Investigation of Leoligin Derivatives as NF-κΒ Inhibitory Agents

The transcription factor NF-κB is an essential mediator of inflammation; thus, the identification of compounds that interfere with the NF-κB signaling pathway is an important topic. The natural products leoligin and 5-methoxyleoligin have served as a starting point for the development of NF-κB inhibitors. Using our modular total synthesis method of leoligin, modifications at two positions were undertaken and the effects of these modifications on the biological activity were investigated. The first modification concerned the ester functionality, where it was found that variations in this position have a significant influence, with bulky esters lacking Michael-acceptor properties being favored. Additionally, the substituents on the aryl group in position 2 of the tetrahydrofuran scaffold can vary to some extent, where it was found that a 3,4-dimethoxy and a 4-fluoro substitution pattern show comparable inhibitory efficiency.

Flavonoids: A Group of Potential Food Additives with Beneficial Health Effects

Recently, there has been an increasing interest in health-promoting products which are also natural and safe for consumption because the consumer market has been searching for a healthy lifestyle. This global market trend has driven the food industry to invest in developing innovative products containing bioactive components. Flavonoids are a group of phenolic compounds of low molecular weight, consisting of 15 carbon atoms. Their alterations in the heterocyclic ring’s substitution pattern generate six subclasses: flavonols, flavanols, flavones, flavanones, isoflavones and anthocyanins. Also, different studies have reported that diets rich in flavonoids provide numerous benefits associated with health-promoting effects by reducing the risk of development of chronic diseases such as cardiovascular diseases, diabetes type II and some types of cancers. These effects have been related to their biological properties which also include other activities such as colorant effects (e.g., anthocyanins), transforming them into potential food additives with desirable capacities. Therefore, this review aims to revise the classes of flavonoids and their main biological properties as well as the most used extraction techniques applied for obtaining these compounds, their bioavailability and the application to formulate new natural food additives.

Transaminase Catalysis for Enantiopure Saturated Heterocycles as Potential Drug Scaffolds

As efforts in rational drug design are driving the pharmaceutical industry towards more complex molecules, the synthesis and production of these new drugs can benefit from new reaction routes. In addition to the introduction of new centers of asymmetry, complexity can be also increased by ring saturation, which also provides improved developability measures. Therefore, in this report, our aim was to develop transaminase (TA)-catalyzed asymmetric synthesis of a new group of potential chiral drug scaffolds comprising a saturated amine heterocycle backbone and an asymmetric primary amine sidechain (55a–g). We screened the Codex® Amine Transaminase Kit of 24 transaminases with the morpholine containing ketone 57a, resulting in one (R)-selective TA and three (S)-selective TAs operating at 100 mM substrate concentration and 25 v/v% isopropylamine (IPA) content. The optimized reaction conditions were than applied for asymmetric transamination of further six ketones (57b–g) containing various amine heterocycles, in which a strong effect of the substitution pattern of the γ-position relative to the substituted N-atom could be observed. Mediated by the most enantiotope selective (S)-TAs in scaled-up process, the (S)-amines [(S)-55a–g] were isolated with moderate-to-excellent yields (47–94%) in enantiopure form (>99% ee).

