Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2.

Abstract

3-halo-4,5-dihydroisoxazoles are attractive warheads for the selective inhibition of nucleophilic active sites in biological systems. A series of 3-bromo-4,5-dihydroisoxazole compounds were prepared and tested for their ability to irreversibly inhibit human transglutaminase 2 (TG2), an enzyme that plays an important role in the pathogenesis of diverse disorders including Celiac Sprue and certain types of cancers. Several compounds showed high specificity for human TG2 (k(inh)/K(I) > 2000 min(-1)M(-1)) but essentially no reactivity (k < 1 min(-1)M(-1)) toward physiological thiols such as glutathione. The pharmacokinetic and pharmacodynamic properties of a prototype dihydroisoxazole inhibitor, 1b, were evaluated; in mice the compound showed good oral bioavailability, short serum half-life and efficient TG2 inhibition in small intestinal tissue, and low toxicity. It also showed excellent synergism with N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU, carmustine) against refractory glioblastoma tumors in mice. A fluorescent dihydroisoxazole inhibitor 5 facilitated microscopic visualization of TG2 endocytosis from the extracellular surface of HCT-116 cells. Together, these findings demonstrate the promise of dihydroisoxazole compounds as probes for the biology of TG2 and its role in human disease.

• Authors: Kihang Choi, Matthew Siegel, Justin L Piper, Liya Yuan, Eun Cho, Pavel Strnad, Bishr Omary, Keith M Rich, Chaitan Khosla
• Journal: Chemistry & biology (Chem Biol) Vol. 12 Issue 4 Pg. 469-75 (Apr 2005) ISSN: 1074-5521 [Print] United States
• PMID: 15850984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Isoxazoles
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• GTP-Binding Proteins
• Carmustine

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Biological Availability
• Carmustine (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Drug Synergism
• Enzyme Inhibitors (chemistry, pharmacokinetics, pharmacology)
• GTP-Binding Proteins (antagonists & inhibitors, biosynthesis)
• Glioblastoma (drug therapy, pathology)
• Intestine, Small (drug effects, metabolism)
• Isoxazoles (chemistry, pharmacokinetics, pharmacology)
• Mice
• Mice, Inbred C3H
• Microscopy, Confocal
• Protein Glutamine gamma Glutamyltransferase 2
• Structure-Activity Relationship
• Transglutaminases (antagonists & inhibitors, biosynthesis)