The iron(III)-catalyzed synthesis of indolizines from commercially available alkyne, pyridine, and diazo precursors is reported. This mild, expedient method is tolerant of various solvents and proceeds with as little as 0.25 mol % [Fe(TPP)Cl]. Significantly, this multicomponent reaction is compatible with electrophilic alkynes; control experiments demonstrate the importance of the catalyst in promoting pyridinium ylide formation over background reactivity.

A silicon mediated intramolecular 1,4-conjugate addition of a homoallylic carbon nucleophile leading to cyclopropanation is reported. Specifically, treatment of 6-trimethylsilyl-5,6-dihydroazocinones with fluoride gives 4-azabicyclo(5.1.0)octenones, presenting an unusual extension to the repertoire of silyl group reactivity.

Cycloaddition reactions between pyridinium ylides and 3-alkenyl oxindoles that proceed in high yield and with very good regio- and diastereoselectivity are reported. The resulting cycloadducts have the same stereochemistry of biologically active oxindole alkaloids, such as strychnofoline.

Protein arginine N-methyltransferases (PRMTs) selectively replace N–H for N–CH3 at substrate protein guanidines, a post-translational modification important for a range of biological processes, such as epigenetic regulation, signal transduction and cancer progression. Selective chemical probes are required to establish the dynamic function of individual PRMTs. Herein, model inhibitors designed to occupy PRMT binding sites for an arginine substrate and S-adenosylmethionine (AdoMet) co-factor are described. Expedient access to such compounds by modular synthesis is detailed. Remarkably, biological evaluation revealed some compounds to be potent inhibitors of PRMT1, but inactive against CARM1. Docking studies show how prototype compounds may occupy the binding sites for a co-factor and arginine substrate. Overlay of PRMT1 and CARM1 binding sites suggest a difference in a single amino acid that may be responsible for the observed selectivity.

Chemically modified cellular co-factors that provide function, such as immobilization or incorporation of fluorescent dyes, are valuable probes of biological activity. A convenient route to obtain S-adenosyl methionine (AdoMet) analogues modified at N-6 adenosine to feature a linker terminating in azide functionality is described herein. Subsequent decoration of such AdoMet analogues with guanidinium terminated linkers leads to novel potential bisubstrate inhibitors for protein arginine methyltransferases, PRMTs.

Prototype inhibitors of protein arginine methyltransferases (PRMTs) have been constructed by attaching guanidine functionality via a variable linker to non-reactive amine analogues of the cellular co-factor (S)-adenosyl methionine (AdoMet). Potent inhibition of PRMT1 (IC50 of ∼3–6 μM) combined with weak inhibition of the lysine methyltransferase SET7 (∼50% of activity at 100 μM) was observed for two such compounds.Non-reactive amine analogues of (S)-adenosyl methionine (AdoMet) bearing guanidine functionality were found to be potent inhibitors of PRMT1 (IC50 of ∼3–6 μM) but weak inhibitors of the lysine methyltransferase SET7 (IC50 >100 μM).

A novel octavalent, resorcin[4]arene derived, cross-linker designed to overcome some of the limitations of commercially available reagents is significantly more efficient for covalent stabilisation of protein–protein interactions.

As a result of a chemical genetic screen for modulators of metalloprotease activity, we report that 2-mercaptopyridine-N-oxide induces a conspicuous undulating notochord defect in zebrafish embryos, a phenocopy of the leviathan mutant. The location of the chemically-induced wavy notochord correlated with the timing of application, thus defining a narrow chemical sensitivity window during segmentation stages. Microscopic observations revealed that notochord undulations appeared during the phase of notochord cell vacuolation and notochord elongation. Notochord cells become swollen as well as disorganized, while electron microscopy revealed disrupted organization of collagen fibrils in the surrounding sheath. We demonstrate by assay in zebrafish extracts that 2-mercaptopyridine-N-oxide inhibits lysyl oxidase. Thus, we provide insight into notochord morphogenesis and reveal novel compounds for lysyl oxidase inhibition. Taken together, these data underline the utility of small molecules for elucidating the dynamic mechanisms of early morphogenesis and provide a potential explanation for the recently established role of copper in zebrafish notochord formation.

Nicotinic acid adenine dinucleotide phosphate (NAADP, 1) is the most potent intracellular Ca2+ mobilizing agent in important mammalian cells and tissues, yet the identity of the NAADP receptor is elusive. Significantly, the coenzyme NADP is completely inactive in this respect. Current studies are restricted by the paucity of any chemical probes beyond NAADP itself, and importantly, none is cell permeant. We report simple nicotinic acid-derived pyridinium analogs as low molecular weight compounds that (1) inhibit Ca2+ release via the NAADP receptor (IC50 ∼15μM – 1 mM), (2) compete with NAADP binding, (3) cross the cell membrane of sea urchin eggs to inhibit NAADP-evoked Ca2+ release, and (4) selectively ablate NAADP-dependent Ca2+ oscillations induced by the external gastric peptide hormone agonist cholecystokinin (CCK) in murine pancreatic acinar cells.

A novel octavalent, resorcin[4]arene derived, cross-linker designed to overcome some of the limitations of commercially available reagents is significantly more efficient for covalent stabilisation of protein–protein interactions.

Protein arginine N-methyltransferases (PRMTs) selectively replace N–H for N–CH3 at substrate protein guanidines, a post-translational modification important for a range of biological processes, such as epigenetic regulation, signal transduction and cancer progression. Selective chemical probes are required to establish the dynamic function of individual PRMTs. Herein, model inhibitors designed to occupy PRMT binding sites for an arginine substrate and S-adenosylmethionine (AdoMet) co-factor are described. Expedient access to such compounds by modular synthesis is detailed. Remarkably, biological evaluation revealed some compounds to be potent inhibitors of PRMT1, but inactive against CARM1. Docking studies show how prototype compounds may occupy the binding sites for a co-factor and arginine substrate. Overlay of PRMT1 and CARM1 binding sites suggest a difference in a single amino acid that may be responsible for the observed selectivity.

A silicon mediated intramolecular 1,4-conjugate addition of a homoallylic carbon nucleophile leading to cyclopropanation is reported. Specifically, treatment of 6-trimethylsilyl-5,6-dihydroazocinones with fluoride gives 4-azabicyclo(5.1.0)octenones, presenting an unusual extension to the repertoire of silyl group reactivity.

Cycloaddition reactions between pyridinium ylides and 3-alkenyl oxindoles that proceed in high yield and with very good regio- and diastereoselectivity are reported. The resulting cycloadducts have the same stereochemistry of biologically active oxindole alkaloids, such as strychnofoline.