500556-98-9Relevant academic research and scientific papers
Chemical validation of a druggable site on Hsp27/HSPB1 using in silico solvent mapping and biophysical methods
Makley, Leah N.,Johnson, Oleta T.,Ghanakota, Phani,Rauch, Jennifer N.,Osborn, Delaney,Wu, Taia S.,Cierpicki, Tomasz,Carlson, Heather A.,Gestwicki, Jason E.
, (2021/02/09)
Destabilizing mutations in small heat shock proteins (sHsps) are linked to multiple diseases; however, sHsps are conformationally dynamic, lack enzymatic function and have no endogenous chemical ligands. These factors render sHsps as classically “undruggable” targets and make it particularly challenging to identify molecules that might bind and stabilize them. To explore potential solutions, we designed a multi-pronged screening workflow involving a combination of computational and biophysical ligand-discovery platforms. Using the core domain of the sHsp family member Hsp27/HSPB1 (Hsp27c) as a target, we applied mixed solvent molecular dynamics (MixMD) to predict three possible binding sites, which we confirmed using NMR-based solvent mapping. Using this knowledge, we then used NMR spectroscopy to carry out a fragment-based drug discovery (FBDD) screen, ultimately identifying two fragments that bind to one of these sites. A medicinal chemistry effort improved the affinity of one fragment by ~50-fold (16 μM), while maintaining good ligand efficiency (~0.32 kcal/mol/non-hydrogen atom). Finally, we found that binding to this site partially restored the stability of disease-associated Hsp27 variants, in a redox-dependent manner. Together, these experiments suggest a new and unexpected binding site on Hsp27, which might be exploited to build chemical probes.
Trimethoxyphenyl (TMP) as a Useful Auxiliary for in situ Formation and Reaction of Aryl(TMP)iodonium Salts: Synthesis of Diaryl Ethers
Gallagher, Rory T.,Basu, Souradeep,Stuart, David R.
, p. 320 - 325 (2019/12/11)
Herein, we describe a synthetic approach for arylation that exploits the in situ formation and reaction of an unsymmetrical diaryliodonium salt. In this way, aryl iodides are used as reagents in a metal-free reaction with phenols, and a trimethoxyphenyl (TMP) group is used as a “dummy” group to facilitate transfer of a wide range of aryl moieties. The scope of aryl electrophiles and phenol nucleophiles is broad (>30 examples) and the yields are high (52–95%, 80% avg.). One-pot coupling reactions avoid the synthesis of diaryliodonium salts and provide opportunities for sequential reactions and novel chemoselectivity. (Figure presented.).
Synthesis of highly functionalized diaryl ethers by copper-mediated O-arylation of phenols using trivalent arylbismuth reagents
Crifar, Cynthia,Petiot, Pauline,Ahmad, Tabinda,Gagnon, Alexandre
supporting information, p. 2755 - 2760 (2014/03/21)
Highly functionalized diaryl ethers were prepared by copper(II) acetate mediated O-arylation reaction of phenols using trivalent organobismuthanes. The reaction is performed under simple conditions and tolerates a wide diversity of functional groups on the phenol and on the organobismuth reagent. Substoichiometric amounts of catalyst can be used by performing the reaction under an oxygen atmosphere. The N-arylation of pyridones is also reported. Highly functionalized diaryl ethers were prepared by a copper(II) acetate mediated O-arylation reaction of phenols using trivalent organobismuthanes (see scheme). The reaction is performed under simple conditions and tolerates a wide diversity of functional groups on the phenol and on the organobismuth reagent. Substoichiometric amounts of catalyst can be used by performing the reaction under an oxygen atmosphere. The N-arylation of pyridones is also reported. FG=functional group.
