Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2.
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.
Choi
Kihang
K
Department of Chemistry, Stanford University, Stanford, California 94305, USA.
Siegel
Matthew
M
Piper
Justin L
JL
Yuan
Liya
L
Cho
Eun
E
Strnad
Pavel
P
Omary
Bishr
B
Rich
Keith M
KM
Khosla
Chaitan
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007555:Isoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D018613:Microscopy, Confocal; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013329:Structure-Activity Relationship; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D002330:Carmustine