2-aminophenols containing electron-withdrawing groups from N-aryl hydroxylamines

Reaction of substituted N-aryl hydroxylamines with methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride under basic conditions leads to the rearranged 2-aminophenols (45-94%). The overall reaction sequence can be performed using polymer-supported sulfonyl chloride resin allowing for the effective conversion of N-aryl hydroxylamines to the 2-aminophenols without the need for chromatography

Baeyer–Villiger oxidation under Payne epoxidation conditions

A novel method for the Baeyer–Villiger oxidation of ketones has been developed and optimized. The transformation involves a transition metal-free activation of hydrogen peroxide under Payne epoxidation conditions. Reaction of a ketone with hydrogen peroxide in the presence of a nitrile under mildly basic reaction conditions leads to the corresponding ester. The transformation has been successfully applied to a range of ketones in moderate to excellent yields (30–91 and good to excellent regioselectivities (7:1 to 20:1)

A cluster of palmitoylated cysteines are essential for aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis

Autosomal-dominant adult-onset neuronal cero id lipofuscinosis (ANCL) is caused by mutation of the DNAJC5 gene encoding cysteine string protein alpha (CSP α ). The disease- causing mutations, which result in substituti on of leucine-115 with an arginine (L115R) or deletion of the neig hbouring leucine-116 ( Δ L116) in the cysteine-string domain cause CSP α to form high molecular weight SDS-resistant aggregates, which are also present in post- mortem brain tissue from patients. Formation and stability of these mutant aggregates is linked to palmitoylation of the cysteine-str ing domain, however the regions of the mutant proteins that drive aggregatio n have not been determined. The importance of specific residues in the cysteine-string domain was in vestigated, revealing that a central core of palmitoylated cysteines is essential for aggregation of ANCL CSP α mutants. Interestingly, palmitoylated monomers of ANCL CSP α mutants were shown to be short-lived compared with wild-type CSP α, suggesting that the mutants eith er have a faster rate of depalmitoylation or that they are consumed in a time-dependent manner into high molecular weight aggregates. These findings provide new insight into the features of CSP α that promote aggregation in the presence of L115R/ Δ L116 mutations and reveal a change in the lifetime of palmitoyla ted monomers of the mutant proteins

Molecular basis of fatty acid selectivity in the zDHHC family of S-acyltransferases revealed by click chemistry

S-Acylation is a major post-translational modification, catalysed by the zDHHC enzyme family. S-acylated proteins can be modified by different fatty acids; however, very little is known about how zDHHC enzymes contribute to acyl chain heterogeneity. Here, we employed fatty acid azide/alkyne labelling of mammalian cells, showing their transformation into acyl-CoAs and subsequent click chemistry-based detection, to demonstrate that zDHHC enzymes have marked differences in their fatty acid selectivity. This was apparent even for highly related enzymes such as zDHHC3 and zDHHC7, which displayed a marked difference in ability to use C18:0 acyl CoA as a substrate. Furthermore, we identified Isoleucine-182 in the third transmembrane domain of zDHHC3 as a key determinant limiting the use of longer chain acyl-CoAs by this enzyme. This is the first study to uncover differences in the fatty acid selectivity profiles of cellular zDHHC enzymes and to map molecular determinants governing this selectivit

Tracking intracellular uptake and localisation of alkyne tagged fatty acids using Raman spectroscopy

Intracellular uptake, distribution and metabolism of lipids is a tightly regulated characteristic in healthy cells. An analytical technique capable of understanding these characteristics with a high level of species specificity in a minimally invasive manner is highly desirable in order to understand better how these become disrupted during disease. In this study, the uptake and distribution of three different alkyne tagged fatty acids in single cells was monitored and compared, highlighting the ability of Raman spectroscopy combined with alkyne tags for better understanding of the fine details with regards to uptake, distribution and metabolism of very chemically specific lipid species. This indicates the promise of using Raman spectroscopy directly with alkyne tagged lipids for cellular studies as opposed to subsequently clicking of a fluorophore onto the alkyne for fluorescence imaging

