1. 1,2,4-Thiadiazole acyclic nucleoside phosphonates as inhibitors of cysteine dependent enzymes cathepsin K and GSK-3β.
- Author
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Pomeislová A, Otmar M, Rubešová P, Benýšek J, Matoušová M, Mertlíková-Kaiserová H, Pohl R, Poštová Slavětínská L, Pomeisl K, and Krečmerová M
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cathepsin K metabolism, Cell Line, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Glycogen Synthase Kinase 3 beta metabolism, Humans, Molecular Structure, Nucleosides chemical synthesis, Nucleosides chemistry, Organophosphonates chemical synthesis, Organophosphonates chemistry, Structure-Activity Relationship, Thiadiazoles chemical synthesis, Thiadiazoles chemistry, Antineoplastic Agents pharmacology, Cathepsin K antagonists & inhibitors, Enzyme Inhibitors pharmacology, Glycogen Synthase Kinase 3 beta antagonists & inhibitors, Nucleosides pharmacology, Organophosphonates pharmacology, Thiadiazoles pharmacology
- Abstract
In analogy to antiviral acyclic nucleoside phosphonates, a series of 5-amino-3-oxo-1,2,4-thiadiazol-3(2H)-ones bearing a 2-phosphonomethoxyethyl (PME) or 3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) group at the position 2 of the heterocyclic moiety has been synthesized. Diisopropyl esters of PME- and HPMP-amines have been converted to the N-substituted ureas and then reacted with benzoyl, ethoxycarbonyl, and Fmoc isothiocyanates to give the corresponding thiobiurets, which were oxidatively cyclized to diisopropyl esters of 5-amino-3-oxo-2-PME- or 2-HPMP- 1,2,4-thiadiazol-3(2H)-ones. The phosphonate ester groups were cleaved with bromotrimethylsilane, yielding N
5 -protected phosphonic acids. The subsequent attempts to remove the protecting group from N5 under alkaline conditions resulted in the cleavage of the 1,2,4-thiadiazole ring. Similarly, compounds with a previously unprotected 5-amino-1,2,4-thiadiazolone base moiety were stable only in the form of phosphonate esters. The series of twenty-one newly prepared 1,2,4-thiadiazol-3(2H)-ones were explored as potential inhibitors of cysteine-dependent enzymes - human cathepsin K (CatK) and glycogen synthase kinase 3β (GSK-3β). Several compounds exhibited an inhibitory activity toward both enzymes in the low micromolar range. The inhibitory potency of some of them toward GSK-3β was similar to that of the thiadiazole GSK-3β inhibitor tideglusib, whereas others exhibited more favorable toxicity profile while retaining good inhibitory activity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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