Toward the Synthesis of Large Oligosaccharide-Based Dendrimers

Abstract

KEYWORDS:carbohydrates´chemoselective ligation´dendrimersó ligosaccharides´reductive aminationIt is now generally acknowledged that cell surface protein ± carbohydrate interactions play a crucial role in a wide range of biological processes [1] necessary for both normal physiological function and the onset of disease. Although protein ± carbohydrate interactions typically display high dissociation constants with K d values in the mM to mM range, [2] Nature can still attain physiologically useful avidities through the cooperative binding [3] of multiple copies of the ligands and receptorsÐthe socalled multivalent effect. [4] Synthetic chemists have successfully exploited this trick from Nature's toolbox in the synthesis of neoglycoconjugates ranging from small cluster glycosides [5] through neoglycoproteins [6] to polymers bearing many pendant saccharide residues. [7] These synthetic tools have not only provided inhibitors with greatly enhanced affinities over monovalent ligands, but they have also led to considerable advances in our understanding [4, 8] of the nature of multivalent interactions. Glycodendrimers [9] are a special class of neoglycoconjugates that combines the welldefined structural homogeneity of small clusters with the nanoscale dimensions of glycopolymers. Most of the glycodendrimer research reported to date has involved the construction of dendrimers bearing saccharide residues only on their peripheries through the use of either i) a convergent strategy [10] or by ii) the divergent modification of preexisting dendrimers. [11] However, monosaccharides are multifunctional building blocks and, as such, they are often found in Nature in branched oligomers and polymers. [1b] Indeed, the use of carbohydrates as building blocks for dendrimer construction confers a number of desirable properties on the dendrimer. In addition to water solubility and biocompatibility, it should be possible to exploit the known conformational preferences [12] of oligosaccharide monomers in order to mold the dendrimer's size and shape in a predetermined manner.We recently described [13] the synthesis of oligosaccharide dendrimers based on b-D-glucopyranosyl repeating units. This synthesis, however, fell foul of the dogma of chemical carbohydrate synthesisÐprotecting group chemistry. In addition to the extensive chemical manipulations required to effect both regioand stereoselectivity, the bulky appendages associated with the saccharide unit introduce considerable steric crowding which restricts the growth of highly branched molecules. Here, we report a very different strategy for the synthesis of oligosaccharide-based glycodendrons using reductive amination [14] as a chemoselective coupling reaction which allows the synthesis to be undertaken using a minimal number of i) protecting groups and ii) protecting-group manipulations.Since one of our aims is to address the synthesis of large glycodendrimers, it seemed appropriate to base our synthetic strategy on an oligosaccharideÐrather than on a monosaccharide [13] ...

Characterization of Natural and Synthetic Sialoglycans Targeting the Hemagglutinin-Neuraminidase of Mumps Virus

“…The thio-3’SL (1) was prepared (see Scheme 1 ) starting from the thrichloroacetimidate 2, ( Turnbull et al, 2000 ), and the methyl-2,3,6-tri-O-benzyl-β-D-glucopyranoside (3), ( Yoneda et al, 2005 ), both prepared accordingly to literature methods. Glycosylation, catalyzed by BF 3 ∙Et 2 O, gives the protected trisaccharide 4 with a 50% yield.…”

Characterization of Natural and Synthetic Sialoglycans Targeting the Hemagglutinin-Neuraminidase of Mumps Virus

“…The thio-3’SL (1) was prepared (see Scheme 1 ) starting from the thrichloroacetimidate 2, ( Turnbull et al, 2000 ), and the methyl-2,3,6-tri-O-benzyl-β-D-glucopyranoside (3), ( Yoneda et al, 2005 ), both prepared accordingly to literature methods. Glycosylation, catalyzed by BF 3 ∙Et 2 O, gives the protected trisaccharide 4 with a 50% yield.…”

Targeting Inflammatory Pathways by Flavonoids for Prevention and Treatment of Cancer

“…Anthocyanin is synthesized by anthocyanidin synthase (ANS), a 2-oxoglutarate iron-dependent oxygenase, which catalyzes the penultimate step in its biosynthesis [35]. The synthesis of anthocyanidins is mediated through in vitro conversion of leucoanthocyanidins to dihydroflavonol and flavonol intermediates (cis-and trans-isoforms) catalyzed by ANS [36]. It has been shown that colored anthocyanidins such as pelargonidin and cyanidin are synthesized from colorless leucoanthocyanidins (leucopelargonidin and leucocyanidin) by the ANS-catalyzed reaction in the presence of ferrous ion, 2-oxoglutarate, and ascorbate, followed by acidification with HCl [37].…”

Dendrimeric Micelles for Controlled Drug Release and Targeted Delivery

“…In fact there are many reports on dendrimers and dendritic polymers made from monomers like glycerol, 37 aliphatic polyether-esters, 38,39 amino acids, 40 and carbohydrates. 41 As an example, glycerol-lactic acid based 42 and poly(glycerol succinic acid) (PGLSA) dendrimers 43 have been synthesized for biomedical applications (Chart 5). Hydroxyl-terminated PGLSA dendrimers were first tested for their ability to encapsulate hydrophobic compounds by experiments with Reichardt's dye.…”

