ABSTRACT
Kinetin (N6-furfuryladenine), a plant growth substance of the cytokinin family, has been shown to modulate aging and various age-related conditions in animal models. Here we report the synthesis of kinetin isosteres with the purine ring replaced by other bicyclic heterocycles, and the biological evaluation of their activity in several in vitro models related to neurodegenerative diseases. Our findings indicate that kinetin isosteres protect FriedreichÌs ataxia patient-derived fibroblasts against glutathione depletion, protect neuron-like SH-SY5Y cells from glutamate-induced oxidative damage, and correct aberrant splicing of the ELP1 gene in fibroblasts derived from a familial dysautonomia patient. Although the mechanism of action of kinetin derivatives remains unclear, our data suggest that the cytoprotective activity of some purine isosteres is mediated by their ability to reduce oxidative stress. Further, the studies of permeation across artificial membrane and model gut and blood-brain barriers indicate that the compounds are orally available and can reach central nervous system. Overall, our data demonstrate that isosteric replacement of the kinetin purine scaffold is a fruitful strategy for improving known biological activities of kinetin and discovering novel therapeutic opportunities.
Subject(s)
Kinetin/pharmacology , Purines/pharmacology , Cell Survival/drug effects , Cells, Cultured , Cytoprotection , Dose-Response Relationship, Drug , Humans , Kinetin/chemical synthesis , Kinetin/chemistry , Molecular Structure , Oxidative Stress/drug effects , Purines/chemical synthesis , Purines/chemistry , Structure-Activity RelationshipABSTRACT
Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG35-55-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Autoimmune Diseases/drug therapy , Imidazoles/therapeutic use , Inflammation/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Pyridines/therapeutic use , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors , Disease Models, Animal , Female , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Male , Mice, Inbred BALB C , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Phosphodiesterase 4 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/therapeutic use , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphodiesterase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats, WistarABSTRACT
In this review, we summarize synthetic approaches to preparing single or fused oxazine and thiazine derivatives using solid-phase synthesis (SPS). The literature survey revealed that diverse compounds bearing variously functionalized 1,2-oxazine, 1,3-oxazine, or 1,4-oxazine scaffolds and the corresponding thiazines are accessible by SPS. The latest contributions involving the stereoselective polymer-supported syntheses of morpholines indicate that the field is continuing to expand.
Subject(s)
Oxazines/chemical synthesis , Polymers/chemistry , Solid-Phase Synthesis Techniques/methods , Thiazines/chemical synthesis , Cycloaddition Reaction , Molecular Structure , Morpholines/chemistry , Oxidation-Reduction , Pyrazoles/chemistry , Small Molecule Libraries/chemistry , StereoisomerismABSTRACT
Herein, we report the stereoselective synthesis of trisubstituted benzoxazino[4,3-b][1,2,5]thiadiazepinone 6,6-dioxides from polymer-supported Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu)-OH. After the solid-phase synthesis of N-alkylated-N-sulfonylated intermediates using various 2-nitrobenzenesulfonyl chlorides and bromoketones, the target compounds were obtained via trifluoroacetic acid (TFA)-mediated cleavage from the resin, followed by cyclization of the diazepinone scaffold. Except for the threonine-based intermediates, the inclusion of triethylsilane (TES) in the cleavage cocktail yielded a specific configuration of the newly formed C3 chiral center. The final cyclization resulted in minor or no inversion of the C12a stereocenter configuration.