Synthesis of cyclopropanes via organoiron methodology: preparation of 2-(2′-carboxy-3′-ethylcyclopropyl)glycine

A route to 1,2,3-trisubstituted cyclopropanes has been developed. The relative stereochemistry at the three cyclopropane centers is established by nucleophilic attack on the pentadienyl ligand on the face opposite to iron and subsequent oxidatively induced reductive elimination with retention of configuration. This methodology was applied to the synthesis of 2-(2′-carboxy-3′-ethylcyclopropyl)glycines. The diastereomeric glycine dimethyl esters are separable as their diphenylmethylene imines. The conformationally restricted glutamate analogs (2S,1′S,2′S,3′R)- and (2R,1′S,2′S,3′R)-ECCG\u27s 5a and5b were prepared in five steps (17 and 15% yield, respectively) from (pentadienyl)Fe(CO)3+ (1R)-6

Iron-mediated Preparation of Vinylcyclopropanes. Scope, Mechanism, and Applications

The addition of stabilized carbon nucleophiles to tricarbonyl(1-methoxycarbonylpentadienyl)iron(1+) cation (1a) proceeds via attack at C2 on the face of the ligand opposite the Fe(CO)3 group to generate tricarbonyl(pentenediyl)iron complexes 2. Oxidation of complexes 2 affords vinylcyclopropanecarboxylates in good yield. In general, the relative stereochemistry about the cyclopropane ring reflects reductive elimination with retention of configuration. In cases where the C2 substituent is bulky (i.e., 2b) the major cyclopropane product 9b represents ring closure with inversion at C3. A mechanism involving π−σ−π rearrangement of the initially oxidized (pentenediyl)iron species is proposed to account for these results. Experiments which probe the stereochemistry of deuterium labeling in the vinyl group of the vinylcyclopropanecarboxylate products were carried out, and these results are consistent with the proposed mechanism. This methodology for the preparation of vinylcyclopropanecarboxylates was applied to the synthesis of 2-(2‘-carboxycyclopropyl)glycines (+)-22 and (−)-23 and the cyclopropane triester (−)-26

Modulation of Ocular Surface Glycocalyx Barrier Function by a Galectin-3 N-terminal Deletion Mutant and Membrane-Anchored Synthetic Glycopolymers

Background: Interaction of transmembrane mucins with the multivalent carbohydrate-binding protein galectin-3 is critical to maintaining the integrity of the ocular surface epithelial glycocalyx. This study aimed to determine whether disruption of galectin-3 multimerization and insertion of synthetic glycopolymers in the plasma membrane could be used to modulate glycocalyx barrier function in corneal epithelial cells. Methodology/Principal Findings Abrogation of galectin-3 biosynthesis in multilayered cultures of human corneal epithelial cells using siRNA, and in galectin-3 null mice, resulted in significant loss of corneal barrier function, as indicated by increased permeability to the rose bengal diagnostic dye. Addition of β-lactose, a competitive carbohydrate inhibitor of galectin-3 binding activity, to the cell culture system, transiently disrupted barrier function. In these experiments, treatment with a dominant negative inhibitor of galectin-3 polymerization lacking the N-terminal domain, but not full-length galectin-3, prevented the recovery of barrier function to basal levels. As determined by fluorescence microscopy, both cellobiose- and lactose-containing glycopolymers incorporated into apical membranes of corneal epithelial cells, independently of the chain length distribution of the densely glycosylated, polymeric backbones. Membrane incorporation of cellobiose glycopolymers impaired barrier function in corneal epithelial cells, contrary to their lactose-containing counterparts, which bound to galectin-3 in pull-down assays. Conclusions/Significance: These results indicate that galectin-3 multimerization and surface recognition of lactosyl residues is required to maintain glycocalyx barrier function at the ocular surface. Transient modification of galectin-3 binding could be therapeutically used to enhance the efficiency of topical drug delivery

Synthesis of (2-carboxycyclopropyl)glycines via Organoiron Methodology

(2-Carboxycyclopropyl)glycines (CCGs) were shown to be useful compounds for-studies of glutamate neurotransmission in the mammalian central nervous system(CNS). This is due to their structural similarity to glutamic acid, one of the most common neurotransmitters, and their selectivity towards specific subtypes of glutamate receptors. This selectivity is associated with conformational rigidity of these compounds and allows for mapping of binding sites of the receptors. Development of new analogs of CCGs could provide a deeper knowledge of the mechanisms and requirements for binding in the glutamate receptors. The goal of this thesis is to develop a novel, simplified method for synthesis of CCG analogs using organometallic methodology

Synthesis of (2-carboxycyclopropyl)glycines via Organoiron Methodology

(2-Carboxycyclopropyl)glycines (CCGs) were shown to be useful compounds for-studies of glutamate neurotransmission in the mammalian central nervous system(CNS). This is due to their structural similarity to glutamic acid, one of the most common neurotransmitters, and their selectivity towards specific subtypes of glutamate receptors. This selectivity is associated with conformational rigidity of these compounds and allows for mapping of binding sites of the receptors. Development of new analogs of CCGs could provide a deeper knowledge of the mechanisms and requirements for binding in the glutamate receptors. The goal of this thesis is to develop a novel, simplified method for synthesis of CCG analogs using organometallic methodology

Nanoscale materials for probing the biological functions of the glycocalyx

Glycans are among the most intriguing carriers of biological information in living systems. The structures of glycans not only convey the cells' physiological state, but also regulate cellular communication and responses by engaging receptors on neighboring cells and in the extracellular matrix. The assembly of simple monosaccharide building blocks into linear or branched oligo- and polysaccharides gives rise to a large repertoire of diverse glycan structures. Despite their structural complexity, individual glycans rarely engage their protein partners with high affinity. Yet, glycans modulate biological processes with exquisite selectivity and specificity. To correctly evaluate glycan interactions and their biological consequences, one needs to look beyond individual glycan structures and consider the entirety of the cell-surface landscape. There, glycans are presented on protein scaffolds, or are linked directly to membrane lipids, forming a complex, hierarchically organized network with specialized functions, called the glycocalyx. Nanoscale glycomaterials, which can mimic the various components of the glycocalyx, have been instrumental in revealing how the presentation of glycans can influence their biological functions. In this review, we wish to highlight some recent developments in this area, while placing emphasis on the applications of glycomaterials providing new insights into the mechanisms through which glycans mediate cellular functions

Nanoscale materials for probing the biological functions of the glycocalyx

Glycans are among the most intriguing carriers of biological information in living systems. The structures of glycans not only convey the cells' physiological state, but also regulate cellular communication and responses by engaging receptors on neighboring cells and in the extracellular matrix. The assembly of simple monosaccharide building blocks into linear or branched oligo- and polysaccharides gives rise to a large repertoire of diverse glycan structures. Despite their structural complexity, individual glycans rarely engage their protein partners with high affinity. Yet, glycans modulate biological processes with exquisite selectivity and specificity. To correctly evaluate glycan interactions and their biological consequences, one needs to look beyond individual glycan structures and consider the entirety of the cell-surface landscape. There, glycans are presented on protein scaffolds, or are linked directly to membrane lipids, forming a complex, hierarchically organized network with specialized functions, called the glycocalyx. Nanoscale glycomaterials, which can mimic the various components of the glycocalyx, have been instrumental in revealing how the presentation of glycans can influence their biological functions. In this review, we wish to highlight some recent developments in this area, while placing emphasis on the applications of glycomaterials providing new insights into the mechanisms through which glycans mediate cellular functions