- Live-Cell Protein Modification by Boronate-Assisted Hydroxamic Acid Catalysis
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Selective methods for introducing protein post-translational modifications (PTMs) within living cells have proven valuable for interrogating their biological function. In contrast to enzymatic methods, abiotic catalysis should offer access to diverse and new-to-nature PTMs. Herein, we report the boronate-assisted hydroxamic acid (BAHA) catalyst system, which comprises a protein ligand, a hydroxamic acid Lewis base, and a diol moiety. In concert with a boronic acid-bearing acyl donor, our catalyst leverages a local molarity effect to promote acyl transfer to a target lysine residue. Our catalyst system employs micromolar reagent concentrations and affords minimal off-target protein reactivity. Critically, BAHA is resistant to glutathione, a metabolite which has hampered many efforts toward abiotic chemistry within living cells. To showcase this methodology, we installed a variety of acyl groups inE. colidihydrofolate reductase expressed within human cells. Our results further establish the well-known boronic acid-diol complexation as abona fidebio-orthogonal reaction with applications in chemical biology and in-cell catalysis.
- Adamson, Christopher,Kajino, Hidetoshi,Kanai, Motomu,Kawashima, Shigehiro A.,Yamatsugu, Kenzo
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supporting information
p. 14976 - 14980
(2021/09/29)
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- THERAPEUTIC INHIBITORY COMPOUNDS
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Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds which are complement factor D inhibitors. Such compounds are useful for treating complement related disorders including, but are not limited to, autoimmune, inflammatory, and neurodegenerative diseases.
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Paragraph 00258
(2017/07/04)
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- Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase
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Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC50 values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors.
- Crocetti, Letizia,Giovannoni, Maria Paola,Schepetkin, Igor A.,Quinn, Mark T.,Khlebnikov, Andrei I.,Cilibrizzi, Agostino,Piaz, Vittorio Dal,Graziano, Alessia,Vergelli, Claudia
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experimental part
p. 4460 - 4472
(2011/09/12)
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- Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors
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A structure-activity relationship study for a 2-chloroanilide derivative of pyrazolo[1,5-a]pyridine revealed that increased EphB3 kinase inhibitory activity could be accomplished by retaining the 2-chloroanilide and introducing a phenyl or small electron donating substituents to the 5-position of the pyrazolo[1,5-a]pyridine. In addition, replacement of the pyrazolo[1,5-a]pyridine with imidazo[1,2-a]pyridine was well tolerated and resulted in enhanced mouse liver microsome stability. The structure-activity relationship for EphB3 inhibition of both heterocyclic series was similar. Kinase inhibitory activity was also demonstrated for representative analogs in cell culture. An analog (32, LDN-211904) was also profiled for inhibitory activity against a panel of 288 kinases and found to be quite selective for tyrosine kinases. Overall, these studies provide useful molecular probes for examining the in vitro, cellular and potentially in vivo kinase-dependent function of EphB3 receptor.
- Qiao, Lixin,Choi, Sungwoon,Case, April,Gainer, Thomas G.,Seyb, Kathleen,Glicksman, Marcie A.,Lo, Donald C.,Stein, Ross L.,Cuny, Gregory D.
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supporting information; experimental part
p. 6122 - 6126
(2010/06/16)
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- CONDENSED PYRAZOLE DERIVATIVES AS PPAR AGONISTS II
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The invention discloses compounds of formula (I) wherein: R is a carboxylic acid or a derivative thereof; R1 and R2 are independently H or alkyl, or together R1 and R2 form an alkylene group; L1 is a
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Page/Page column 14
(2010/11/26)
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