1,2,4-Thiadiazole acyclic nucleoside phosphonates as inhibitors of cysteine dependent enzymes cathepsin K and GSK-3β
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
33440320
DOI
10.1016/j.bmc.2021.115998
PII: S0968-0896(21)00006-7
Knihovny.cz E-resources
- Keywords
- 5-Amino-1,2,4-thiadiazol-3-(2H)-one, Acyclic nucleoside phosphonates, Cathepsin K, Glycogen synthase kinase 3β, Epigenetic, Thiadiazoles,
- MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Cell Line MeSH
- Glycogen Synthase Kinase 3 beta antagonists & inhibitors metabolism MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Cathepsin K antagonists & inhibitors metabolism MeSH
- Drug Screening Assays, Antitumor MeSH
- Humans MeSH
- Molecular Structure MeSH
- Nucleosides chemical synthesis chemistry pharmacology MeSH
- Organophosphonates chemical synthesis chemistry pharmacology MeSH
- Cell Proliferation drug effects MeSH
- Thiadiazoles chemical synthesis chemistry pharmacology MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antineoplastic Agents MeSH
- CTSK protein, human MeSH Browser
- Glycogen Synthase Kinase 3 beta MeSH
- Enzyme Inhibitors MeSH
- Cathepsin K MeSH
- Nucleosides MeSH
- Organophosphonates MeSH
- Thiadiazoles MeSH
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 N5-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.
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