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Parkinson's Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson's Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson's Disease. Here, we describe the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid (7) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson's Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson's Disease. [ABSTRACT FROM AUTHOR]

Rational modulations of molecular interactions are of significant importance in compound properties optimization. We have previously shown that fluorination of conformationally rigid cyclohexanols leads to attenuation of their hydrogen-bond (H-bond) donating capacity (designated by p KAHY) when OH⋅⋅⋅F intramolecular hydrogen-bond (IMHB) interactions occur, as opposed to an increase in p KAHY due to the fluorine electronegativity. This work has now been extended to a wider range of aliphatic β-fluorohydrins with increasing degrees of conformational flexibility. We show that the observed differences in p KAHY between closely related diastereomers can be fully rationalized by subtle variations in populations of conformers able to engage in OH⋅⋅⋅F IMHB, as well as by the strength of these IMHBs. We also show that the Kenny theoretical Vα(r) descriptor of H-bond acidity accurately reflects the observed variations and a calibration equation extended to fluorohydrins is proposed. This work clearly underlines the importance of the weak OH⋅⋅⋅F IMHB in the modulation of alcohol H-bond donating capacity. [ABSTRACT FROM AUTHOR]

Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (logP) modulation. However, the determination of logP is cumbersome for non-UV-active compounds. A new variation of the shake-flask logP determination method is presented, enabling the measurement of logP for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic. No calibration curves or measurements of compound masses/aliquot volumes are required. With this method, the influence of fluorination on the lipophilicity of fluorinated aliphatic alcohols was determined, and the logP values of fluorinated carbohydrates were measured. Interesting trends and changes, for example, for the dependence on relative stereochemistry, are reported. [ABSTRACT FROM AUTHOR]

Fluorination induces significant modulations of molecular properties. The focus herein is on quantifying its influence on the hydrogen ‐ bond (H ‐ bond) donating capacity of a vicinal OH group. Using β ‐ fluorohydrin probes, changes in H ‐ bond acidity are rationalized by subtle differences in the conformational landscape. The OH⋅⋅⋅F intramolecular H ‐ bonds form five ‐ membered rings, symbolized here by the “Anneaux de Buren” (Nantes, France), and imply a decrease of the OH H ‐ bond acidity in monofluorinated compounds. In contrast, di ‐ and trifluorination of β ‐ fluorohydrins lead to a successive increase of H ‐ bond acidity. More information can be found in the Full Paper by J. Graton, J. ‐ Y. Le Questel, B. Linclau et al. on page 2811 ff. [ABSTRACT FROM AUTHOR]

Parkinson's Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson's Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson's Disease. Here, we describe the synthesis of novel C- nor -D- homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid ( 7 ) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson's Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson's Disease.

A highly enantioselective, organocatalytic, and scalable synthesis of a very unusual cis-decalin-cis-hydrindane tricyclic diterpenoid system has been achieved. Despite the prevalent pharmacological space that the related trans,trans and trans,cis-systems occupy, there have been no reports of an asymmetric synthesis of the cis,cis systems in the literature until now. We demonstrate the flexibility of our approach not only through access to a diverse range of products, all of which are attained in exceptionally high selectivities, but also by showing their easy conversion to the corresponding trans,cis-system and other derivatives., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Rational modulations of molecular interactions are of significant importance in compound properties optimization. We have previously shown that fluorination of conformationally rigid cyclohexanols leads to attenuation of their hydrogen-bond (H-bond) donating capacity (designated by pK AHY ) when OH⋅⋅⋅F intramolecular hydrogen-bond (IMHB) interactions occur, as opposed to an increase in pK AHY due to the fluorine electronegativity. This work has now been extended to a wider range of aliphatic β-fluorohydrins with increasing degrees of conformational flexibility. We show that the observed differences in pK AHY between closely related diastereomers can be fully rationalized by subtle variations in populations of conformers able to engage in OH⋅⋅⋅F IMHB, as well as by the strength of these IMHBs. We also show that the Kenny theoretical V α (r) descriptor of H-bond acidity accurately reflects the observed variations and a calibration equation extended to fluorohydrins is proposed. This work clearly underlines the importance of the weak OH⋅⋅⋅F IMHB in the modulation of alcohol H-bond donating capacity., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (log P) modulation. However, the determination of log P is cumbersome for non-UV-active compounds. A new variation of the shake-flask log P determination method is presented, enabling the measurement of log P for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic. No calibration curves or measurements of compound masses/aliquot volumes are required. With this method, the influence of fluorination on the lipophilicity of fluorinated aliphatic alcohols was determined, and the log P values of fluorinated carbohydrates were measured. Interesting trends and changes, for example, for the dependence on relative stereochemistry, are reported., (© 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)