13669-51-7Relevant articles and documents
Discovery of potent and specific dihydroisoxazole inhibitors of human transglutaminase 2
Kl?ck, Cornelius,Herrera, Zachary,Albertelli, Megan,Khosla, Chaitan
, p. 9042 - 9064 (2014)
Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme that catalyzes the posttranslational modification of glutamine residues on protein or peptide substrates. A growing body of literature has implicated aberrantly regulated activity of TG2 in the pathogenesis of various human inflammatory, fibrotic, and other diseases. Taken together with the fact that TG2 knockout mice are developmentally and reproductively normal, there is growing interest in the potential use of TG2 inhibitors in the treatment of these conditions. Targeted-covalent inhibitors based on the weakly electrophilic 3-bromo-4,5-dihydroisoxazole (DHI) scaffold have been widely used to study TG2 biology and are well tolerated in vivo, but these compounds have only modest potency, and their selectivity toward other transglutaminase homologues is largely unknown. In the present work, we first profiled the selectivity of existing inhibitors against the most pertinent TG isoforms (TG1, TG3, and FXIIIa). Significant cross-reactivity of these small molecules with TG1 was observed. Structure-activity and -selectivity analyses led to the identification of modifications that improved potency and isoform selectivity. Preliminary pharmacokinetic analysis of the most promising analogues was also undertaken. Our new data provides a clear basis for the rational selection of dihydroisoxazole inhibitors as tools for in vivo biological investigation.
Na2S·9H2O mediated facile synthesis of 1,3-dihydrofuro[3,4-b]quinoline derivatives via domino reduction approach
Singh, Rashmi,Gupta, Tanu,Sharma, Vishal Prasad,Singh, Radhey M.,Tewari, Ashish Kumar
supporting information, (2021/09/22)
A simple, highly efficient method for synthesis of 1,3-dihydrofuro[3,4-b]quinoline is described by the reaction of o-arylalkynyl quinoline aldehydes with Na2S·9H2O via domino reduction approach. The method is simple and proceeds under mild condition under an air atmosphere to give 1,3-dihydrofuro[3,4-b]quinoline in good to excellent yields. The beauty of the reaction is cyclization as well as reduction has been taken place in the same reaction pot. Also the conversion of aldehyde into primary alcohol has been discussed under the same reaction condition.
In vivo evaluation of two tissue transglutaminase PET tracers in an orthotopic tumour xenograft model
van der Wildt, Berend,Wilhelmus, Micha M. M.,Beaino, Wissam,Kooijman, Esther J. M.,Schuit, Robert C.,Bol, John G. J. M.,Breve, John J. P.,Pasternack, Ralf,Lammertsma, Adriaan A.,Windhorst, Albert D.,Drukarch, Benjamin
, (2018/05/31)
Background: The protein cross-linking enzyme tissue transglutaminase (TG2; EC 2.3.2.13) is associated with the pathogenesis of various diseases, including cancer. Recently, the synthesis and initial evaluation of two high-potential radiolabelled irreversible TG2 inhibitors were reported by us. In the present study, these two compounds were evaluated further in a breast cancer (MDA-MB-231) tumour xenograft model for imaging active tissue transglutaminase in vivo. Results: The metabolic stability of [11C]1 and [18F]2 in SCID mice was comparable to the previously reported stability in Wistar rats. Quantitative real-time polymerase chain reaction analysis on MDA-MB-231 cells and isolated tumours showed a high level of TG2 expression with very low expression of other transglutaminases. PET imaging showed low tumour uptake of [11C]1 (approx. 0.5 percentage of the injected dose per gram (%ID/g) at 40–60?min p.i.) and with relatively fast washout. Tumour uptake for [18F]2 was steadily increasing over time (approx. 1.7 %ID/g at 40–60?min p.i.). Pretreatment of the animals with the TG2 inhibitor ERW1041E resulted in lower tumour activity concentrations, and this inhibitory effect was enhanced using unlabelled 2. Conclusions: Whereas the TG2 targeting potential of [11C]1 in this model seems inadequate, targeting of TG2 using [18F]2 was achieved. As such, [18F]2 could be used in future studies to clarify the role of active tissue transglutaminase in disease.
