Background:The enzyme myeloperoxidase produces chlorine bleach at sites of inflammation. Results: 2-Thioxanthines are potent mechanism-based inactivators of myeloperoxidase. Conclusion: 2-Thioxanthines block production of chlorine bleach during inflammation. Significance: Mechanism-based inactivators of myeloperoxidase should limit oxidative stress at sites of inflammation.
Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of 1 and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma.
The g-secretase inhibitor dibenzazepine (DBZ) and the g-secretase modulators 1 and AZ8349 were prepared as tritium-labeled compounds with high specific activity and radiochemical purity. [ 3 H]DBZ was labeled via an iodinated precursor, [ 3 H]1 was labeled by [ 3 H]methylation of an O-desmethyl precursor, and [2-3 H]AZ8349 was labeled via a tribromoacetyl precursor by catalytic hydrogenation. [ 3 H]DBZ, [ 3 H]1, and [2-3 H]AZ8349 are promising in vitro imaging radioligands and have the potential to provide key information with regard to g-secretase expression, function, stoichiometry, and pharmacology.
The myeloperoxidase (MPO) inhibitors 1 and 2 were prepared as their isotopologues with carbon-14, carbon-13, and nitrogen-15 or tritium with high specific activity and purity. Starting from potassium [ 14 C]cyanide or [ 14 C]formate provided metabolically stable 14 C-labels on [ 14 C]-1 and [ 14 C]-2. Catalytic hydrogenation was used for the preparation of [ 3 H]-2, giving multiple enriched positions as shown by 3 H NMR. 1 and 2 are promising in vitro and in vivo imaging radioligands and have the potential to provide key information with regard to MPO expression, function, stoichiometry, and pharmacology.
A method for the preparation of [2,3,4-3 H]BMS299897 has been developed. The methyl ester of BMS299897 was oxidized to its double bond derivative, via a phenyl selenide. The resulting double bond was reduced with tritium using Wilkinson's catalyst. The tritiated BMS299897 was isolated, after basic hydrolysis, with a specific activity of 1.6 TBq/mmol.
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