Synthesis of Furan-Annelated BINOL Derivatives: Acid-Catalyzed Cyclization Induces Partial Racemization.

In this account, we describe the synthesis of a series of BINOL-based bis- and trisphosphoric acids 11d/e/f, which commonly feature an unusual phosphoric acid monoester motif. This motif is generated by an acid-catalyzed 5- endo- dig cyclization of the 3-alkynyl-substituted BINOL precursors to give the corresponding Furan-annelated derivatives, followed by phosphorylation of the remaining phenolic alcohols. In the cyclization reaction, we observed an unexpected partial racemization in the bis- and tris-BINOL scaffolds, leading to mixtures of diastereomers that were separated and characterized spectroscopically and by X-ray crystal structure analyses. The cyclization and racemization processes were investigated both experimentally and by DFT-calculations, showing that although the cyclization proceeds faster, the barrier for the acid-catalyzed binaphthyl-racemization is only slightly higher.

Screening of Neu5Acα(2-6)gal isomer preferences of siglecs with a sialic acid microarray.

Sialic acids (Sias) are important terminal sugars on cell surfaces involved in a wide range of protein-carbohydrate interactions. Hence, agents modulating sias-mediated protein interactions are promising inhibitors or vaccine candidates. Here, we report the synthesis of Neu5Acα(2-6)Gal structural analogs and their binding to a series of siglecs. The results showed distinct binding patterns with conserved siglecs (hCD22 and mCD22) compared to rapid evolving siglecs (Siglecs -3 & -10).

Sialic Acid Hydroxamate: A Potential Antioxidant and Inhibitor of Metal-Induced ß-Amyloid Aggregates.

Current methods for Alzheimer's treatment require a three-component system: metal chelators, antioxidants, and amyloid ß (Aß)-peptide-binding scaffolds. We report sialic acid (Sia) hydroxamate as a potential radical scavenger and metal chelator to inhibit Aß aggregation. A cell viability assay revealed that Sia hydroxamate can protect HeLa and glioblastoma (LN229) cells from oxidative damage induced by the Fenton reaction. Sedimentation and turbidity assays showed profound protection of neuroblastoma SH-SY5Y cells from metal-induced Aß aggregation and neural toxicity.

Multivalent Sialosides: A Tool to Explore the Role of Sialic Acids in Biological Processes.

Sialic acids (Sias) are fascinating nine-carbon monosaccharides that are primarily found on the terminus of the oligosaccharide chains of glycoproteins and glycolipids on cell surfaces. These Sias undergo a variety of structural modifications at their hydroxy and amine positions, thereby resulting in structural diversity and, hence, coordinating a variety of biological processes. However, deciphering the structural functions of such interactions is highly challenging, because the monovalent binding of Sias is extremely weak. Over the last decade, several multivalent Sia ligands have been synthesized to modulate their binding affinity with proteins/lectins. In this Minireview, we highlight recent developments in the synthesis of multivalent Sia probes and their potential applications. We will discuss four key multivalent families, that is, polymers, dendrimers, liposomes, and nanoparticles, and will emphasize the major parameters that are essential for the specific interactions of these molecules with proteins in biological systems.

Chiral Receptors for Lysine Based on Covalently Linked Bis- and Tris-binaphthylphosphoric Acids.

The synthesis and application of three chiral receptors based on the covalent linkage of 1,1'-binaphthylphosphoric acids is reported. The binding of the lysine enantiomers to the chiral receptors was investigated by DOSY-NMR and NMR titrations, revealing that the bisphosphoric acid 1d acts as a highly stereoselective receptor for binding of d-lysine.

Imaging and Targeting of the α(2-6) and α(2-3) Linked Sialic Acid Quantum Dots in Zebrafish and Mouse Models.

Sialic acid-conjugated nanocarriers have emerged as attractive biomarkers with promising biomedical applications. The translation of these nanocarriers into clinical applications requires in-depth assessment in animal models. However, due to the complexity, ethical concerns, and cost of the high-order animal system, there is an immediate need of information-rich simple animal models to decipher the biological significance. Herein, we performed in vivo head-to-head comparison of Neu5Acα(2-6) and α(2-3)Gal conjugated quantum dots (QDs) toxicity, biodistribution, and sequestration in wild-type zebrafish ( Danio rerio) and mouse model (C57BL). The fluorescent properties and cadmium composition of quantum dots were used to map the blood clearance, biodistribution, and sequestration of the sialylated QDs in major organs of both models. We observed that α(2-6) sialylated QDs preferentially have prolonged circulating half-life and broader biodistribution in both models. On the contrary, α(2-3) sialic acid and galactose-conjugated QDs have shortened blood circulation time and are sequestered in the liver, and cleared after several hours in both models. These results demonstrate the applicability of the zebrafish and sialylated QDs to target specific organs, as well as drug delivery and biomedical diagnostics.

Optimization of a Functionally Graded Material Stem in the Femoral Component of a Cemented Hip Arthroplasty: Influence of Dimensionality of FGM.

The longevity of hip prostheses is contingent on the stability of the implant within the cavity of the femur bone. The cemented fixation was mostly adopted owing to offering the immediate stability from cement-stem and cement-bone bonding interfaces after implant surgery. Yet cement damage and stress shielding of the bone were proven to adversely affect the lifelong stability of the implant, especially among younger subjects who tend to have an active lifestyle. The geometry and material distribution of the implant can be optimized more efficiently with a three-dimensional realistic design of a functionally graded material (FGM). We report an efficient numerical technique for achieving this objective, for maximum performance stress shielding and the rate of early accumulation of cement damage were concurrently minimized. Results indicated less stress shielding and similar cement damage rates with a 2D-FGM implant compared to 1D-FGM and Titanium alloy implants.

Minimizing Stress Shielding and Cement Damage in Cemented Femoral Component of a Hip Prosthesis through Computational Design Optimization.

The average life expectancy of many people undergoing total hip replacement (THR) exceeds twenty-five years and the demand for implants that increase the load-bearing capability of the bone without affecting the short- or long-term stability of the prosthesis is high. Mechanical failure owing to cement damage and stress shielding of the bone are the main factors affecting the long-term survival of cemented hip prostheses and implant design must realistically adjust to balance between these two conflicting effects. In the following analysis we introduce a novel methodology to achieve this objective, the numerical technique combines automatic and realistic modeling of the implant and embedding medium, and finite element analysis to assess the levels of stress shielding and cement damage and, finally, global optimization, using orthogonal arrays and probabilistic restarts, were used. Applications to implants, fabricated using a homogeneous material and a functionally graded material, were presented.

A rationally designed peptidomimetic biosensor for sialic acid on cell surfaces.

We have developed peptidomimetic sialic acid (Sia) biosensors using boronic acid and arginine groups on the peptide backbone. The designed peptides were conjugated to fluorescent streptavidin via biotin enabling the optical labeling of cells. This approach provides unique opportunities to detect Sia composition on the cell surfaces and filopodia.

Carbohydrate functionalized iron(III) complexes as biomimetic siderophores.

Catechol functionalized iron(III) glycodendrimers have been prepared using a self-assembly process for targeting a specific strain of E. coli bacteria and have been shown to exhibit carbohydrate-lectin mediated iron delivery in growth promotion assay.

Exploring the effect of sialic acid orientation on ligand-receptor interactions.

Here, we present the synthesis of two sialo-micelles to validate the significance of sialic acid orientation during specific carbohydrate-protein and carbohydrate-carbohydrate interactions. Our data clearly suggest that orientation of carboxylic acid and glycerol side chains of sialic acid moieties exert fine tuning of ligand-receptor interactions.