548740-06-3Relevant academic research and scientific papers
Assessment of Tractable Cysteines for Covalent Targeting by Screening Covalent Fragments
Petri, László,ábrányi-Balogh, Péter,Tímea, Imre,Pálfy, Gyula,Perczel, András,Knez, Damijan,Hrast, Martina,Gobec, Martina,Sosi?, Izidor,Nyíri, Kinga,Vértessy, Beáta G.,J?nsch, Niklas,Desczyk, Charlotte,Meyer-Almes, Franz-Josef,Ogris, Iza,Goli? Grdadolnik, Simona,Iacovino, Luca Giacinto,Binda, Claudia,Gobec, Stanislav,Keser?, Gy?rgy M.
, p. 743 - 753 (2021)
Targeted covalent inhibition and the use of irreversible chemical probes are important strategies in chemical biology and drug discovery. To date, the availability and reactivity of cysteine residues amenable for covalent targeting have been evaluated by proteomic and computational tools. Herein, we present a toolbox of fragments containing a 3,5-bis(trifluoromethyl)phenyl core that was equipped with chemically diverse electrophilic warheads showing a range of reactivities. We characterized the library members for their reactivity, aqueous stability and specificity for nucleophilic amino acids. By screening this library against a set of enzymes amenable for covalent inhibition, we showed that this approach experimentally characterized the accessibility and reactivity of targeted cysteines. Interesting covalent fragment hits were obtained for all investigated cysteine-containing enzymes.
Comparative reactivity analysis of small-molecule thiol surrogates
ábrányi-Balogh, Péter,Imre, Tímea,Keser?, Gy?rgy Miklós,Petri, László,Varga, Petra Regina
, (2020/02/22)
Targeted covalent inhibitors represent an increasingly popular approach to modulate challenging drug targets. Since covalent and non-covalent interactions are both contributing to the affinity of these compounds, evaluation of their reactivity is a key-step to find feasible warheads. There are well-established HPLC- and NMR-based kinetic assays to tackle this task, however, they use a variety of cysteine-surrogates including cysteamine, cysteine or acetyl-cysteine and GSH. The diverse nature of the thiol sources often makes the results incomparable that prevents compiling a comprehensive knowledge base for the design of covalent inhibitors. To evaluate kinetic measurements from different sources we performed a comparative analysis of the different thiol surrogates against a designed set of electrophilic fragments equipped with a range of warheads. Our study included seven different thiol models and 13 warheads resulting in a reactivity matrix analysed thoroughly. We found that the reactivity profile might be significantly different for various thiol models. Comparing the different warheads, we concluded that – in addition to its human relevance - glutathione (GSH) provided the best estimate of reactivity with highest number of true positives identified.
π-deficient 2-(arylsulfonyl)ethyl esters as protecting groups for carboxylic acids
Alonso, Diego A.,Nájera, Carmen,Varea, Montserrat
, p. 277 - 287 (2007/10/03)
Several π-deficient 2-(arylsulfonyl)ethyl groups have been studied as carboxylic acid protecting groups. The 2-[3,5-bis(trifluoromethyl)phenylsulfonyl]ethyl group is the most easily removed protecting group for acids under mild basic conditions using aqueous NaHCO3.
