
102 β-Glc-N
103 α-Glc-N
104 β-Glc-N
105 β-Gal-N
106 α-Gal-N
107 β-Glc-N
108 α-Man-N
109 β-Man-N
110 α-Man-N
Galantamine
hydrobromide
Source: Adapted from Schwarz etal.[89].
9
CP >100 17.5 ± 2.6 112 α-Glc-N7ACP 2.5 ± 0.3 >10
7
CP >20 9.6 ± 2.3 113 β-Glc-N7ACP >100 23.0 ± 1.9
7
CP >2 >2 114 β-Glc-N9ACP >2 >2
9
CP >100 17.0 ± 2.0 115 α-Gal-N7ACP 50.0 ± 7.0 42.0 ± 9.2
9
CP >100 16.0 ± 2.7 116 β-Gal-N7ACP >20 >20
7
CP >20 >20 117 α-Gal-N9ACP >2 >2
9
CP >10 5.6 ± 0.8 118 β-Gal-N9ACP >2 >2
9
CP >100 25.6 ± 2.1 119 α-Man-N7ACP 0.05 ± 0.01 18.1 ± 4.8
7
CP 30.9 ± 2.2 23.4 ± 3.6 120 β-Man-N7ACP 1.4 ± 0.1 3.0 ± 0.3
7
CP 9.6 ± 0.7 28.5 ± 6.5 121 α-Man-N9ACP 10.3 ± 2.6 17.1 ± 2.5
9
CP 2.8 ± 0.3 2.4 ± 0.3 122 β-Man-N9ACP >10 >10
9.4 ± 0.7 0.5 ± 0.0 Galantamine
9.4 ± 0.7 0.5 ± 0.0
hydrobromide
structural features. Indeed, glucosyl and galactosyl linkage to chloropurine favor the
7
formation of selective AChE inhibitors, while α-glucosyl and α-mannosyl N
ligation
to 2-acetamido-6-chloropurine favors selective BChE inhibitors.
Noteworthy, in 2021, Jasiecki etal. [92] revised and discussed the relationship
between BChE levels and iron concentration in the brain, highlighting that production of BChE by glial cells is iron-dependent. Moreover, AD patients exhibit higher
iron brain levels than healthy individuals, which contributes to the overexpression
of BChE and subsequent decrease in ACh levels[89].
Several reports indicate that increased Aβ plaque formation is observed when Aβ
is expressed in a context of increased AChE levels[93–95], with the neurotoxicity
induced by AChE-Aβ complexes being greater than when promoted by Aβ alone[96].
Regarding BChE and Aβ interactions, however, much remains unclear. Although
BChE is found in amyloid-β plaques and NFTs, its role in the amyloid hypothesis of
AD is yet not fully understood. Some studies imply that BChE has a catalytic role in
Aβ aggregation, while others point to a different scenario, where BChE is actually
able to inhibit Aβ aggregation[97, 98]. In 2012, the results of a study published by
Darvesh etal. suggested that BChE is associated with a subpopulation of Aβ deposits and could take part in AD plaque maturation[99]. On the other hand, in 2016,
Kumar etal. reported that low levels of BChE (0.02–0.004 μM–cerebrospinal fluid
concentrations in AD patients) increased the formation of Aβ42 fibrils by 20–30%;
yet, higher concentrations (0.2 μM) of BChE attenuated the kinetics of amyloid-β
fibrillization process [100]. Furthermore, when present simultaneously with
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330
apolipoprotein E4 (ApoE4), highly stable and soluble complexes between Aβ and
BChE are formed (BAβACs), leading to a reduction in Aβ amyloid aggregation[100].
Also, it seems that Aβ interacts with a presumed activation site in the catalytic tunnel of BChE, which results in an increased ACh influx to the catalytic site, with a
consequent increase in the rate of ACh hydrolysis[100]. Altogether, these data suggest that further studies are required, aiming to clarify the role of BChE in Aβ aggregation processes.
