Synthesis and Characterisation of Substrate-Based Peptides as Inhibitors of Histone Demethylase KDM4C.

The design and synthesis of modified pentapeptides based on a truncated version of the substrate for KDM4C, a histone lysine demethylase (KDM), and investigation of their inhibitory activity at KDM4C is reported. By modifying the lysine residue corresponding to lysine 9 at histone 3 (H3K9), three different series of peptides were designed and synthesized. One series contained N-acylated H3K9 and two series introduced triazoles in this position via click chemistry to enable facile variation of headgroups.

Differential role of AMPA receptors in mouse tests of antidepressant and anxiolytic action.

Depression and anxiety often co-occur, and conventional monoamine-facilitating antidepressants show efficacy against symptoms in both disorders. Rodent studies indicate that antidepressant effects of monoamine-based antidepressants involve increased α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid glutamate receptor (AMPAR) neurotransmission, and positive allosteric modulators (PAMs) at AMPARs produced antidepressant-like effects in rodents. While this suggests that increased AMPAR-mediated neurotransmission is beneficial in depression management, preclinical studies addressing AMPARs in relation to anxiety have given ambiguous results with both anxiolytic-like and anxiogenic-like effects observed after AMPAR blockade.

Does increasing the ratio of AMPA-to-NMDA receptor mediated neurotransmission engender antidepressant action? Studies in the mouse forced swim and tail suspension tests.

Monoamine-based antidepressant drugs increase α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function and decrease N-methyl-d-aspartate receptor (NMDAR) function. The NMDAR antagonist ketamine shows potent antidepressant action in humans and the antidepressant-like effects of ketamine and monoamine-based antidepressants in rodents depend on increased AMPAR throughput. Further, the antidepressant-like effects of monoamine-based antidepressants are enhanced by AMPAR potentiation and by NMDAR antagonism.

Development of 2'-substituted (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine analogues as potent N-methyl-d-aspartic acid receptor agonists.

A series of 2'-substituted analogues of the selective NMDA receptor ligand (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine ((S)-CCG-IV) have been designed, synthesized, and pharmacologically characterized. The design was based on a docking study hypothesizing that substituents in the 2'-position would protrude into a region where differences among the NMDA receptor GluN2 subunits exist. Various synthetic routes were explored, and two different routes provided a series of alkyl-substituted analogues.

Synthesis and application of a new fluorous-tagged ammonia equivalent.

A novel fluorous-tagged ammonia equivalent has been developed. It is based on a nitrogen-oxygen bond, which can be cleaved in a traceless manner by a molybdenum complex or samarium diiodide. The application in the synthesis of ureas, amides, sulfonamides, and carbamates is described.

Aryl-Csp(3) bond rotation barriers of 2-aryl perhydropyrrolo[3,4-c]pyrrole-1,3-diones.

The static and dynamic features of 2-aryl perhydropyrrolo[3,4-c]pyrrole-1,3-diones bearing N-acyl substituents have been assessed with the aid of crystal structures and VT NMR spectra. Rotation barriers for the aryl-Csp(3) bonds in these molecules show surprising variation. Amide-substituted derivatives and fused piperazinediones (six-membered fusion) exhibit very substantial barriers of 14-15 kcal/mol.

Fluorous parallel synthesis of a piperazinedione-fused tricyclic compound library.

A fluorous-linker-assisted solution-phase protocol has been developed and applied to parallel synthesis of a piperazinedione-fused tricyclic compound library. The one-pot [3 + 2] cycloaddition of fluorous amino esters, aldehydes, and maleimides afforded bicyclic proline derivatives. The intermediates were subjected to N-acylation with chloroacetyl chloride, followed by displacement reactions with amines.

Nanoporous magnesium aluminometasilicate tablets for precise, controlled, and continuous dosing of chemical reagents and catalysts: applications in parallel solution-phase synthesis.

Mechanically robust tablets of nanoporous magnesium aluminometasilicate with high surface area and porosity can be loaded with a variety of organic and inorganic reagents and catalysts. The scope of this novel dosing methodology is demonstrated through the evaluation of 14 diverse organic reactions, including Mitsunobu, Suzuki, and bromination reactions.