Chemistry Reference
In-Depth Information
Man
O
OH
O
HO
N
HO
HO
N
N
166
Man
O
Man
Man
Man
Man
Man
O
O
Man
O
O
N
O
O
N
Man
N
Man
O
O
O
HO
N
N
N
HO
N
N
N
N
N
N
HO
N
N
N
N
O
N
O
N
O
O
N
N
HO
N
N
HO
HO
N
HO
N
HO
O
N
HO
HO
HO
O
O
N
N
O
HO
O
O
HO
HO
OH
HO
HO
HO
169
167
168
SCHEME 5.37
Multimannosides on carbohydrate scaffolds.
deacetylation. A new family of glycoclusters with a valency ranging from 1 to 4
were obtained (Scheme 5.37). Binding affinities towards Con A were investigated by
ELLA. The synthetic multivalent compounds exhibited a remarkable cluster effect
with a relative potency per mannoside residue ranging from 8.1 to 9.1 depending
on the structures. Molecular dynamics performed on representative glycoconjugates
revealed interesting structural features such as rigidity of the scaffold and highly
flexible mannose counterparts.
We also synthesized a second family of glycoclusters based on carbohydrate scaf-
folds, bearing one to four lactoside epitopes linked through flexible oligoethylenegly-
col (EG) spacers of different lengths (
170-173
) with yields ranging between 40% and
75% (Scheme 5.38). We demonstrated the relevance of the EG linkers lengths in the
binding process by crosslinking-type assays. Alkynyl-armed lactosides were clicked
onto azide-functionalized carbohydrate scaffolds. The solution-phase-binding affini-
ties for galectin-1, galectin-3, and the lactose-binding plant lectin
Arachis hypogaea
(peanut) agglutinin were assessed by fluorescence polarization methods and ELLA,
respectively. Besides, the crosslinking properties of the glycoclusters were specif-
ically assessed by a two-site ELLA (sandwich assay). Molecular dynamic (MD)
simulations were performed on the entire set of synthetic glycoconjugates to study
their structural and dynamical features. Kd values of the multivalent lactosides ranged
between 42
M and 244
M for galectin-1 while for galectin-3 the values ranged
between 16
M. Taking into account our results, the optimal distance
of the EG-linker must be considered for an efficient binding process to the target
receptor. This is particularly relevant in antiadhesive therapies, where a “natural”
occurring binding phenomenon is to be inhibited by promoting an aggregation pro-
cess involving a synthetic analog. On the other hand, shorter spacers could favor the
“rebinding” mechanism if a single binding site is required, which is frequently the
case for effector molecules [61].
M and 73
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