10.6 Fyn Kinase Inhibitors
Fyn kinase, a member of the Sec family of tyrosine kinases, is increasingly recognized as a promising disease-modifying therapeutic target against AD[11]. Over the
past decade, evidence has shown that soluble amyloid β oligomers (Aβo) bind to the
C
at the neuronal surface of the postsynaptic neuron, resulting in the activation
PrP
of the metabotropic glutamate receptor 5 (mGluR5), with subsequent Fyn kinase
phosphorylation, followed by phosphorylation of downstream substrates, including
the tau protein. Chronic exposure to soluble Aβo hence contributes to the accumulation of hyperphosphorylated Tau, which composes the NFTs responsible for synaptic dysfunction in the brain of AD patients. What’s more, Fyn kinase can also
phosphorylate tau directly. By taking part in this signaling pathway, Fyn arises as a
unique linker of the two major hallmarks of AD pathology[11] (Figure10.8).
APP is sequentially cleaved by BACE-1, and γ-gamma secretase, to produce Aβ
monomers, including Aβ1–40 and Aβ1–42, at the surface of the postsynaptic neuronal membrane. These monomers aggregate into oligomers, which in turn bind to
C
PrP
APP
BACE-1
γ-Secretase
Aβ Monomers
Phosphorylation of
downstream signalling
molecules
P
P
P
P
P
P
P
P
P
P
P
P
hyperphosphorylated
Tau
Aβo
NMDA
NR2B
P
2+
Ca
Synaptic dysfunction
Fyn
mGluR5
Postsynaptic neuron - CYTOPLASM
P
EXTRACELLULAR
Figure10.8 Simplified illustration of Aβo-induced Fyn activation leading to Tau
hyperphosphorylation.
MEDIUM
10.6 Fyn Kinase Inhibitors
their high-affinity partner, the PrPC. Once in complex with Aβo, PrPC interacts physically with the mGluR5 and, in the cytoplasm, Fyn kinase binds to mGluR5 and is
phosphorylated. This activated complex then results in the phosphorylation of the
NR2B subunit of the N-methyl--aspartate receptor (NMDA), which then leads to a
calcium influx that triggers the phosphorylation of downstream signaling molecules. With chronic exposure to Aβo at the neuronal surface, this cascade of events
ultimately culminates in Tau hyperphosphorylation, which is responsible for synaptic dysfunction and cognitive decline in AD patients.
Not many compounds have been identified to this point as Fyn kinase inhibitors
with proven concomitant downstream effects. In 2015, Kaufman etal.[101] investigated the brain-permeable Src family kinase inhibitor AZD0530, also known as
saracatinib (123, Scheme10.15), as a compound with potential against AD.
Saracatinib is a non-glycosylated C-5-substituted anilinoquinazoline and was
originally discovered as an anticancer agent by Hennequin etal.[103] in 2006, along
with a series of analogs investigated in structure–activity relationship (SAR) studies.
1
Biological assays showed that, when given at 5 mg kg
per day, this Fyn kinase
inhibitor prevented Aβo-induced signaling, Tau phosphorylation, and deposition,
while being able to rescue special memory and synaptic depletion in AD transgenic
mice[98]. In another study by Tang etal.[104], later in 2020, the same dose of saracatinib promoted similar improvements in phosphorylated Tau accumulation in the
331
Scheme 10.15 Synthesis of saracatinib (123)[102]. Reagents/solvent and yield: (a)
formamidine acetate, 2-methoxyethanol, DIPEA, then IPA (52%); (b) BnOH, NaH, DMA; (c)
HCl, 98%; (d) anhydrous toluene, POCl
92%; (g), Ph
(j) distillation, NaOH, 89%; (k) 2-(4-methylpiperazin-1-yl)ethanol, Ph
IPA, 86%.
P, DTAD, tetrahydropyran-4-ol, toluene; (h) HCl, dioxane, then IPA, 80%; (i) TFA;
3
, DIPEA; (e) anhydrous toluene, 69%; (f) pyridine, HCl,
3
P, DTAD, THF, then
3
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332
hippocampus, accompanied by memory improvements in mice with transgenic and
traumatic tauopathy.
