Diflunisal Analogues Stabilize the Native State of Transthyretin. Potent Inhibition of Amyloidogenesis was written by Adamski-Werner, Sara L.;Palaninathan, Satheesh K.;Sacchettini, James C.;Kelly, Jeffery W.. And the article was included in Journal of Medicinal Chemistry in 2004.Formula: C7H5BrF2O This article mentions the following:
Analogs of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. High inhibitory activity was observed for 26 of the compounds Of those, eight exhibited excellent binding selectivity for TTR in human plasma (binding stoichiometry >0.50, with a theor. maximum of 2.0 inhibitors bound per TTR tetramer). Biophys. studies reveal that these eight inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation Kinetic stabilization of WT TTR by these eight inhibitors is further substantiated by the decreasing rate of amyloid fibril formation as a function of increasing inhibitor concentration (pH 4.4). X-ray cocrystal structures of the TTR-3′,5′-difluorobiphenyl-4-carboxylic acid (I) and TTR-2′,6′-difluorobiphenyl-4-carboxylic acid (II) complexes reveal that I and II bind in opposite orientations in the TTR binding site. Moving the fluorines from the meta positions in I to the ortho positions in II reverses the binding orientation, allowing the hydrophilic aromatic ring of II to orient in the outer binding pocket where the carboxylate engages in favorable electrostatic interactions with the ε-ammonium groups of Lys 15 and 15′. The hydrophilic aryl ring of I occupies the inner binding pocket, with the carboxylate positioned to hydrogen bond to the serine 117 and 117′ residues. Diflunisal itself appears to occupy both orientations based on the electron d. in the TTR·12 structure. Structure-activity relationships reveal that para-carboxylate substitution on the hydrophilic ring and dihalogen substitution on the hydrophobic ring afford the most active TTR amyloid inhibitors. In the experiment, the researchers used many compounds, for example, 4-Bromo-2,6-difluoroanisole (cas: 104197-14-0Formula: C7H5BrF2O).
4-Bromo-2,6-difluoroanisole (cas: 104197-14-0) belongs to ethers. Of all the functional groups, ethers are the least reactive ones. Ether bonds are quite stable towards bases, oxidizing agents and reducing agents. At room temperature, ethers are pleasant-smelling colourless liquids. Relative to alcohols, ethers are generally less dense, are less soluble in water, and have lower boiling points. They are relatively unreactive, and as a result they are useful as solvents for fats, oils, waxes, perfumes, resins, dyes, gums, and hydrocarbons. Vapours of certain ethers are used as insecticides, miticides, and fumigants for soil.Formula: C7H5BrF2O
Referemce:
Ether – Wikipedia,
Ether | (C2H5)2O – PubChem