Volatile Anesthetic Sevoflurane Precursor 1,1,1,3,3,3-Hexafluoro-2-Propanol (HFIP) Exerts an Anti-Prion Activity in Prion-Infected Culture Cells

Prion disease is a neurodegenerative disorder with progressive neurologic symptoms and accelerated cognitive decline. The causative protein of prion disease is the prion protein (PrP), and structural transition of PrP from the normal helix rich form (PrPC) to the abnormal β-sheet rich form (PrPSc) occurs in prion disease. While so far numerous therapeutic agents for prion diseases have been developed, none of them are still useful. A fluorinated alcohol, hexafluoro isopropanol (HFIP), is a precursor to the inhalational anesthetic sevoflurane and its metabolites. HFIP is also known as a robust α-helix inducer and is widely used as a solvent for highly aggregated peptides. Here we show that the α-helix-inducing activity of HFIP caused the conformational transformation of the fibrous structure of PrP into amorphous aggregates in vitro. HFIP added to the ScN2a cell medium, which continuously expresses PrPSc, reduced PrPSc protease resistance after 24-h incubation. It was also clarified that ScN2a cells are more susceptible to HFIP than any of the cells being compared. Based on these findings, HFIP is expected to develop as a therapeutic agent for prion disease.

HFIP-Promoted Synthesis of Substituted Tetrahydrofurans by Reaction of Epoxides with Electron-Rich Alkenes

In the present work, the employment of fluorinated alcohols, specifically 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), as solvent and promoter of the catalyst-free synthesis of substituted tetrahydrofuranes through the addition of electron-rich alkenes to epoxydes is described. The unique properties of this fluorinated alcohol, which is very different from their non-fluorinated analogs, allows carrying out this new straightforward protocol under smooth reaction conditions affording the corresponding adducts in moderate yields in the majority of cases. Remarkably, this methodology has allowed the synthesis of new tetrahydrofuran-based spiro compounds as well as tetrahydrofurobenzofuran derivatives. The scope and limitations of the process are also discussed. Mechanistic studies were also performed pointing towards a purely ionic or a SN2-type process depending on the nucleophilicity of the alkene employed.

Similar Behavior of Rheological Properties and the Evaluation of the Melting Temperatures of Fluorinated Aliphatic Alcohols

On the basis of experimental data obtained for the viscosity, density, and refractive index of fluorinated alcohols and proceeding from the similarity laws, the structural features of molecules of the researched liquids are determined. A comparison of molecular refraction values determined for fluorinated and non-fluorinated alcohols made it possible to reveal a modification of the structure of fluorinated alcohol molecules. Namely, this is a probable minor change in the arrangement of fluorine atoms in the alcohol molecule, at which the structure of a molecule remains similar to the structure of molecules of aliphatic alcohols. A similarity in the behavior of the rheological properties of 2,2,3,3-tetrafluoropropan-1-ol and 1H,1H-pentafluoropropan-1-ol, on the one hand, and propan-1-ol, on the other hand, as well as 1H,1H,7H-dodecafluoroheptan-1-ol and 1H,1H-tridecafluoroheptan-1-ol, on the one hand, and heptan-1-ol, on the other hand, is found. A method for estimating the melting temperatures of halogenated molecular liquids, which is based on the similarity of the rheological properties of those liquids, is proposed. The melting temperatures for 1H,1H-pentafluoropropan-1-ol, Tm = (244.5 ± 1.0) K, and 1H,1H-tridecafluoroheptan-1-ol, Tm = (255.0 ± 1.0) K, which are not available in the literature, are evaluated.

Fluorinated alcohol mediated N,N′-dialkylation of amino acid derivatives via cascade [1,5]-hydride transfer/cyclization for concise synthesis of tetrahydroquinazoline

Structurally diverse amino acids and their ester derivatives were conveniently N,N′-dialkylated via TFE promoted cascade condensation/[1,5]-hydride transfer/cyclization for straightforward construction of tetrahydroquinazolines incorporating various amino acids.

About TFE: Old and New Findings

The fluorinated alcohol 2,2,2-Trifluoroethanol (TFE) has been implemented for many decades now in conformational studies of proteins and peptides. In peptides, which are often disordered in aqueous solutions, TFE acts as secondary structure stabilizer and primarily induces an α -helical conformation. The exact mechanism through which TFE plays its stabilizing roles is still debated and direct and indirect routes, relying either on straight interaction between TFE and molecules or indirect pathways based on perturbation of solvation sphere, have been proposed. Another still unanswered question is the capacity of TFE to favor in peptides a bioactive or a native-like conformation rather than simply stimulate the raise of secondary structure elements that reflect only the inherent propensity of a specific amino-acid sequence. In protein studies, TFE destroys unique protein tertiary structure and often leads to the formation of non-native secondary structure elements, but, interestingly, gives some hints about early folding intermediates. In this review, we will summarize proposed mechanisms of TFE actions. We will also describe several examples, in which TFE has been successfully used to reveal structural properties of different molecular systems, including antimicrobial and aggregation-prone peptides, as well as globular folded and intrinsically disordered proteins.