The original 100
mg-scale synthesis of saracatinib[103] included 17linear steps, 7
of which were protection/deprotection reactions. With some practical concerns
raised for a potential scale-up synthesis, four years later, an optimized route for the
kilogram manufacture of saracatinib was developed [102]. This route started from
the difluoro quinazolinone 125, accessed in 52% yield from ester 124 by using forma-
midine acetate in 2-methoxyethanol (Scheme10.15), followed by addition of isopropanol and crystallization. Then, after a double S
Ar reaction to allow the replacement
N
of both fluorine groups with benzyloxy moieties by reaction with benzyl alcohol in
the presence of sodium hydride and dimethylacetamide (DMA), intermediate 126
was chlorinated in the presence of phosphorous oxychloride and DIPEA but 127 was
not isolated and reacted with 128 to give anilinoquinazoline 129, which was obtained
as a hydrochloride salt in 69% yield. Selective debenzylation gave the 5-hydroxy intermediate 130 in 92% yield. Compound 131 was then accessed as a hydrochloride salt
in 80% yield by reaction with tetrahydropyran-4-ol under Mitsunobu conditions,
with subsequent addition of hydrochloric acid in 1,4-dioxane, followed by crystallization. After deprotection of the remaining benzyl group, followed by distillation to
dryness and neutralization with sodium hydroxide, the final Mitsunobu coupling of
intermediate 132 with 2-(4-methylpiperazin-1-yl)ethanol gave saracatinib 123 which,
after crystallization, was obtained as a difumarate in 86% yield.
To the best of our knowledge, saracatinib (123) was the first Fyn kinase inhibitor
with proven downstream effects in an AD model and with adequate pharmacokinetic properties. However, the very first sugar-based Fyn kinase inhibitors were not
published until 2020[103]. Indeed, Rauter and coworkers identified a new family of
nature-inspired glucosylpolyphenols (121–124, Figure10.9) that were shown to distinctively interfere with the Aβo-Fyn-Tau neuronal signaling cascade, with the
advantage of having a much easier, straightforward, and efficient synthesis compared to the route described for saracatinib.
Synthesis of the three per-O-methylated C-glucosyl polyphenols 133–135 was
conducted by Matos et al.[105] in only two reaction steps, in good to very good
overall yield (Scheme10.16). Briefly, after full methylation of the commercially
available methyl α--glucopyranoside (137) with sodium hydride and methyl iodide,
the TMSOTf-promoted C-glucosylation reaction of each polyphenol in the presence
of drierite gave the desired final compound. This final reaction step afforded compound 133 in 53% yield, compound 134 in 37% yield, and compound 135 in 45% yield.
Synthesis of compound 136 required a few additional reaction steps (Scheme10.17)
but is still simpler than that of saracatinib (123). Firstly, the C-glycosylation reaction
carried out as previously described afforded the intermediate 139 in 63% yield. It is
interesting to note that this reaction occurred via a Friedel–Crafts-type mechanism,
being the first exception to the Fries-type rearrangement ever reported in the
C-glycosylation of unprotected phenols. Compound 139 was then submitted to a
benzoylation reaction with benzoyl chloride, imidazole, and dichloromethane as a
solvent to afford its derivative 140 in 88% yield, which was deprotected to give the
MeO
OMe
MeO
OMe
MeO
135
136
OMe
OMe
10.6 Fyn Kinase Inhibitors
333
MeO
MeO
HO
O
H
H
OH
133
OMe
OH
OHHO
OMe
O
OH
O
MeO
HO
HO
HO
O
H
OH
134
OH
OH
O
H
O
O
O
O
Figure10.9 Structure of Fyn kinase inhibitor 134 and of the inhibitors of Aβo induced Fyn
activation 133, 135, and 136.
desired compound 136 in 8% yield. The low yield of this final step was due to the
hydrolysis of the ester groups and could potentially be further optimized.
