Abstract
Due to their promotory action on the transport of some drugs through various membranes (lipophilic barriers), oxo derivatives of bile acids have recently been increasingly used in biopharmacy. These compounds exhibit also a lower membranolytic (toxic) activity than their hydroxy analogues. Because of that it is of special importance to find out the descriptors that would adequately describe the structure of bile acids and their biological activity and be used to model the quantitative structure-activity relationship. In view of this, the present work is concerned with the application of the chromatographic parameter RM0 obtained by normal-phase thin-layer chromatography in the solvent system toluene-butanol and silica gel as stationary phase to describe the lipophilicity of bile acids. Also, the work introduces a new molecular descriptor (ND) that reflects both 2D and 3D topological characteristics of the molecule. Between the retention constant, RM0 and the descriptor ND there is a good correlation, and both RM0, and ND describe sufficiently well the structural (conformational) changes that arise in the process of oxidation of the OH group of the steroid skeleton to an oxo group. On the other hand, the in silico descriptors of lipophilicity, logP (atomic-based prediction) and ClogP (fragment-based prediction) predict the hydrophobicity of bile acid oxo derivatives with a certain error.
Highlights
Due to their promotory action on the transport of some drugs through various membranes, oxo derivatives of bile acids have recently been increasingly used in biopharmacy
It is known that the hydrophilic–hydrophobic balance (HHB) of bile acids determines their ability to bind to the large conductance Ca2+-activated K+ (BKCa) channel, which results in the relaxation of the endothelial smooth muscles [5]
This can be explained by the fact that the substitution of the α-oriented OH group with oxo groups shifts the position of the oxygen atom towards the mean plane of the steroid system (Figure 3A)
Summary
Due to their promotory action on the transport of some drugs through various membranes (lipophilic barriers), oxo derivatives of bile acids have recently been increasingly used in biopharmacy. These compounds exhibit a lower membranolytic (toxic) activity than their hydroxy analogues. The aim of this work was to compare the experimental retention constants (normal-phase thin-layer chromatography, NP TLC) and molecular lipophilicity descriptors, i.e., in silico descriptors of partition coefficients – log P (atom-based prediction) and Clog P (fragment-based prediction) – that are obtained by conventional software packages ChemDraw, Alchemica, etc.
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