Synthesis as an Expanding Resource in Human Milk Science.

Few classes of natural products rival the structural audacity of oligosaccharides. Their complexity, however, has stood as an immense roadblock to translational research, as access to homogeneous material from nature is challenging. Thus, while carbohydrates are critical to the myriad functional and structural aspects of the biological sciences, their behavior is largely descriptive. This challenge presents an attractive opportunity for synthetic chemistry, particularly in the area of human milk science. First, there is an inordinate need for synthesizing homogeneous human milk oligosaccharides (HMOs). Superimposed on this goal is the mission of conducting syntheses at scale to enable animal studies. Herein, we present a personalized rumination of our involvement, and that of our colleagues, which has led to the synthesis and characterization of HMOs and mechanistic probes. Along the way, we highlight chemical, chemoenzymatic, and synthetic biology based approaches. We close with a discussion on emergent challenges and opportunities for synthesis, broadly defined, in human milk science.

Prospecting Human Milk Oligosaccharides as a Defense Against Viral Infections.

In addition to providing maximal nutritional value for neonatal growth and development, human milk functions as an early defense mechanism against invading pathogens. Human milk oligosaccharides (HMOs), which are abundant in human milk, are a diverse group of heterogeneous carbohydrates with wide ranging protective effects. In addition to promoting the colonization of beneficial intestinal flora, HMOs serve as decoy receptors, effectively blocking the attachment of pathogenic bacteria. HMOs also function as bacteriostatic agents, inhibiting the growth of gram-positive bacteria. Based on this precedence, an emerging area in the field has focused on characterizing the antiviral properties of HMOs. Indeed, HMOs have been evaluated as antiviral agents, with many possessing activity against life-threatening infections. This targeted review provides insight into the known glycan-binding interactions between select HMOs and influenza, rotavirus, respiratory syncytial virus, human immunodeficiency virus, and norovirus. Additionally, we review the role of HMOs in preventing necrotizing enterocolitis, an intestinal disease linked to viral infections. We close with a discussion of what is known broadly regarding human milk oligosaccharides and their interactions with coronaviruses.

Leveraging Stereoelectronic Effects in Biofilm Eradication: Synthetic ß-Amino Human Milk Oligosaccharides Impede Microbial Adhesion As Observed by Scanning Electron Microscopy.

Alongside Edward, Lemieux was among the earliest researchers studying negative hyperconjugation (i.e., the anomeric effect) or the preference for gauche conformations about the C1-O5 bond in carbohydrates. Lemieux also studied an esoteric, if not controversial, theory known as the reverse anomeric effect (RAE). This theory is used to rationalize scenarios where predicted anomeric stabilization does not occur. One such example is the Kochetkov amination where reducing end amines exist solely as the ß-anomer. Herein, we provide a brief account of Lemieux's contributions to the field of stereoelectronics and apply this knowledge toward the synthesis of ß-amino human milk oligosaccharides (ßΑ-HMOs). These molecules were evaluated for their ability to inhibit growth and biofilm production in Group B Streptococcus (GBS) and Staphylococcus aureus. While the parent HMOs lacked antimicrobial and antibiofilm activity, their ß-amino derivatives significantly inhibited biofilm formation in both species. Field emission gun-scanning single electron microscopy (FEG-SEM) revealed that treatment with ß-amino HMOs significantly inhibits bacterial adherence and eliminates the ability of both microbes to form biofilms.

An effective reagent to functionalize alcohols with phosphocholine.

Phosphocholine is a small haptenic molecule that is both a precursor and degradation product of choline. Phosphocholine decorates a number of biologics such as lipids and oligosaccharides. In this study, an air and bench stable phosphocholine donor has been developed and evaluated with a number of alcohol acceptors. Using a one-pot, three-step sequence, (phosphitylation, oxidation, and phosphate deprotection) phosphocholine derivatives are synthesized in high yields. Of particular interest is the synthesis of miltefosine, the lone oral drug approved to treat leishmaniasis. Due to its prohibitive expense ($1500 per g), miltefosine is not accesable for the majority of the world's patients. Based on the described reaction sequence, this drug can be produced for $25 per g.

Microwave-Assisted, Asymmetric Synthesis of 3-Amino-2,3-Dihydrobenzofuran Flavonoid Derivatives from Chalcones.

A route to access 3-amino-2,3-dihydrobenzofurans that utilizes microwave-assisted organic synthesis to rapidly generate analogues has been developed. The route begins with an acid-catalyzed, microwave-assisted aldol condensation to generate chalcone intermediates, followed by a Corey-Bakshi-Shibata reduction and subsequent Sharpless asymmetric epoxidation to access stereoisomeric epoxyalcohols. The final step is a one-pot, microwave-assisted, regioselective, acid-catalyzed epoxide opening with various amines followed by an intramolecular nucleophilic aromatic substitution reaction to generate the 3-amino-2,3-dihydrobenzofurans. This route provides ready access to stereochemically and structurally diverse analogues of these flavonoid scaffolds. Additionally, a pilot library was synthesized, and the biological activity diversity of the chalcones and dihydrobenzofurans was explored in human carcinoma cell lines.