Optical control of adenosine A3 receptor function in psoriasis.

Psoriasis is a chronic and relapsing inflammatory skin disease lacking a cure that affects approximately 2% of the population. Defective keratinocyte proliferation and differentiation, and aberrant immune responses are major factors in its pathogenesis. Available treatments for moderate to severe psoriasis are directed to immune system causing systemic immunosuppression over time, and thus concomitant serious side effects (i.e. infections and cancer) may appear. In recent years, the Gi protein-coupled A3 receptor (A3R) for adenosine has been suggested as a novel and very promising therapeutic target for psoriasis. Accordingly, selective, and high affinity A3R agonists are known to induce robust anti-inflammatory effects in animal models of autoimmune inflammatory diseases. Here, we demonstrated the efficacy of a selective A3R agonist, namely MRS5698, in preventing the psoriatic-like phenotype in the IL-23 mouse model of psoriasis. Subsequently, we photocaged this molecule with a coumarin moiety to yield the first photosensitive A3R agonist, MRS7344, which in photopharmacological experiments prevented the psoriatic-like phenotype in the IL-23 animal model. Thus, we have demonstrated the feasibility of using a non-invasive, site-specific, light-directed approach to psoriasis treatment.

Synthesis of C-linked α-Gal and α-GalNAc-1'-hydroxyalkanes by way of C2 functionality transfer.

Inspired by reports of water sculpted Tn antigen (α-GalNAc-O-Ser/Thr) epitopes and our interest in producing metabolically more stable C-linked analogs of Tn, we explored the utility of C2 functionality on α-Gal-C-alkenes to deliver hydroxyl to the pendant alkenyl chain. Toward this end, a cyclic carbonate approach gave rise to a single C-linked α-Gal-1'(S)-hydroxyethane in 3 steps, and use of a 2-(hydroxyimino)galactoside cyclization transferred an oxygen to a pendant cis-substituted C-linked alkene affording the R-configuration at the newly formed stereocenter (7:1 dr). Reduction and acetylation of the resultant isoxazoline demonstrated this approach as a viable route to C-linked α-GalNAc-1'-hydroxyalkanes.

Synthesis of ß-C-GlcNAc Ser from ß-C-Glc Ser.

The glycosylation of proteins, specifically installation of O-GlcNAc on Ser/Thr residues, is a dynamic control element for transcription repression, protein degradation, and nutrient sensing. To provide homogeneous and stable structures with this motif, the synthesis of a C-linked mimic, C-GlcNAc Ser, has been prepared from the C-Glc Ser by a double inversion strategy using azide to insert the C-2 nitrogen functionality. The C-Glc Ser was available by a ring-closing metathesis and hydroalkoxylation route.

Stereoselective Synthesis of (4S,5S)-5-Vinyloxazolidin-2-one-4-carboxylate as a ß-Vinylserine Synthetic Equivalent by Vinyl Grignard Addition to an N-Tosyl Version of Garner's Aldehyde.

A highly efficient synthesis of a ß-vinylserine synthetic equivalent is reported that exploits the stereodirecting effect of the N-toluenesulfonamide in an anti-diastereoselective (8.5:1) vinyl Grignard addition to an analogue of Garner's aldehyde. Both aryl and alkyl Grignards are shown to give increased anti-selectivity compared with N-Boc Garner's aldehyde.

Remote control of movement disorders using a photoactive adenosine A2A receptor antagonist.

G protein-coupled adenosine receptors are promising therapeutic targets for a wide range of neuropathological conditions, including Parkinson's disease (PD). However, the ubiquity of adenosine receptors and the ultimate lack of selectivity of certain adenosine-based drugs have frequently diminished their therapeutic use. Photopharmacology is a novel approach that allows the spatiotemporal control of receptor function, thus circumventing some of these limitations. Here, we aimed to develop a light-sensitive caged adenosine A2A receptor (A2AR) antagonist to photocontrol movement disorders. We synthesized MRS7145 by blocking with coumarin the 5-amino position of the selective A2AR antagonist SCH442416, which could be photoreleased upon violet light illumination (405 nm). First, the light-dependent pharmacological profile of MRS7145 was determined in A2AR-expressing cells. Upon photoactivation, MRS7145 precluded A2AR ligand binding and agonist-induced cAMP accumulation. Next, the ability of MRS7145 to block A2AR in a light-dependent manner was assessed in vivo. To this end, A2AR antagonist-mediated locomotor activity potentiation was evaluated in brain (striatum) fiber-optic implanted mice. Upon irradiation (405 nm) of the dorsal striatum, MRS7145 induced significant hyperlocomotion and counteracted haloperidol-induced catalepsy and pilocarpine-induced tremor. Finally, its efficacy in reversing motor impairment was evaluated in a PD animal model, namely the hemiparkinsonian 6-hydroxydopamine (6-OHDA)-lesioned mouse. Photo-activated MRS7145 was able to potentiate the number of contralateral rotations induced by L-3,4-dihydroxyphenylalanine (l-DOPA). Overall, MRS7145 is a new light-operated A2AR antagonist with potential utility to manage movement disorders, including PD.

Stereoselective synthesis of alpha-C-glucosyl serine and alanine via a cross-metathesis/cyclization strategy.

C-Glycosyl amino acids represent stable mimics of monomeric units within natural O-linked glycoproteins. Olefin cross-metathesis has been used to provide alkene precursors for a mercury(II)-mediated cyclization, yielding alpha-C-glucosyl serine and alanine.

Synthesis of C-linked glycopyranosyl serines via a chiral glycine enolate equivalent.

[formula: see text] The stereoselective preparation of C-linked D-gluco- and D-galactopyranosyl L-serines in their alpha and beta forms is herein reported. The syntheses require the conversion of the allyl C-glycopyranosides into their iodoethyl derivatives, which then undergo substitution with the Williams' chiral glycine enolate equivalent. Deprotection and acetylation affords Boc-protected amino acids for peptide synthesis.

Highly stereoselective synthesis of C-vinyl pyranosides via a Pd0-mediated cycloetherification of 1-acetoxy-2,3-dideoxy-oct-2-enitols.

Oct-2-enitols undergo a Pd(0)-mediated cyclization to produce C-vinyl α-gluco- and α-galactopyranosides, and C-vinyl ß-mannopyranoside in good yield and with high stereoselectivity. While substrate control demonstrates a clear stereochemical preference during cyclization, the α- and ß-epimeric ratios are enhanced by double diastereoselection using the (S,S) or (R,R)-DACH ligands.

Syntheses of alpha- and beta-C-glucopyranosyl serines from a common intermediate.

A versatile synthesis leading to either C-linked alpha- or beta-glucopyranosyl serines is presented from a common, advanced synthetic intermediate. Cyclization of the penultimate carbinol onto the alkene and methanolysis of the lactone yields selectively the alpha-linkage. A transposition of these last steps leads to the beta-linked isomer selectively.