SYNTHESIS OF MULTI-EPITOPIC GLYCOPEPTIDE-BASED CANCER VACCINES - Biologically-Responsive Hybrid Biomaterials - page 143

antigen [30]. The last coupling step with protected amino acid building blocks is
realized using glycal activation, or alternatively under classical glycosylation
reaction with halide or trichloroacetimidate activation. The direct coupling of a
trichloroacetimidate glycosyl donor bearing non-participating azide group with
Fmoc-L-hydroxynorleucine benzyl ester using TMSOTf as promoter [31]
providing the ŋ - O -linked product in 71% yield, whereas glycal epoxide donor
leads to the Ȳ - O -linked product in 60-80% yield. Both complementary strategies
were followed to prepare glycosylamino acids building blocks containing the Tn,
TF, STn, Le y or Globo-H antigens.
The same group proposed a three steps synthetic methodology comprising
the ozonolysis of n -pentenyl glycosyls, an Horner-Emmons olefination using
tetramethylguanidine and a protected glycine-derived phosphonate, then a
catalytic asymetric hydrogenation (Figure 6, strategy B) [32]. This protocol was
proved efficient to prepare unnatural glycosylamino acids containing the Tn, the
Globo-H and the Le y antigens with excellent diastereomeric selectivity.
In addition, Gb3, GM2, and fucosyl GM1 glycosylamino acid building
blocks were synthesized by olefin cross-metathesis reactions followed by
hydrogenation (Figure 6, strategy C) [33]. This strategy was explored starting
from allyl glycosides and Fmoc-L-allylglycine benzyl ester and by varying the
catalyst nature. The structure of both substrates was finally optimized by adding
a methyl group on the terminal olefin to prevent side product formation. Clusters
of Gb3 antigen displayed by a MUC5AC associated with breast and gastric
cancers peptide epitope was thus obtained from a Gb3 glycosylamino acid
building block [34].
More recently, a new generation of peptide linker presenting multiple
carbohydrate antigens was reported to reflect the degree of heterogeneity of the
tumor surface glycopattern [35-36]. The authors postulated that the association of
several TACAs associated with a particular cancer type within the same
polyantigenic clustered vaccine could improve the immune response.
3.2. Chemoselective methods
From a synthetic point of view, the glycopeptide assembly still suffers from
difficulties as it requires the preparation of large quantities of often complex
glycosyl amino acids building blocks for their incorporation during peptide
synthesis. In addition, each glycopeptide requires a specific and adapted
synthetic route. Therefore, this strategy remains illusory to follow in a scale-up
perspective. By contrast, chemoselective ligation strategies revealed an elegant
alternative for the convergent assembly of complex biomolecules [37-38], firstly