Increased understanding of the important roles that oligosaccharides and glycoconjugates play in biological processes has led to a demand for significant amounts of these materials for biological, medicinal, and pharmacological studies. Therefore, tremendous effort has been made to develop new procedures for the synthesis of glycosides, whereby the main focus is often the formation of the glycosidic bonds. Accordingly, quite a few review articles have been published over the past few years on glycoside synthesis; however, most are confined to either a specific type of glycoside or a specific strategy for glycoside synthesis. In this Review, new principles for the formation of glycoside bonds are discussed. Developments, mainly in the last ten years, that have led to significant advances in oligosaccharide and glycoconjugate synthesis have been compiled and are evaluated.

New principles for glycoside-bond formation.

Chemical and biochemical transformations in ionic liquids

The reactivity of a number of p-methylphenyl thioglycoside (STol) donors which are either fully protected or have one hydroxyl group exposed has been quantitatively determined by HPLC in conjunction with the development of a broadly applicable approach for a facile one-pot synthesis of oligosaccharides. The influence on reactivity of the structural effects of different monosaccharide cores and different protecting groups on each glycoside donor is characterized and quantified. In addition, a correlation between glycosyl donor reactivity and the chemical shift of the anomeric proton by 1 H NMR has been established. A database of thioglycosides as glycosyl donors has been created using this reactivity data. The utility is demonstrated by the easy and rapid one-pot assembly of various linear and branched oligosaccharide structures. In addition, a computer program as been described for use as a database search tool and guide for the selection of building blocks for the one-pot assembly of a desired oligosaccharide or a library of individual oligosaccharides.

Programmable one-pot oligosaccharide synthesis

Regioselective manipulation of hydroxyl groups via organotin derivatives

Antimicrobial peptides (AMPs) are essential components of immune defenses of multicellular organisms and are currently in development as anti-infective drugs. AMPs have been classically assumed to have broad-spectrum activity and simple kinetics, but recent evidence suggests an unexpected degree of specificity and a high capacity for synergies. Deeper evaluation of the molecular evolution and population genetics of AMP genes reveals more evidence for adaptive maintenance of polymorphism in AMP genes than has previously been appreciated, as well as adaptive loss of AMP activity. AMPs exhibit pharmacodynamic properties that reduce the evolution of resistance in target microbes, and AMPs may synergize with one another and with conventional antibiotics. Both of these properties make AMPs attractive for translational applications. However, if AMPs are to be used clinically, it is crucial to understand their natural biology in order to lessen the risk of collateral harm and avoid the crisis of resistance now facing conventional antibiotics.

Antimicrobial peptides: Application informed by evolution

n-Pentenyl Glycosides in Organic Chemistry: A Contemporary Example of Serendipity

A general rationalization for armed/disarmed effects, first recognized in n-pentenyl glycosides but recently extended to a variety of other glycosyl donors, is postulated. Reaction of a glycosyl donor with an appropriate electrophile gives a positively charged intermediate which is less favorable when there is an adjacent electron-withdrawing group (for example OCOR, as in a disarmed donor) than when there is an adjacent alkoxy group (as in the armed counterpart). The latter therefore reacts faster and if, in the reaction medium, there is a disarmed species carrying a free hydroxyl group, a pathway based on Le Chatelier's principle can be envisaged that leads to products of cross-coupling with (virtually) none of the self-coupled analogue. In n-pentenyl glycosides activation of the anomeric center involves two preequilibrium steps, the second of which can be sidetracked to afford a vicinal dibromo derivative

Armed/disarmed effects in glycosyl donors: rationalization and sidetracking

Bacterial resistance against classical antibiotics is a growing problem and the development of new antibiotics is limited. Thus, novel alternatives to antibiotics are warranted. Antimicrobial peptides (AMPs) are effector molecules of innate immunity that can be induced by several compounds, including vitamin D and phenyl-butyrate (PBA). Utilizing a luciferase based assay, we recently discovered that the histone deacetylase inhibitor Entinostat is a potent inducer of the CAMP gene encoding the human cathelicidin LL-37. Here we investigate a mechanism for the induction and also find that Entinostat up-regulates human β-defensin 1. Analysis of the CAMP promoter sequence revealed binding sites for the transcription factors STAT3 and HIF-1α. By using short hairpin RNA and selective inhibitors, we found that both transcription factors are involved in Entinostat-induced expression of LL-37. However, only HIF-1α was found to be recruited to the CAMP promoter, suggesting that Entinostat activates STAT3, which promotes transcription of CAMP by increasing the expression of HIF-1α. Finally, we provide in vivo relevance to our findings by showing that Entinostat-elicited LL-37 expression was impaired in macrophages from a patient with a STAT3-mutation. Combined, our findings support a role for STAT3 and HIF-1α in the regulation of LL-37 expression.

/pdf/entinostat-up-regulates-the-camp-gene-encoding-ll-37-via-2oaqog30yg.pdf

Entinostat up-regulates the CAMP gene encoding LL-37 via activation of STAT3 and HIF-1α transcription factors.

A new concept for treatment of infections is induction of our own antimicrobial peptides and the presented novel class of inducer, aroylated phenylenediamines (APDs), gives up to 20 to 30-fold induction of the human antimicrobial peptide LL-37, in vitro. In addition, oral administration of an APD in a rabbit model of Shigellosis resulted in recovery from the infection in a few days implying that APD’s are promising candidates for treatment of infections.

/pdf/potent-inducers-of-endogenous-antimicrobial-peptides-for-4xgxvwmyax.pdf

Potent Inducers of Endogenous Antimicrobial Peptides for Host Directed Therapy of Infections.

Innate immunity, the front line of our defence against pathogens, relies, to a great extent, on the production of antimicrobial peptides (AMPs). These peptides exhibit antimicrobial activity and immunomodulatory properties. In humans, AMPs include the defensins (α- and β-families) and the cathelicidin, LL-37. Bacterial resistance against antibiotics is a growing concern, and novel antimicrobial strategies are needed urgently. Hence, the concept of strengthening immune defences against infectious microbes by inducing AMP expression may represent novel or complementary pharmaceutical interventions in the treatment or prevention of infections. We have developed and validated a robust cell-based reporter assay for LL-37 expression, which serves as a marker for a healthy epithelial barrier. This reporter assay can be a powerful tool for high-throughput screenings. We first employed our assay to screen a panel of histone deacetylase inhibitors and derivatives, and then the Prestwick Chemical Library of Food and Drug Administration-approved compounds. After hit confirmation and independent validation in the parental cell line we identified five novel inducers of LL-37. This reporter assay will help to identify novel drug candidates for the treatment and prevention of infections. Importantly, the pattern of hits obtained may suggest cellular pathways and key mediators involved in the regulation of AMP expression.

https://journals.sagepub.com/doi/pdf/10.1177/1753425913493338

Håkan Ottosson

Papers

n-Pentenyl Glycosides in Organic Chemistry: A Contemporary Example of Serendipity

Armed/disarmed effects in glycosyl donors: rationalization and sidetracking

Entinostat up-regulates the CAMP gene encoding LL-37 via activation of STAT3 and HIF-1α transcription factors.

Potent Inducers of Endogenous Antimicrobial Peptides for Host Directed Therapy of Infections.

Boosting innate immunity: development and validation of a cell-based screening assay to identify LL-37 inducers