Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001–2011)

Wang, Jiang; Sánchez‐Roselló, María; Aceña, José Luis; Pozo, Carlos del; Sorochinsky, Alexander E.; Fustero, Santos; Soloshonok, Vadim A.; Liu, Hong

doi:10.1021/cr4002879

Cited by 4,176 publications

(1,772 citation statements)

References 457 publications

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“…Fluorine is often used in medicinal chemistry, one reason being that its lipophilic character can make drugs better soluble in lipid membranes and thereby improve their ability to penetrate into cells (13). With this motivation in mind, we measured the effect of fluorine on ΔG app by changing the terminal methyl group on AcLys and AcLys(C2) to -CF 3 .…”

Section: Fluorination Increases the Hydrophobicity Of A Transmembranementioning

confidence: 99%

Energetics of side-chain snorkeling in transmembrane helices probed by nonproteinogenic amino acids

Öjemalm

Higuchi

Lara

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cotranslational translocon-mediated insertion of membrane proteins into the endoplasmic reticulum is a key process in membrane protein biogenesis. Although the mechanism is understood in outline, quantitative data on the energetics of the process is scarce. Here, we have measured the effect on membrane integration efficiency of nonproteinogenic analogs of the positively charged amino acids arginine and lysine incorporated into model transmembrane segments. We provide estimates of the influence on the apparent free energy of membrane integration (ΔG app ) of "snorkeling" of charged amino acids toward the lipid-water interface, and of charge neutralization. We further determine the effect of fluorine atoms and backbone hydrogen bonds (H-bonds) on ΔG app . These results help establish a quantitative basis for our understanding of membrane protein assembly in eukaryotic cells. Using a cotranslational insertion assay, we previously measured the contribution of each of the 20 natural amino acids to the membrane integration efficiency of model transmembrane segments, and derived a "biological" hydrophobicity scale that assigns an apparent free-energy of membrane integration, ΔG aaðiÞ, j app , to each amino acid of type i [aa(i) = A, C, D, E, . . ., W, Y] as a function of its position j within a transmembrane α-helix (2). To further probe the physicochemical basis for membrane insertion, we also analyzed a series of aliphatic and aromatic nonproteinogenic amino acids, using the same insertion assay (3). This approach made it possible to quantitate the "hydrophobic effect" during membrane protein insertion, giving nonpolar solvation energy parameter values of -10 cal/(mol·Å 2 ) and -7 cal/(mol·Å 2 ) for aliphatic and aromatic surface area, respectively.Here, we extend our analysis of nonproteinogenic amino acids to analogs of the positively charged amino acids Arg and Lys. We provide estimates of the influence on the apparent free energy of membrane integration (ΔG app ) of "snorkeling" of charged amino acids toward the lipid-water interface, and of charge neutralization. We further determine the effect of fluorine atoms and backbone H-bonds on ΔG app .

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Section: Fluorination Increases the Hydrophobicity Of A Transmembranementioning

confidence: 99%

Energetics of side-chain snorkeling in transmembrane helices probed by nonproteinogenic amino acids

Öjemalm

Higuchi

Lara

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The present study shows that the CF 3 and CHF 2 groups significantly stabilize the 1,4,2-oxathiazolidine ring and, therefore, enable their exploration in organic synthesis either as target molecules or as building blocks for the preparation of more complex systems. This is an important issue as fluorinated heterocycles found applications as drugs, agrochemicals, and materials with special properties [18].…”

Section: Discussionmentioning

confidence: 99%

1,3-Dipolar cycloadditions of fluorinated nitrones with thioketones

Mlostoń

Obijalska

Celeda

et al. 2014

Journal of Fluorine Chemistry

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Fluorinated nitrones derived from fluoral and difluoroacetaldehyde react with thioketones via [3 + 2] cycloaddition yielding 1,4,2-oxathiazolidines in a regioselective manner. Unexpectedly, cycloaliphatic thioketones react faster than aromatic thioketones. Due to the presence of a fluorinated alkyl group, the cycloadducts display a remarkable stability and do not decompose at room temperature in the crystalline form nor in solution.

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“…Furthermore, it is estimated that about 15-20% of pharmaceuticals licensed each year (new chemical entities) contain a fluorine atom [3,4]. The presence of a fluorine serves to increase drug lipophilicity [5,6] which is especially important when designing drugs that are intended to cross the blood-brain barrier [7].…”

Section: Conclusion 58 Introductionmentioning

confidence: 99%