5339-27-5Relevant articles and documents
Bicyclobutane carboxylic amide as a cysteine-directed strained electrophile for selective targeting of proteins
Shindo, Naoya,Ojida, Akio,Tokunaga, Keisuke,Sato, Mami,Kuwata, Keiko,Miura, Chizuru,Fuchida, Hirokazu,Matsunaga, Naoya,Koyanagi, Satoru,Ohdo, Shigehiro
supporting information, p. 18522 - 18531 (2020/11/02)
Expanding the repertoire of electrophiles with unique reactivity features would facilitate the development of covalent inhibitors with desirable reactivity profiles. We herein introduce bicyclo[1.1.0]butane (BCB) carboxylic amide as a new class of thiol-reactive electrophiles for selective and irreversible inhibition of targeted proteins. We first streamlined the synthetic routes to generate a variety of BCB amides. The strain-driven nucleophilic addition to BCB amides proceeded chemoselectively with cysteine thiols under neutral aqueous conditions, the rate of which was significantly slower than that of acrylamide. This reactivity profile of BCB amide was successfully exploited to develop covalent ligands targeting Bruton's tyrosine kinase (BTK). By tuning BCB amide reactivity and optimizing its disposition on the ligand, we obtained a selective covalent inhibitor of BTK. The in-gel activitybased protein profiling and mass spectrometry-based chemical proteomics revealed that the selected BCB amide had a higher target selectivity for BTK in human cells than did a Michael acceptor probe. Further chemical proteomic study revealed that BTK probes bearing different classes of electrophiles exhibited distinct off-target profiles. This result suggests that incorporation of BCB amide as a cysteine-directed electrophile could expand the capability to develop covalent inhibitors with the desired proteome reactivity profile.
Ratiometric double channel borondipyrromethene based chemodosimeter for the selective detection of nerve agent mimics
Gotor,Costero,Gavi?a,Gil, Salvador
, p. 76 - 83 (2014/05/20)
A new chromo-fluorogenic probe based on the borondipyrromethene dye has been synthesized. The dye has been attached to a sensing unit for the diethylcyanophosphonate and di-isopropylfluorophosphate detection. The new probe has been fully characterized, an
Chromo-fluorogenic detection of nerve-agent mimics using triggered cyclization reactions in push-pull dyes
Costero, Ana M.,Parra, Margarita,Gil, Salvador,Gotor, Raffll,Mancini, Pedro M. E.,Martinez-Macez, Ramon,Sancenon, Felix,Royo, Santiago
experimental part, p. 1573 - 1585 (2011/08/05)
A family of azo and stilbene derivatives (1-9) are synthesized, and their chromo-fluorogenic behavior in the presence of nerve-agent simulants, diethylchlorophosphate (DCP), diisopropylfluorophosphate (DFP), and diethylcyanophosphate (DCNP) in acetonitrile and mixed solution of water/acetonitrile (3:1 v/v) buffered at pH 5.6 with MES, is investigated. The prepared compounds contain 2-(2-N,N-dimethylaminophenyl) ethanol or 2-[(2-N,N-dimethylamino)phenoxy]ethanol reactive groups, which are part of the conjugated π-system of the dyes and are able to give acylation reactions with phosphonate substrates followed by a rapid intramolecular N-alkylation. The nerve-agent mimic-triggered cyclization reaction transforms a dimethylamino group into a quaternary ammonium, inducing a change of the electronic properties of the delocalized systems that results in a hypsochromic shift of the absorption band of the dyes. Similar reactivity studies are also carried out with other "non-toxic" organophosphorus compounds, but no changes in the UV/Vis spectra were observed. The emission behaviour of the reagents in acetonitrile and water-acetonitrile 3:1 v/v mixtures is also studied in the presence of nerve-agent simulants and other organophosphorous derivatives. The reactivity between 1-9 and DCP, DCNP, or DFP in buffered water-acetonitrile 3:1 v/v solutions under pseudo first-order kinetic conditions, using an excess of the corresponding simulant, are studied in order to determine the rate constants (k) and the half-life times (t1/2=ln2/k) for the reaction. The detection limits in water/acetonitrile 3:1 v/v are also determined for 1-9 and DCP, DCNP, and DFP. Finally, the chromogenic detection of nerve agent simulants both in solution and in gas phase are tested using silica gel containing adsorbed compounds 1, 2, 3, 4, or 5 with fine results.