“…Another approach to obtain biocompatible dendrimers is to synthesize them from biocompatible monomers. In fact there are many reports on dendrimers and dendritic polymers made from monomers like glycerol, aliphatic polyether-esters, , amino acids, and carbohydrates . As an example, glycerol−lactic acid based and poly(glycerol succinic acid) (PGLSA) dendrimers have been synthesized for biomedical applications (Chart ).…”

Characterization of Natural and Synthetic Sialoglycans Targeting the Hemagglutinin-Neuraminidase of Mumps Virus

“…The thio-3’SL (1) was prepared (see Scheme 1 ) starting from the thrichloroacetimidate 2, ( Turnbull et al, 2000 ), and the methyl-2,3,6-tri-O-benzyl-β-D-glucopyranoside (3), ( Yoneda et al, 2005 ), both prepared accordingly to literature methods. Glycosylation, catalyzed by BF 3 ∙Et 2 O, gives the protected trisaccharide 4 with a 50% yield.…”

Targeting Inflammatory Pathways by Flavonoids for Prevention and Treatment of Cancer

“…Anthocyanin is synthesized by anthocyanidin synthase (ANS), a 2-oxoglutarate iron-dependent oxygenase, which catalyzes the penultimate step in its biosynthesis [35]. The synthesis of anthocyanidins is mediated through in vitro conversion of leucoanthocyanidins to dihydroflavonol and flavonol intermediates (cis-and trans-isoforms) catalyzed by ANS [36]. It has been shown that colored anthocyanidins such as pelargonidin and cyanidin are synthesized from colorless leucoanthocyanidins (leucopelargonidin and leucocyanidin) by the ANS-catalyzed reaction in the presence of ferrous ion, 2-oxoglutarate, and ascorbate, followed by acidification with HCl [37].…”

Dendrimeric Micelles for Controlled Drug Release and Targeted Delivery

“…In fact there are many reports on dendrimers and dendritic polymers made from monomers like glycerol, 37 aliphatic polyether-esters, 38,39 amino acids, 40 and carbohydrates. 41 As an example, glycerol-lactic acid based 42 and poly(glycerol succinic acid) (PGLSA) dendrimers 43 have been synthesized for biomedical applications (Chart 5). Hydroxyl-terminated PGLSA dendrimers were first tested for their ability to encapsulate hydrophobic compounds by experiments with Reichardt's dye.…”

“…Another approach to obtain biocompatible dendrimers is to synthesize them from biocompatible monomers. In fact there are many reports on dendrimers and dendritic polymers made from monomers like glycerol, aliphatic polyether-esters, , amino acids, and carbohydrates . As an example, glycerol−lactic acid based and poly(glycerol succinic acid) (PGLSA) dendrimers have been synthesized for biomedical applications (Chart ).…”

Characterization of Natural and Synthetic Sialoglycans Targeting the Hemagglutinin-Neuraminidase of Mumps Virus

“…The thio-3’SL (1) was prepared (see Scheme 1 ) starting from the thrichloroacetimidate 2, ( Turnbull et al, 2000 ), and the methyl-2,3,6-tri-O-benzyl-β-D-glucopyranoside (3), ( Yoneda et al, 2005 ), both prepared accordingly to literature methods. Glycosylation, catalyzed by BF 3 ∙Et 2 O, gives the protected trisaccharide 4 with a 50% yield.…”

Targeting Inflammatory Pathways by Flavonoids for Prevention and Treatment of Cancer

“…Anthocyanin is synthesized by anthocyanidin synthase (ANS), a 2-oxoglutarate iron-dependent oxygenase, which catalyzes the penultimate step in its biosynthesis [35]. The synthesis of anthocyanidins is mediated through in vitro conversion of leucoanthocyanidins to dihydroflavonol and flavonol intermediates (cis-and trans-isoforms) catalyzed by ANS [36]. It has been shown that colored anthocyanidins such as pelargonidin and cyanidin are synthesized from colorless leucoanthocyanidins (leucopelargonidin and leucocyanidin) by the ANS-catalyzed reaction in the presence of ferrous ion, 2-oxoglutarate, and ascorbate, followed by acidification with HCl [37].…”

Dendrimeric Micelles for Controlled Drug Release and Targeted Delivery

“…In fact there are many reports on dendrimers and dendritic polymers made from monomers like glycerol, 37 aliphatic polyether-esters, 38,39 amino acids, 40 and carbohydrates. 41 As an example, glycerol-lactic acid based 42 and poly(glycerol succinic acid) (PGLSA) dendrimers 43 have been synthesized for biomedical applications (Chart 5). Hydroxyl-terminated PGLSA dendrimers were first tested for their ability to encapsulate hydrophobic compounds by experiments with Reichardt's dye.…”

“…Another approach to obtain biocompatible dendrimers is to synthesize them from biocompatible monomers. In fact there are many reports on dendrimers and dendritic polymers made from monomers like glycerol, aliphatic polyether-esters, , amino acids, and carbohydrates . As an example, glycerol−lactic acid based and poly(glycerol succinic acid) (PGLSA) dendrimers have been synthesized for biomedical applications (Chart ).…”