Predicting Pharmacokinetic Properties of Potential Anticancer Agents via Their Chromatographic Behavior on Different Reversed Phase Materials.

Małgorzata Janicka,Krzysztof Sztanke,Anna Mycka,Małgorzata Sztanke

doi:10.3390/ijms22084257

Abstract

The Quantitative Structure-Activity Relationship (QSAR) methodology was used to predict biological properties, i.e., the blood–brain distribution (log BB), fraction unbounded in the brain (fu,brain), water-skin permeation (log Kp), binding to human plasma proteins (log Ka,HSA), and intestinal permeability (Caco-2), for three classes of fused azaisocytosine-containing congeners that were considered and tested as promising drug candidates. The compounds were characterized by lipophilic, structural, and electronic descriptors, i.e., chromatographic retention, topological polar surface area, polarizability, and molecular weight. Different reversed-phase liquid chromatography techniques were used to determine the chromatographic lipophilicity of the compounds that were tested, i.e., micellar liquid chromatography (MLC) with the ODS-2 column and polyoxyethylene lauryl ether (Brij 35) as the effluent component, an immobilized artificial membrane (IAM) chromatography with phosphatidylcholine column (IAM.PC.DD2) and chromatography with end-capped octadecylsilyl (ODS) column using aqueous solutions of acetonitrile as the mobile phases. Using multiple linear regression, we derived the statistically significant quantitative structure-activity relationships. All these QSAR equations were validated and were found to be very good. The investigations highlight the significance and possibilities of liquid chromatographic techniques with three different reversed-phase materials and QSARs methods in predicting the pharmacokinetic properties of our important organic compounds and reducing unethical animal testing.

Highlights

Two-dimensional Quantitative Structure-Activity Relationship (QSAR) methodology was successful in modeling pharmacokinetic properties, i.e., the distribution between the blood and brain, the unbounded fraction in the brain (f u,brain ), water–skin permeation, binding to human plasma proteins, and intestinal permeability (Caco-2) of fused azaisocytosine-containing congeners
Micellar parameters and log kw values measured on an artificial membrane (IAM) and on an end-capped ODS column were compared as lipophilicity descriptors and applied in the QSARs methodology
Apart from the chromatography-derived lipophilicity, the quantitative structure-activity relationships included both structural and electronic descriptors related to drug-like properties, i.e., topological polar surface area, molecular weight, and polarizability of the investigated molecules

Summary

Introduction

The search for new biologically active substances, considered as potential drugs or plant protection products, is an important task in modern science. The intensive development of the Quantitative Structure-Activity Relationships (QSARs) method began in the 1960s and continues today [1,2,3] In this method, searches are conducted to identify the multidimensional relationships that exist between the biological properties and structural parameters for a group of congeneric compounds. The derived mathematical model can be extended to new compounds with similar structures and used to predict their biological properties. In this way, it is possible to design new molecules that have the desired properties. The interpretation of a mathematical model can lead to an overall model of a given biological property, which provides information that can be used to obtain the optimal design of desired chemical substances

Methods

Results

Conclusion