Oxyamine Linkers for the Protecting Group Free Synthesis of Glycoconjugates

<p>Glycoconjugates, such as glycolipids and glycoproteins, are involved in a variety of cellular functions including cell-to-cell signalling and carbohydrate-protein recognition. Accordingly, glycoconjugates play important roles in health and disease and are promising new leads as carbohydrate-based therapeutics. However, for the development of glycoconjugates to study biological processes, or for the use of these adducts as therapeutics, the glycan needs to be conjugated to the carrier molecule or scaffold of choice. Many procedures for the conjugation of glycans involve lengthy protecting group strategies that install the aglycone at the start of glycan total synthesis and are therefore unsuitable for naturally derived sugars. Other glycan conjugation strategies can affect the integrity of the reducing end sugar or lead to adducts where the reducing end sugar adopts the ring-opened rather than the ring-closed form. N,O-Dialkyl oxyamine linkers, however, can be attached to the free reducing end of sugars in a single step without the need for protecting groups. This thesis therefore explores the synthesis and application of oxyamine linkers for the synthesis of glycoconjugates. First, the synthesis of an O-alkyl-N-methyl oxyamine linker (“Type A”) containing an amine at its terminus was improved by reducing the number of synthetic steps from six to four and by increasing the overall yield from 8% to 38%. This oxyamine linker was then conjugated to GlcNAc in 83% yield. The hydrolytic stability of this glycosyloxyamine was then compared to that of the analogous N-alkyl-O-methyl glycosyloxyamine (“Type B”). The stability of the two types of glycosyloxyamines has never been directly compared. Accordingly, it was not known whether the difference in substitution pattern between the two linkers affects their hydrolytic stability. To this end, the hydrolysis rates of the GlcNAc conjugated linkers were assessed at various pH values, glycoconjugate concentrations and buffer concentrations. In all instances, the “Type B” glycoside was found to have marginally better kinetic stability, while the “Type A” glycoside had marginally better thermodynamic stability, but overall, these differences were negligible. The pKa of the conjugate acid of these glycosyloxyamines was also determined to provide insight into the mechanism of hydrolysis. By considering this data, along with the observation that the rate of hydrolysis of these glycoconjugates increases with increasing buffer concentration, it was proposed that the hydrolysis of the oxyamines occurs via general acid catalysis at pH 4-6. A novel dithiol functionalised oxyamine linker was also designed and synthesised for the multivalent display of glycans on gold nanoparticles. With the successful attachment of this thiol linker to GlcNAc, the monomer unit of chitin, this work has paved the way for the future syntheses of chitin-functionalised gold nanoparticles. Such chitinfunctionalised AuNPs can be used to assess chitin’s ability to invoke the asthma allergic immune response, thereby bringing the possibility of an anti-asthma vaccine a step closer to fruition.</p>

Oxyamine Linkers for the Protecting Group Free Synthesis of Glycoconjugates

<p>Glycoconjugates, such as glycolipids and glycoproteins, are involved in a variety of cellular functions including cell-to-cell signalling and carbohydrate-protein recognition. Accordingly, glycoconjugates play important roles in health and disease and are promising new leads as carbohydrate-based therapeutics. However, for the development of glycoconjugates to study biological processes, or for the use of these adducts as therapeutics, the glycan needs to be conjugated to the carrier molecule or scaffold of choice. Many procedures for the conjugation of glycans involve lengthy protecting group strategies that install the aglycone at the start of glycan total synthesis and are therefore unsuitable for naturally derived sugars. Other glycan conjugation strategies can affect the integrity of the reducing end sugar or lead to adducts where the reducing end sugar adopts the ring-opened rather than the ring-closed form. N,O-Dialkyl oxyamine linkers, however, can be attached to the free reducing end of sugars in a single step without the need for protecting groups. This thesis therefore explores the synthesis and application of oxyamine linkers for the synthesis of glycoconjugates. First, the synthesis of an O-alkyl-N-methyl oxyamine linker (“Type A”) containing an amine at its terminus was improved by reducing the number of synthetic steps from six to four and by increasing the overall yield from 8% to 38%. This oxyamine linker was then conjugated to GlcNAc in 83% yield. The hydrolytic stability of this glycosyloxyamine was then compared to that of the analogous N-alkyl-O-methyl glycosyloxyamine (“Type B”). The stability of the two types of glycosyloxyamines has never been directly compared. Accordingly, it was not known whether the difference in substitution pattern between the two linkers affects their hydrolytic stability. To this end, the hydrolysis rates of the GlcNAc conjugated linkers were assessed at various pH values, glycoconjugate concentrations and buffer concentrations. In all instances, the “Type B” glycoside was found to have marginally better kinetic stability, while the “Type A” glycoside had marginally better thermodynamic stability, but overall, these differences were negligible. The pKa of the conjugate acid of these glycosyloxyamines was also determined to provide insight into the mechanism of hydrolysis. By considering this data, along with the observation that the rate of hydrolysis of these glycoconjugates increases with increasing buffer concentration, it was proposed that the hydrolysis of the oxyamines occurs via general acid catalysis at pH 4-6. A novel dithiol functionalised oxyamine linker was also designed and synthesised for the multivalent display of glycans on gold nanoparticles. With the successful attachment of this thiol linker to GlcNAc, the monomer unit of chitin, this work has paved the way for the future syntheses of chitin-functionalised gold nanoparticles. Such chitinfunctionalised AuNPs can be used to assess chitin’s ability to invoke the asthma allergic immune response, thereby bringing the possibility of an anti-asthma vaccine a step closer to fruition.</p>

