Multivalent interaction and selectivities in selectin binding of functionalized gold colloids decorated with carbohydrate mimetics

Abstract

Colloidal gold particles with functionalized organic shells were applied as novel selectin binders. The ligand shell was terminated with different monocyclic carbohydrate mimetics as simplified analogs of the sLe x unit found in biological selectin ligands. The multivalent presentation of the sulfated selectin binding epitopes on the gold particles led to extremely high binding affinities towards L-and P-selectin and IC 50 values in the subnanomolar range. Depending on the ring size of the sulfated carbohydrate mimetic, its substitution pattern and its configuration, different selectivities for either L-selectin or P-selectin were obtained. These selectivities were not found for gold particles with simple acyclic sulfated alcohols, diols and triols in the ligand shell. In addition, the influence of the particle size and the thickness of the hydrophobic organic shell were systematically investigated.

Synthesis of multivalent carbohydrate mimetics with aminopolyol end groups and their evaluation as L-selectin inhibitors

“…The polysulfation of the presented carbohydrate mimetics proved to be the most demanding step of the synthesis requiring many attempts and optimizations to find a suitable and reasonably reproducible procedure. Since other sulfation methods such as SO 3 ∙pyridine [35] provided unsatisfactory results an excess of SO 3 ∙DMF [13,36] was used as sulfating agent and the resulting sulfuric acid monoesters (in a mixture with an excess of the sulfating reagent) were directly converted into the corresponding sodium salts using a 1 M solution of sodium hydroxide. Subsequent purification by dialysis against water should afford the desired pure polysulfated compounds.…”

“…These compounds and their conjugates were prepared to be examined as selectin inhibitors. There we have found that sulfated aminopyrans connected by amide bonds to gold nanoparticles are highly potent inhibitors of L- and P-selectin with IC 50 values in the subnanomolar range [12–13]. These lectins are crucial in the inflammatory process [14–18] and hence compounds inhibiting their activity are of interest as potential therapeutics [19–23].…”

Glyco-gold nanoparticles: synthesis and applications

“…AuNP core dimension and shape are important parameters to take into consideration for the multivalent carbohydrate presentation [51–53]. In fact, a denser ligand packing can be obtained when NP dimensions are bigger and the curvature radius is reduced.…”

Iodination of carbohydrate-derived 1,2-oxazines to enantiopure 5-iodo-3,6-dihydro-2H-1,2-oxazines and subsequent palladium-catalyzed cross-coupling reactions

“…Subsequently we investigated modifications and synthetic applications of 1,2-oxazines 3 including the preparation of seven-membered N,O-heterocycles by ring enlargement [5], functionalization of the enol ether unit [6–11], and N,O-cleavage reactions leading to amino alcohols [8,10,12], pyrroles [13] or α,β-unsaturated β-alkoxy-γ-amino-aldehydes and ketones [14]. In this context, a series of publications of our group reported on syntheses of carbohydrate mimetics [15–20] that are based on aminopyrans, aminooxepanes or other aminopolyols and that were examined for example as ligands of L- and P-selectin [21–22]. We previously reported the synthesis of enantiopure 1,2-oxazin-4-yl nonaflates and phosphates starting from precursors of type 3 and their conversion into differently C-4-substituted products employing palladium-catalyzed cross-coupling reactions [23].…”