記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/yea.3819

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Medicinal Chemistry  

The mechanism for the cutoff, an activity cliff at which long-chain alcohols lose their biological effects, has not been elucidated. Highly hydrophobic oleyl alcohol (C18:1) exists as a mixture of monomers and aggregated droplets in water. C18:1did not inhibit the yeast growth but inhibited the growth of the slime mold without a cell wall. C18:1exhibited toxicity to the yeast protoplast, which was enhanced by polyethylene glycol, a fusogen. Therefore, direct interactions of C18:1with the membrane are crucial for the toxicity. The cutoff alcohols, C14and C16, also exhibited strong toxicity obeying the Meyer-Overton correlation, in intact yeast cells whose membrane growth was suppressed in water. Taken together, the cutoff is avoidable by securing sufficient accumulation of the wall-permeable monomers in the membrane, which supports the lipid theory. It would be important to distinguish the effective drug structure localizing in the membrane and deal with the amount in the membrane.

DOI： 10.1021/acs.jmedchem.2c00629

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記述言語：その他   掲載種別：研究論文（学術雑誌）  

The cutoff phenomenon associated with the effectiveness of long-chain alcohols in the induction of anesthesia is also observed for various antimicrobial activities, although the mechanism has remained unknown for over eight decades. The minimum inhibitory concentrations at 25°C for budding yeast growth exponentially decreased with increasing chain length of n-alcohols (C₂-C₁₂), whereas alcohols ≥C₁₃ lost the inhibitory effect. Thus, growth inhibition by n-alcohols obeys the Meyer-Overton correlation up to C₁₂ and exhibits a cutoff phenomenon. The densities of n-alcohols are low, and the melting point and hydrophobicity increase with chain length. C₁₃ and C₁₄ inhibited yeast growth at 39.8°C, above their melting points. Alcohols ≤C₁₄ inhibited thermophilic bacterial growth at 50°C, whereas C₁₆ inhibited it at 67.5°C, above their melting points. Thus, the high melting points of long-chain alcohols contribute to the cutoff phenomenon. C₁₄ did not effectively inhibit yeast growth in a static culture at 39.8°C, in contrast to a shaking culture, in which the low density-dependent concentration gradient was eliminated. The duration of the transient growth inhibition of yeast by C₁₂ was prolonged by sonication, which prevented hydrophobic aggregation. Therefore, a nonuniform distribution owing to low density and high hydrophobicity contributes to the cutoff. C₁₄ inhibited the growth at 25°C of the pdr1,3,5 mutant, defective in multidrug efflux pumps, whereas C₁₂ did not inhibit the growth of yeast overexpressing PDR5, indicating that the sensitivity to long-chain alcohols contributed to the cutoff. A balance between the physicochemical solubility of and the biological sensitivity to long-chain alcohols determines the cutoff chain length.

DOI： 10.1124/mol.118.112656

記述言語：英語   出版者・発行元：Journal of the American Chemical Society  

Fluorescence thermometry has emerged as a significant area of research in the field of remote temperature sensing with high accuracy. However, the development of noninvasive and reliable small organic fluorescence thermometers (FTs) remains challenging. In this study, we developed a high-sensitivity, high-resolution small organic ratiometric FT with a solvatochromic dye and analyzed its temperature response mechanism. π-Extended fluorene-based D−π-A-type small solvatochromic dyes (FπAc, FπF, and FπVC) were synthesized and characterized. A significant solvatochromic shift of >200 nm was observed between n-hexane and tetrahydrofuran (THF) for both FπF and FπVC, with emission in THF reaching the red region (701 nm, 828 nm). This substantial solvatochromic shift was accompanied by a concurrent decrease in the fluorescence quantum yield and is attributable to accelerated internal conversion. The fluorescence spectra of FπF in THF and FπVC in diethyl ether exhibited blue shifts and increased fluorescence intensities with a decrease in polarity at increased temperatures. Our observations revealed an absolute sensitivity of 21%/°C and a relative sensitivity of 3.0%/°C at the maximum. These results represent the highest sensitivity and resolution reported for single fluorophore small organic ratiometric FTs dispersed in solution. The positive temperature coefficient of the fluorescence intensity was attributed to control of the nonradiative decay pathway by solvatochromism. The temperature responsiveness of FπF could be detected in living HeLa cells by ratiometric confocal microscopy. Using the proposed strategy to develop FTs, we plan to build a library of FTs that will cover various environments of interest in both simple and complex systems.

DOI： 10.1021/jacs.5c01173

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記述言語：英語   出版者・発行元：Biochimica et Biophysica Acta - General Subjects  

Background: The potency of anesthetics with various structures increases exponentially with lipophilicity, which is the Meyer-Overton (MO) correlation discovered over 120 years ago. The MO correlation was also observed with various biological effects and chemicals, including alcohols; thus, the correlation represents a fundamental relationship between chemicals and organisms. The MO correlation was explained by the lipid and protein theories, although the principle remains unknown because these are still debating. Methods: The gentle hydration method was used to form giant unilamellar vesicles (GUVs) consisting of high- and low-melting phospholipids and cholesterol in the presence of n-alcohols (C2-C12). Confocal fluorescence microscopy was used to determine the percentage of GUVs with domains in relation to the n-alcohol concentrations. Results: n-Alcohols inhibited the domain formation of GUVs, and the half inhibitory concentration (IC50) in the aqueous phase (Cw) decreased exponentially with increasing chain length (lipophilicity). In contrast, the membrane concentrations (Cm) of alcohols for the inhibition, which is a product of the membrane-water partition coefficient and the IC50 values, remained constant irrespective of the chain length. Conclusions: The MO correlation is established in GUVs, which supports the lipid theory. When alcohols reach the same critical concentration in the membrane, similar biological effects appear irrespective of the chain length, which is the principle underlying the MO correlation. General significance: The protein theory states that a highly lipophilic compound targets minor membrane proteins due to the low Cw. However, our lipid theory states that the compound targets various membrane proteins due to the high Cm.

DOI： 10.1016/j.bbagen.2024.130717

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記述言語：日本語