Novel Aminoguanidine Hydrazone Analogues: From Potential Antimicrobial Agents to Potent Cholinesterase Inhibitors

A series of thirty-one hydrazones of aminoguanidine, nitroaminoguanidine, 1,3-diaminoguanidine, and (thio)semicarbazide were prepared from various aldehydes, mainly chlorobenzaldehydes, halogenated salicylaldehydes, 5-nitrofurfural, and isatin (yields of 50–99%). They were characterized by spectral methods. Primarily, they were designed and evaluated as potential broad-spectrum antimicrobial agents. The compounds were effective against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus with minimum inhibitory concentrations (MIC) from 7.8 µM, as well as Gram-negative strains with higher MIC. Antifungal evaluation against yeasts and Trichophyton mentagrophytes found MIC from 62.5 µM. We also evaluated inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The compounds inhibited both enzymes with IC50 values of 17.95–54.93 µM for AChE and ≥1.69 µM for BuChE. Based on the substitution, it is possible to modify selectivity for a particular cholinesterase as we obtained selective inhibitors of either AChE or BuChE, as well as balanced inhibitors. The compounds act via mixed-type inhibition. Their interactions with enzymes were studied by molecular docking. Cytotoxicity was assessed in HepG2 cells. The hydrazones differ in their toxicity (IC50 from 5.27 to >500 µM). Some of the derivatives represent promising hits for further development. Based on the substitution pattern, it is possible to modulate bioactivity to the desired one.

Covalent Functionalization of Nickel Phosphide Nanocrystals with Aryl-Diazonium Salts

Covalent functionalization of Ni2P nanocrystals was demonstrated using aryl-diazonium salts. Spontaneous adsorption of aryl functional groups was observed, with surface coverages ranging from 20-96% depending on the native reactivity of the salt as determined by the aryl substitution pattern. Increased coverage was possible for low reactivity species using a sacrificial reductant. Functionalization was confirmed using thermogravimetric analysis, FTIR and X-ray photoelectron spectroscopy. The structure and energetics of this nanocrystal electrocatalyst system, as a function of ligand coverage, was explored with density functional theory calculations. The Hammett parameter of the surface functional group was found to linearly correlate with the change in Ni and P core-electron binding energies and the nanocrystal’s experimentally and computationally determined work-function. The electrocatalytic activity and stability of the functionalized nanocrystals for hydrogen evolution were also improved when compared to the unfunctionalized material, but a simple trend based on electrostatics was not evident. Density functional theory was used to understand this discrepancy, revealing that H adsorption energies on the covalently functionalized Ni2P also do not follow the electrostatic trend and are predictive descriptors of the experimental results.

Substituent effect on iron phthalocyanines as cyclohexene oxidation catalysts

Two iron phthalocyanines peripherally octasubstituted either with electron-withdrawing isobutylsulfonyl moities or electron-donating isobutoxy moieties were designed to investigate the effect of the substitution pattern on their oxidation catalytic activity, and were then tested in oxidation of cyclohexene as a reaction model. For both catalysts, the main product of oxidation was 2-cyclohexen-1-ol which is an allylic oxidation product. The electron-withdrawing isobutylsulfonyl substituted iron phthalocyanine 1exhibited better catalytic activities than the electron-donating isobutoxy substituted iron phthalocyanine 2.