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Exploring a unique pocket in Galectin-8N by the synthesis of D-galactoside-based benzimidazole inhibitors

Bartold, Sid LU (2023) KASM05 20222
Centre for Analysis and Synthesis
Abstract
Galectins are a family of glycan-binding proteins where galectin-8 is a part of the subgroup
known as tandem-repeat type galectins. Galectin-8 is composed of two homologous CRDs, one
N- and one C-terminal CRD. As it stands now, galectin-8N has been found to bind to a larger
number of glycans than galectin-8C. Thus, it is currently of a higher therapeutical interest to
focus research on the N-terminal CRD of galectin-8 than on the C-terminal. Studies on galectin-
8N inhibitors have revealed that benzimidazole-galactoside derivates show a greater affinity
and selectivity for galectin-8N by binding to unique amino acids, namely Arg45. However,
recent research has shown that there are two more unique amino acids, Arg59 and Tyr141,
... (More)
Galectins are a family of glycan-binding proteins where galectin-8 is a part of the subgroup
known as tandem-repeat type galectins. Galectin-8 is composed of two homologous CRDs, one
N- and one C-terminal CRD. As it stands now, galectin-8N has been found to bind to a larger
number of glycans than galectin-8C. Thus, it is currently of a higher therapeutical interest to
focus research on the N-terminal CRD of galectin-8 than on the C-terminal. Studies on galectin-
8N inhibitors have revealed that benzimidazole-galactoside derivates show a greater affinity
and selectivity for galectin-8N by binding to unique amino acids, namely Arg45. However,
recent research has shown that there are two more unique amino acids, Arg59 and Tyr141,
existing in a pocket of galectin-8N. It was found that this pocket and its unique amino acids
can be exploited by placing substituents on the C-4 position of the benzimidazole leading to a
galectin-8N inhibitor with a higher affinity and selectivity, which was the aim of this thesis.
Ten inhibitors were synthesized in six synthesis steps starting with an equatorial chlorination
at C-1 of β-D-galactose pentaacetate, followed by an SN2 reaction yielding an α-thioglycoside.
A Zemplén deacetylation was then performed following a regioselective 3-O-monoalkylation
with methyl bromoacetate as the reagent, which was then cyclized into a benzimidazole. For
the final step, Suzuki-couplings were executed at C-4 of the benzimidazole with a p-
carboxyphenyl substituent having the highest affinity for galectin-8N with Kd of 11 ± 1 μM of
the ten synthesized inhibitors. Whilst none of the synthesized compounds managed to surpass
current more potent galectin-8N inhibitors, it highlighted the importance of a substituent at the
C-6 position of the benzimidazole, which was omitted in this project. However, the importance
of the substituent at C-4 should not be ignored considering the synthesized compounds differ
by a factor of a 100 with the p-carboxyphenyl substituent revealing promising results for further
exploration of the pocket. (Less)
Popular Abstract
Galectins are a group of proteins that bind strongly to galactosides, which is a galactose, one
type of sugar, that is connected or bound to another organic compound, which in many cases
can be another sugar. Many different galectins have been discovered inside and throughout our
bodies which has led to a lot of scientific and medicinal interest in galectins, and their function.
What has been found is that they play a part in a wide range of biological processes where they
are implicated in many diseases, such as diabetes, cancer, HIV, arthritis, and many more.
Galectin-8 (abbreviated as Gal-8), as the name suggests, is a member of this protein group that
is involved in multiple of diseases with ongoing research on its role in... (More)
Galectins are a group of proteins that bind strongly to galactosides, which is a galactose, one
type of sugar, that is connected or bound to another organic compound, which in many cases
can be another sugar. Many different galectins have been discovered inside and throughout our
bodies which has led to a lot of scientific and medicinal interest in galectins, and their function.
What has been found is that they play a part in a wide range of biological processes where they
are implicated in many diseases, such as diabetes, cancer, HIV, arthritis, and many more.
Galectin-8 (abbreviated as Gal-8), as the name suggests, is a member of this protein group that
is involved in multiple of diseases with ongoing research on its role in fibrosis, corneal
inflammation, organ graft rejection, various cancers such as breast cancer, and inflammatory
and immune diseases. Being implicated in such a plethora of disease makes it a highly
interesting target for drug discovery and development. (Less)
Please use this url to cite or link to this publication:
author
Bartold, Sid LU
supervisor
organization
course
KASM05 20222
year
type
H2 - Master's Degree (Two Years)
subject
keywords
organic chemistry, synthesis, gal, gal-8, gal-8N, galectin, galectin-8, galectin-8N, inhibitor, drug development, benzimidazole, galactoside, carbohydrate, carbohydrate chemistry, Suzuki-coupling
language
English
id
9130481
date added to LUP
2023-08-29 11:37:46
date last changed
2023-08-29 11:37:46
@misc{9130481,
  abstract     = {{Galectins are a family of glycan-binding proteins where galectin-8 is a part of the subgroup
known as tandem-repeat type galectins. Galectin-8 is composed of two homologous CRDs, one
N- and one C-terminal CRD. As it stands now, galectin-8N has been found to bind to a larger
number of glycans than galectin-8C. Thus, it is currently of a higher therapeutical interest to
focus research on the N-terminal CRD of galectin-8 than on the C-terminal. Studies on galectin-
8N inhibitors have revealed that benzimidazole-galactoside derivates show a greater affinity
and selectivity for galectin-8N by binding to unique amino acids, namely Arg45. However,
recent research has shown that there are two more unique amino acids, Arg59 and Tyr141,
existing in a pocket of galectin-8N. It was found that this pocket and its unique amino acids
can be exploited by placing substituents on the C-4 position of the benzimidazole leading to a
galectin-8N inhibitor with a higher affinity and selectivity, which was the aim of this thesis.
Ten inhibitors were synthesized in six synthesis steps starting with an equatorial chlorination
at C-1 of β-D-galactose pentaacetate, followed by an SN2 reaction yielding an α-thioglycoside.
A Zemplén deacetylation was then performed following a regioselective 3-O-monoalkylation
with methyl bromoacetate as the reagent, which was then cyclized into a benzimidazole. For
the final step, Suzuki-couplings were executed at C-4 of the benzimidazole with a p-
carboxyphenyl substituent having the highest affinity for galectin-8N with Kd of 11 ± 1 μM of
the ten synthesized inhibitors. Whilst none of the synthesized compounds managed to surpass
current more potent galectin-8N inhibitors, it highlighted the importance of a substituent at the
C-6 position of the benzimidazole, which was omitted in this project. However, the importance
of the substituent at C-4 should not be ignored considering the synthesized compounds differ
by a factor of a 100 with the p-carboxyphenyl substituent revealing promising results for further
exploration of the pocket.}},
  author       = {{Bartold, Sid}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Exploring a unique pocket in Galectin-8N by the synthesis of D-galactoside-based benzimidazole inhibitors}},
  year         = {{2023}},
}