Thermal Rearrangement of the S-N Bond of Thiooxime Esters.

The labile O-N bond of oxime esters has enabled versatile access to many heterocyclic scaffolds. Alternatively, the analogous chemistry for thiooxime esters, which contain an S-N bond, has not been explored. Herein, we interrogate the reactivity of thiooxime esters and identify a homolytic fragmentation and rearrangement mechanism. This work provides the first exploration of the reactivity of this S-N functional group.

Thioimidates provide general access to thioamide, amidine, and imidazolone peptide-bond isosteres.

Thioamides, amidines, and heterocycles are three classes of modifications that can act as peptide-bond isosteres to alter the peptide backbone. Thioimidate protecting groups can address many of the problematic synthetic issues surrounding installation of these groups. Historically, amidines have received little attention in peptides due to limitations in methods to access them. The first robust and general procedure for the introduction of amidines into peptide backbones exploits the utility of thioimidate protecting groups as a means to side-step reactivity that ultimately renders existing methods unsuitable for the installation of amidines along the main-chain of peptides. Further, amidines formed on-resin can be reacted to form (4H)-imidazolone heteorcycles which have recently been shown to act as cis-amide isosteres. General methods for heterocyclic installation capable of geometrically restricting peptide conformation are also under-developed. This work is significant because it describes a generally applicable and divergent approach to access unexplored peptide designs and architectures.

General Installation of (4H)-Imidazolone cis-Amide Bioisosteres Along the Peptide Backbone.

Imidazolones represent an important class of heterocycles present in a wide range of pharmaceuticals, metabolites, and bioactive natural products and serve as the active chromophore in green fluorescent protein. Recently, imidazolones have received attention for their ability to act as a nonaromatic amide bond bioisotere which improves pharmacological properties. Herein, we present a tandem amidine installation and cyclization with an adjacent ester to yield (4H)-imidazolone products. Using amino acid building blocks, we can access the first examples of α-chiral imidazolones that have been previously inaccessible. Additionally, our method is amenable to on-resin installation which can be seamlessly integrated into existing solid-phase peptide synthesis protocols. Finally, we show that peptide imidazolones are potent cis-amide bond surrogates that preorganize linear peptides for head-to-tail macrocyclization. This work represents the first general approach to the backbone and side-chain insertion of imidazolone bioisosteres at various positions in linear and cyclic peptides.

Finding the best location: Improving the anti-amyloid ability of ruthenium(III) complexes with pyridine ligands.

Alzheimer's disease (AD) is a devastating neurological disorder where one of the primary pathological hallmarks are aggregate deposits of the peptide amyloid-beta (Aß). Although the Food and Drug Administration (FDA) has recently approved therapeutics that specifically target Aß, resulting in the removal of these deposits, the associated costs of such treatments create a need for effective, yet cheaper, alternatives. Metal-based compounds are propitious therapeutic candidates as they exploit the metal-binding properties of Aß, forming stable interactions with the peptide, thereby limiting its aggregation and toxicity. Previously, ruthenium-based complexes have shown a strong ability to modulate the aggregation and cytotoxicity of Aß, where the incorporation of a primary amine on the coordinated heterocyclic ligand gave the greatest activity. To determine the importance of the location of the primary amine on the pyridine ligand, thereby establishing structure-activity relationships (SAR), four complexes (RuP1-4) were prepared and evaluated for their ability to coordinate and subsequently modulate the aggregation and cytotoxicity of Aß. Coordination to Aß was determined using three complementary spectroscopic methods: UV-Vis, 1H NMR, and circular dichroism (CD). Similarly, the impact of the complexes on Aß aggregation was evaluated using three sequential methods of turbidity, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Overall, the location of the primary amine on the pyridine ligand did affect the resultant anti-Aß performance, with the 2-aminopyridine complex (RuP2) being the most active. This SAR will provide another guiding principle in the design of future metal-based anti-Aß complexes.

Anomeric Answer to Sulfenamide Stability and α-Nucleophilicity.

The S-N bond remains a synthetically challenging motif for organic chemists to access. The problem arises from instability in many sulfenamide derivatives, which has led to fewer S-N bond surrogate molecules compared to their hydroxylamine (NH2OH) and hydrazine (NH2NH2) analogues. In turn, sulfenamides have often been omitted in studies regarding α-nucleophilicity. Herein, we provide factors responsible for the stability of the sulfenamide motif and provide new insights on the nucleophilic properties of sulfenamides as they relate to the α-effect.

Attached Nitrogen Test by 13C-14N Solid-State NMR Spectroscopy for the Structure Determination of Heterocyclic Isomers.

Differentiation of heterocyclic isomers by solution 1H, 13C, and 15N NMR spectroscopy is often challenging due to similarities in their spectroscopic signatures. Here, 13C{14N} solid-state NMR spectroscopy experiments are shown to operate as an "attached nitrogen test", where heterocyclic isomers are easy to distinguish based on one-dimensional nitrogen-filtered 13C solid-state NMR. We anticipate that these NMR experiments will facilitate the assignment of heterocyclic isomers during synthesis and natural product discovery.

Importance of Hydrogen Bonding: Structure-Activity Relationships of Ruthenium(III) Complexes with Pyridine-Based Ligands for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is the most common form of dementia, where one of the pathological hallmarks of AD is extracellular protein deposits, the primary component of which is the peptide amyloid-ß (Aß). Recently, the soluble form of Aß has been recognized as the primary neurotoxic species, making it an important target for therapeutic development. Metal-based drugs are promising candidates to target Aß, as the interactions with the peptide can be tuned by ligand design. In the current study, 11 ruthenium complexes containing pyridine-based ligands were prepared, where the functional groups at the para position on the coordinated pyridine ligand were varied to determine structure-activity relationships. Overall, the complexes with terminal primary amines had the greatest impact on modulating the aggregation of Aß and diminishing its cytotoxicity. These results identify the importance of specific intermolecular interactions and are critical in the advancement of metal-based drugs for AD therapy.