240798-91-8Relevant 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.
Asymmetric synthesis of cyclic α-amino acid derivatives by the intramolecular reaction of magnesium carbenoid with an N-magnesio arylamine
Mitsunaga, Shintaro,Ohbayashi, Tohru,Sugiyama, Shimpei,Saitou, Takahito,Tadokoro, Makoto,Satoh, Tsuyoshi
scheme or table, p. 1697 - 1708 (2009/12/06)
The synthesis of pipecolic acid and homopipecolic acid derivatives was developed from ω-(2-aminophenyl)-1-chloroalkyl p-tolyl sulfoxides by treatment with i-PrMgCl. An intramolecular nucleophilic substitution reaction of a magnesium carbenoid with an N-magnesio arylamine is the key step of this reaction. Proline and pipecolic acid derivatives were also synthesized from ω-(arylamino)-1-chloroalkyl p-tolyl sulfoxides by the same chemistry. Starting from enantiomerically pure (1S,RS)-1-chloro-3-[2-(N-methylamino)phenyl]propyl p-tolyl sulfoxide, enantiomerically pure (R)-pipecolic acid derivative was obtained. The intramolecular nucleophilic substitution reaction of the magnesium carbenoid with N-magnesio arylamine was proven to take place with inversion of the carbenoid carbon. The stereochemistry of these reactions is also discussed.
A new synthesis of cyclic α-amino acid derivatives by the intramolecular reaction of magnesium carbenoid with N-magnesio arylamine as the key reaction
Ohbayashi, Tohru,Mitsunaga, Shintaro,Satoh, Tsuyoshi
, p. 7829 - 7833 (2008/03/11)
A new synthesis of pipecolic acid and homopipecolic acid derivative was accomplished from 1-chloroalkyl p-tolyl sulfoxides having a 2-aminophenyl group at the ω-position by treatment with i-PrMgCl via the intramolecular reaction of magnesium carbenoid wit
