Simon C. Hirst

Conjugate addition of imidazolines: a protocol for 1,4-addition to enones and other acceptors

Abstract The enaminoester 1-benzyl-2-ethoxycarbonylmethyleneimidazolidine reacts with α,β-enones and other Michael acceptors to give 1,4-adducts; removal of the ethoxycarbonyl group completes overall conjugate addition of the imidazoline α-anion (which itself adds 1,2 to enones), and hydrolysis affords carboxylic acids.

Annulation of imidazolines with bis-electrophiles: Synthesis of imidazo[1,2-a]pyridines

Abstract 1-Benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole undergoes annulation with a variety of 1,3-bis-electrophiles (α,β-unsaturated acid derivatives, β-ketoesters, α,β-unsaturated aldehydes) to form imidazo[1,2-a]pyridines.

Alkylation of an imidazolidine enaminoester: A new sequence for the Cα-alkylation of 4,5-dihydroimidazoles

Abstract 1-Benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole undergoes preferred C-alkylation with halogenoalkanes, dihalogenoalkanes and epoxides; subsequent removal of of the ethoxycarbonyl group provides a new route to 2-alkyl-4,5-dihydroimidazoles. 1,3-Dihalogenoalkanes afford imidazo[1,2-a]pyridines via C,N-dialkylation.

Nucleophilic attack on 2-(4-oxoalkyl)-2-imidazolines: a novel route to tetrahydropyridines and piperidines

Abstract 2-(1-Ethoxycarbonyl-4-oxoalkyl)-2-imidazolines add organometallic carbon nucleophiles to produce new lactones, whereas hydrogenation affords 1,4,5,6-tetrahydropyridines and piperidines via a novel reductive cyclisation-cleavage pathway.

Pharmacological chaperones increase the cell-surface expression of intracellularly retained mutants of the melanocortin 4 receptor with unique rescuing efficacy profiles.

Mutated versions of membrane proteins often fail to express at the plasma membrane, but instead are trapped in the secretory pathway, resulting in disease. The retention of these mutant proteins is thought to result from local misfolding, which prevents export from the ER (endoplasmic reticulum), targeting the receptor for degradation via the ER-associated quality control system. The rhodopsin-like G-protein-coupled MC4R (melanocortin 4 receptor) is an example of such a membrane protein. Over 100 natural MC4R mutations are linked with an obese phenotype and to date represent the most common monogenic cause of severe early-onset obesity. More than 80% of these mutations result in a substantial proportion of MC4R being retained intracellularly. If these receptors were expressed at the plasma membrane, many could be functional, as mutations often occur in regions distinct from those associated with ligand or G-protein binding. Our aim is to show proof of concept that selective compounds can rescue the function of MC4R mutants by increasing their cell-surface expression, and further to this, examine whether the rescue profile differs between mutants. Whole-cell ELISA and 96-well fluorescence-based assays with N-terminally HA (haemagglutinin)-tagged and C-terminally mCherry-tagged mutant MC4Rs were used to screen a number of novel MC4R-selective compounds. A total of four related compounds increased the cell-surface expression of wild-type and three intracellularly retained mutant MC4Rs, thus acting as pharmacological chaperones. There appears to be a unique rescue efficacy profile for each compound that does not correlate with potency, suggesting distinct receptor conformations induced by the different mutations. A degree of functionality of V50M and S58C was also rescued following relocation to the cell surface.

Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor.

Serum retinol binding protein (sRBP) is released from the liver as a complex with transthyretin (TTR), a process under the control of dietary retinol. Elevated levels of sRBP may be involved in inhibiting cellular responses to insulin and in generating first insulin resistance and then type 2 diabetes, offering a new target for therapeutic attack for these conditions. A series of retinoid analogues were synthesized and examined for their binding to sRBP and their ability to disrupt the sRBP-TTR and sRBP-sRBP receptor interactions. A number inhibit the sRBP-TTR and sRBP-sRBP receptor interactions as well as or better than Fenretinide (FEN), presenting a potential novel dual mechanism of action and perhaps offering a new therapeutic intervention against type 2 diabetes and its development. Shortening the chain length of the FEN derivative substantially abolished binding to sRBP, indicating that the strength of the interaction lies in the polyene chain region. Differences in potency against the sRBP-TTR and sRBP-sRBP receptor interactions suggest variant effects of the compounds on the two loops of sRBP guarding the entrance of the binding pocket that are responsible for these two protein-protein interactions.

Perkin communications. A new sequence for the Cα-alkylation of 4,5-dihydroimidazoles

The C-alkylation of 1-benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole with halogeno-and dihalogeno-alkanes is described; subsequent removal of the ethoxycarbonyl group provides a new route to 2-alkyl-4,5-dihydroimidazoles. 1,3-Dihalogenoalkanes afford imidazo[1,2-a] pyridines.