In terms of their bioactivity, the per-O-methylated C-glucosyl phloroglucinol 133
and the per-O-methylated C-glucosyl hydroquinone 134 (Figure10.9) were found to
significantly inhibit Fyn kinase activity at 10 μM (p< 0.01 vs. untreated controls) in
hiPSC-derived neural progenitor cells. On the other hand, compounds 133, 135, and
136 (Figure 10.9) were able to inhibit Aβo-induced Fyn activation at the same
–
Scheme 10.16 Synthesis of per-O-methylated C-glucosyl polyphenols 133–135[105]].
Reagents/solvent and yield: (a) DMF, NaH, MeI, 91%; (b) dry CH
CN, hydroquinone,
3
phloroglucinol or acetophloroglucinol, drierite, TMSOTf. Source: Adapted from Matos
etal.[105].
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334
Scheme 10.17 Synthesis of per-O-methylated C-glucosyl polyphenols[103]. Reagents/
solvent and yield: (a) DMF, NaH, MeI, 91%; (b) dry CH
imidazole, BzCl, 88%; (d) DCM, BBr
.
SMe2, 8%.
3
CN, drierite, TMSOTf, 63%; (c) DCM,
3
concentration (p < 0.001 vs. untreated Aβo controls). Importantly, all four compounds (133–136) reduced Aβo-induced Tau hyperphosphorylation (at 10
levels below controls, which once more supports Fyn kinase as a therapeutic target for AD.
Even though other analog molecules also exhibited bioactivity in the SAR study
conducted by the authors, this group of glycoconjugates displayed the adequate
physicochemical features (optimal log D and effective permeability in a PAMPA
assay) without any relevant cytotoxic effects at 50
μM[103], which makes them can-
didates for further development as CNS-active therapeutic agents.
μM) to
10.7 Amyloid Protein–Protein Interaction Inhibitors
As previously discussed, the interactions between Aβo and its high-affinity partner
C
at the neuronal cell surface are crucial in triggering Fyn activation and subse-
PrP
quent events leading to tau hyperphosphorylation in AD (Figure10.10). Hence,
when thinking of protein–protein interaction inhibition strategies aiming to directly
disrupt the involvement of Aβ in the development of this signaling cascade, two
main approaches arise: (i) tackling the aggregation process that turns Aβ monomers
(Aβm) into Aβo and (ii) inhibiting the binding between Aβo and the PrP
(Figure10.10).
In the context of approach (i), a group of flavonoids was investigated for their ability to inhibit Aβ aggregation[106]. The authors highlighted the ability of catecholtype flavonoids, such as the natural compound quercetin (141, Figure 10.11), to
completely abolish Aβ aggregation by acting as Michael acceptors once oxidized
into the corresponding o-quinones. This process is characteristic of Pan Assay
C
10.7 Amyloid Protein–Protein Interaction Inhibitors
HO
143
144
OH
335
(i)
(iI)
Aβ
Aβ
m
o
Aβ
o
Aβo + PrP
c
Figure10.10 Two major processes to be targeted by amyloid protein–protein interaction
inhibitors in the context of AD.
Interference Compounds (PAINS) with the catechol motif, which are able to indiscriminately interfere with many other molecular targets. Hence, highly promiscuous compounds such as quercetin (141) should not be regarded as ideal candidates
for further optimization. Yet, they ultimately uncovered the potential of chrysin
(142, Figure10.11), another natural compound, to act as an anti-aggregation compound. Even though ThT fluorescence assays did not reveal a significant change in
the presence of amyloid aggregates by the effects of this compound (tested in concentrations from 0.5 to 100 μM), Atomic Force Microscopy (AFM) experiments
showed that, compared with structurally similar compounds, chrysin preferably
OH
OH O
142
OH
O
OH O
O
OH
N
O
N
HO
OH O
141
OH O
O
OH
N
O
N
HO
HO
HO
HO
H
Figure10.11 Amyloid anti-aggregation agents (141, 142) and Aβo-PrPC disrupting agents
(143, 144).
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