Synthesis, chemistry, and absolute configuration of novel transglutaminase inhibitors containing a 3-halo-4,5-dihydroisoxazole

Castelhano, Arlindo L.; Billedeau, Roland; Pliura, Diana H.; Bonaventura, Bonnie J.; Krantz, A.

doi:10.1016/0045-2068(88)90019-3

Cited by 37 publications

(27 citation statements)

References 13 publications

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“…Decarboxylated acivicin derivatives had increased activity as TG2 inhibitors. (18) The inhibitors studied were mostly comprised of α-amino acids functionalized with N-carbamate moieties and coupled to the dihydroisoxazole electrophile. Several trends in the structure-activity relationships of this class of TG2 inhibitors emerged.…”

Section: Introductionmentioning

confidence: 99%

Structure−Activity Relationship Analysis of the Selective Inhibition of Transglutaminase 2 by Dihydroisoxazoles

2006

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Human transglutaminase 2 (TG2) is believed to play an important role in the pathogenesis of various human disorders including celiac sprue, certain neurological diseases, as well as some types of cancer. Selective inhibition of TG2 should therefore enable further investigation of its role in physiology and disease, and may lead to effective clinical treatment. Recently we showed that certain 3-halo-4-, 5-dihydroisoxazole containing compounds are selective inhibitors of human TG2 with promising pharmacological activities. Here we present definitive evidence that this class of compounds targets the active site of human TG2. Structure-activity relationship studies have provided insights into the structural prerequisites for selectivity, and have led to the discovery of an inhibitor with ca. fifty-fold higher activity than a prototypical dihydroisoxazole inhibitor with good in vivo activity. A method for preparing enantiomerically enriched analogues was also developed. Our studies show that the 5-(S-) dihydroisoxazole is a markedly better inhibitor of human TG2 than its 5-(R-) stereoisomer.

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Section: Introductionmentioning

confidence: 99%

Structure−Activity Relationship Analysis of the Selective Inhibition of Transglutaminase 2 by Dihydroisoxazoles

2006

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“…For this purpose, CS that inactivates the enzyme acti vity by binding to the active site and MDC, a compe titive amine substrate inhibitor that inhibits specifically the endogenous protein crosslinking by TGase (Lorand et al, 1979;Folk, 1980;Castelhano et al, 1990;Auger et al, 1993) were used at millimolar concentration. The results indicate that neither inhibitor affects larval via bility of S. vulgaris and S. equinus.…”

Section: Discussionmentioning

confidence: 99%

“…Effect on L4 viability with MDC and growth with both the inhibitors strongly supports the notion that TGase is involved in growth and development of these nematodes. N-bezyloxycarbonyl-D,L-b-(3-bromo-4,5-dihydroisoxazol-5-yl)-alanine benzylamide (Syntex Inc., Palo Alto, CA), ano ther TGase inhibitor that like CS binds to the active site of TGase (Auger et al, 1993;Castelhano et. al, 1990), also inhibited О. volvulus larval molting (Lustigman et al, 1995) and Nippostrongylus brazi liensis L4 viability and molting to adult (Castelhano et al 1990).…”

Section: Discussionmentioning

confidence: 99%

“…N-bezyloxycarbonyl-D,L-b-(3-bromo-4,5-dihydroisoxazol-5-yl)-alanine benzylamide (Syntex Inc., Palo Alto, CA), ano ther TGase inhibitor that like CS binds to the active site of TGase (Auger et al, 1993;Castelhano et. al, 1990), also inhibited О. volvulus larval molting (Lustigman et al, 1995) and Nippostrongylus brazi liensis L4 viability and molting to adult (Castelhano et al 1990). Although these studies have identified the presence of TGase enzyme in a wide range of nema tode species, additional studies are needed to deter mine the regulatory activity of TGase in molting pro cess and worm development in vivo (Geary et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

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Transglutaminase activity in equine strongyles and its potential role in growth and development

Rao

Chapman²,

Singh

et al. 1999

Parasite

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Summary :Transglutaminases (E.C. 2.3.3.13) are a family of Ca 2+ -dependent enzymes that stabilize protein structure by catalyzing the formation of isopeptide bonds. A novel form of transglutaminase has been identified and characterized that seem to play an important role in growth, development, and molting in adult and larval stages of filarial nematodes. The aim of this study was to identify the ubiquitous nature of this enzyme in other nematodes and to measure its significance to larval growth, molting, and development. For this purpose, equine Strongylus spp. were used. Activity of this enzyme was identified in extracts of larvae and adults of Strongylus vulgaris, S. edentatus, Parascaris equorum and Cylicocyclus insigne. The significance of transglutaminase in the early growth and development of Strongylus vulgaris, S. edentatus and S. equinus was tested by adding specific inhibitors, monodansylcadaverine (MDC) or cystamine (CS), to in vitro cultures of third (L3) and fourth stage larvae (L4). The viability, molting and growth of these nematode species were affected by both inhibitors. Cystamine promoted abnormal development of Strongylus edentatus L3, resulting in an aberrant expansion of the anterior end. Addition of these inhibitors to cultures of L4 also reduced growth of the three species. The results indicated that transglutaminase is present in a wide array of nematode parasites and may be important in growth and development of their larval stages.KEY WORDS : equine, strongyles, L3, L4, transglutaminase, growth, molting, inhibitors, monodansylcadaverine (MDC), cystamine (CS). Résumé : ACTIVITÉ ET RÔLE POTENTIEL DE LA TRANSGLUTAMINASE DANS LA CROISSANCE ET LE DÉVELOPPEMENT DES STRONGYLES ÉQUINS

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“…Several series of peptidic inhibitors emerged following this concept, the chemical structure of the warhead being generally used to differentiate among them ( Fig. 2): 3-halo-4,5-dihydroisoxazoles (Choi et al 2005;Watts et al 2006;Castelhano et al 1988), epoxides (de Macedo et al 2002;Marrano et al 2001b), a,b-unsaturated amides (de Macedo et al 2002;Marrano et al 2001b;Pardin et al 2006), chloroacetamides (Pardin et al 2006), thiadiazoles (Marrano et al 2001a), maleimides (Halim et al 2007;Pardin et al 2006), sulfonium methyl ketones (Pliura et al 1992).…”

Section: Introductionmentioning

confidence: 99%

Recent advances in the development of tissue transglutaminase (TG2) inhibitors

2011

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Synthesis, chemistry, and absolute configuration of novel transglutaminase inhibitors containing a 3-halo-4,5-dihydroisoxazole

Cited by 37 publications

References 13 publications

Structure−Activity Relationship Analysis of the Selective Inhibition of Transglutaminase 2 by Dihydroisoxazoles

Structure−Activity Relationship Analysis of the Selective Inhibition of Transglutaminase 2 by Dihydroisoxazoles

Transglutaminase activity in equine strongyles and its potential role in growth and development

Recent advances in the development of tissue transglutaminase (TG2) inhibitors

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