Preparation of the MacMillan Imidazolidinones

A general method for the preparation of the MacMillan imidazolidinones is described. Treatment of an α-amino amide with a carbonyl compound in refluxing chloroform in the presence of Yb(OTf)3 (1 mol%) provides convenient access to the corresponding imidazolidinone

The endoplasmic reticulum-localized enzyme zDHHC6 mediates S-acylation of short transmembrane constructs from multiple type I and II membrane proteins

In this study, we investigated the S-acylation of two host cell proteins important for viral infection: TMPRSS2 (transmembrane serine protease 2), which cleaves SARS-CoV-2 spike to facilitate viral entry, and BST2 (Bone marrow stromal antigen 2), a general viral restriction factor. We found that both proteins were S-acylated by zDHHC6, an S-acyltransferase enzyme localized at the endoplasmic reticulum (ER), in co-expression experiments. Mutagenic analysis revealed that zDHHC6 modifies a single cysteine in each protein, which are in proximity to the transmembrane domains (TMDs). For TMPRSS2, the modified cysteine is positioned two residues into the TMD, whereas the modified cysteine in BST2 has a cytosolic location two amino acids upstream of the TMD. Cysteine swapping revealed that repositioning the target cysteine of TMPRSS2 further into the TMD substantially reduced S-acylation by zDHHC6. Interestingly, zDHHC6 efficiently S-acylated truncated forms of these proteins that contained only the TMDs and short juxtamembrane regions. The ability of zDHHC6 to modify short TMD sequences was also seen for the transferrin receptor (another type II membrane protein) and for five different type I membrane protein constructs, including CD4. Collectively, the results of this study show that zDHHC6 can modify diverse membrane proteins (Type I and II) and requires only the presence of the TMD and target cysteine for efficient S-acylation. Thus, zDHHC6 may be a broad specificity S-acyltransferase specialized for the modification of a diverse set of transmembrane proteins at the endoplasmic reticulum

An azide and acetylene free synthesis of 1-substituted 1,2,3-triazoles

This paper details a simple and efficient 3-component synthesis of 1-substituted 1,2,3-triazoles using a primary amine, 2,2-dimethoxyacetaldehyde and tosylhydrazide. The reaction proceeds in good to excel- lent yields using either aliphatic or aromatic amine substrates and is tolerant of a wide range of functional groups including electron-rich and deficient aryl groups, terminal alkynes, ketones and highly sterically encumbered amine

Investigating the effects of the core nitrogen atom configuration on the thermodynamic solubility of 6,​5-​bicyclic heterocycles

Physicochemical properties, such as solubility, are important when prioritising compounds for progression on a drug discovery project. There is limited literature around the systematic effects of core changes on thermodynamic solubility. This work details the synthesis of nitrogen containing 6,5-bicyclic heterocyclic cores which are common scaffolds in medicinal chemistry and the analysis of their physicochemical properties, particularly, thermodynamic solubility. Crystalline solids were obtained where possible to enable a robust comparison of the thermodynamic solubility. Other parameters such as pKa, melting point and lipophilicity were also measured to determine the key factors affecting the observed solubility

bbSelect : an open-source tool for performing a 3D pharmacophore-driven diverse selection of R-groups

The design of compounds during hit-to-lead often seeks to explore a vector from a core scaffold to form additional interactions with the target protein. A rational approach to this is to probe the region of a protein accessed by a vector with a systematic placement of pharmacophore features in 3D, particularly when bound structures are not available. Herein, we present bbSelect, an open-source tool built to map the placements of pharmacophore features in 3D Euclidean space from a library of R-groups, employing partitioning to drive a diverse and systematic selection to a user-defined size. An evaluation of bbSelect against established methods exemplified the superiority of bbSelect in its ability to perform diverse selections, achieving high levels of pharmacophore feature placement coverage with selection sizes of a fraction of the total set and without the introduction of excess complexity. bbSelect also reports visualizations and rationale to enable users to understand and interrogate results. This provides a tool for the drug discovery community to guide their hit-to-lead activities