Fluorinated Gamma-carboline Derivatives as Promising Neuroprotective Candidates. Structure-Activity Relationships
Maria A. Lapshina, Elena F. Shevtsova, German L. Perlovich, Alexey A. Ustyugov, Alexey Y. Aksinenko, Daria V. Vinogradova, Vladimir P. Fisenko, Tatyana V. Volkova, Olga R. Simonova, Maria N. Zakharova, Sergey O. BachurinIntroduction:
The structure-property relationship of drug candidates determines their transport to target organs and is used as a tool to design drugs with optimal properties and minimal undesirable effects. The effects of fluorinated derivatives of gamma-carboline on the formation of cytosolic aggregates of the FUS protein and the relationships among structure, physicochemical characteristics, and anti-aggregation properties were studied.
Methods:
The effect of the compounds on FUS protein aggregation in SH-SY5Y cells was evaluated using confocal fluorescence microscopy. Partition coefficients were determined using the isothermal saturation method, and all descriptors were calculated with a software package.
Results:
A series of fluorinated γ‑carboline derivatives was synthesized and demonstrated the ability to reduce pathological FUS protein aggregation in a cellular model of proteinopathy. The influence of substituents on the distribution coefficients of the studied compounds was revealed. Among the most active compounds, this study highlights DF-302 and DF-402, which feature a methyl group and a trifluoromethyl group on the pyridinium fragment, respectively.
Discussion:
The structure-activity relationships for the inhibition of FUS protein aggregation by fluorinated γ-carbolines were analyzed in relation to their physicochemical properties. A linear correlation was observed between the anti-aggregation efficacy and the total hydrogen bond acceptor capacity: as the compound's propensity to form hydrogen bonds with the FUS protein increased, its ability to prevent large aggregate formation in cells decreased. An assumption has been made that off-target interactions of the studied compounds with membrane proteins increase with their hydrogen bond acceptor capacity. This effect can limit compounds' availability to influence the processes of cytosolic FUS protein aggregates.
Conclusion:
The positive correlation of lipophilicity with FUS aggregate reduction underscores the role of cellular penetration in the anti-aggregation effect. Conversely, the negative correlation with hydrogen-bond acceptor capacity suggests that off-target interactions with membrane proteins may compete with binding to FUS aggregates.